Sample records for based pharmacokinetic modeling

  1. Optimizing nanomedicine pharmacokinetics using physiologically based pharmacokinetics modelling. (United States)

    Moss, Darren Michael; Siccardi, Marco


    The delivery of therapeutic agents is characterized by numerous challenges including poor absorption, low penetration in target tissues and non-specific dissemination in organs, leading to toxicity or poor drug exposure. Several nanomedicine strategies have emerged as an advanced approach to enhance drug delivery and improve the treatment of several diseases. Numerous processes mediate the pharmacokinetics of nanoformulations, with the absorption, distribution, metabolism and elimination (ADME) being poorly understood and often differing substantially from traditional formulations. Understanding how nanoformulation composition and physicochemical properties influence drug distribution in the human body is of central importance when developing future treatment strategies. A helpful pharmacological tool to simulate the distribution of nanoformulations is represented by physiologically based pharmacokinetics (PBPK) modelling, which integrates system data describing a population of interest with drug/nanoparticle in vitro data through a mathematical description of ADME. The application of PBPK models for nanomedicine is in its infancy and characterized by several challenges. The integration of property-distribution relationships in PBPK models may benefit nanomedicine research, giving opportunities for innovative development of nanotechnologies. PBPK modelling has the potential to improve our understanding of the mechanisms underpinning nanoformulation disposition and allow for more rapid and accurate determination of their kinetics. This review provides an overview of the current knowledge of nanomedicine distribution and the use of PBPK modelling in the characterization of nanoformulations with optimal pharmacokinetics.

  2. MEGen: A Physiologically Based Pharmacokinetic Model Generator

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    George D Loizou


    Full Text Available Physiologically based pharmacokinetic models are being used in an increasing number of different areas. These not only include the human safety assessment of pharmaceuticals, pesticides, biocides and environmental chemicals but also for food animal, wild mammal and avian risk assessment. The value of PBPK models is that they are tools for estimating tissue dosimetry by integrating in vitro and in vivo mechanistic, pharmacokinetic and toxicological information through their explicit mathematical description of important anatomical, physiological and biochemical determinants of chemical uptake, disposition and elimination. However, PBPK models are perceived as complex, data hungry, resource intensive and time consuming. In addition, model validation and verification are hindered by the relative complexity of the equations. To begin to address these issues a freely available web application for the rapid construction and documentation of bespoke PBPK models is under development. Here we present an overview of the current capabilities of MEGen, a model equation generator and parameter database and discuss future developments.

  3. Human physiologically based pharmacokinetic model for propofol

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    Schnider Thomas W


    Full Text Available Abstract Background Propofol is widely used for both short-term anesthesia and long-term sedation. It has unusual pharmacokinetics because of its high lipid solubility. The standard approach to describing the pharmacokinetics is by a multi-compartmental model. This paper presents the first detailed human physiologically based pharmacokinetic (PBPK model for propofol. Methods PKQuest, a freely distributed software routine, was used for all the calculations. The "standard human" PBPK parameters developed in previous applications is used. It is assumed that the blood and tissue binding is determined by simple partition into the tissue lipid, which is characterized by two previously determined set of parameters: 1 the value of the propofol oil/water partition coefficient; 2 the lipid fraction in the blood and tissues. The model was fit to the individual experimental data of Schnider et. al., Anesthesiology, 1998; 88:1170 in which an initial bolus dose was followed 60 minutes later by a one hour constant infusion. Results The PBPK model provides a good description of the experimental data over a large range of input dosage, subject age and fat fraction. Only one adjustable parameter (the liver clearance is required to describe the constant infusion phase for each individual subject. In order to fit the bolus injection phase, for 10 or the 24 subjects it was necessary to assume that a fraction of the bolus dose was sequestered and then slowly released from the lungs (characterized by two additional parameters. The average weighted residual error (WRE of the PBPK model fit to the both the bolus and infusion phases was 15%; similar to the WRE for just the constant infusion phase obtained by Schnider et. al. using a 6-parameter NONMEM compartmental model. Conclusion A PBPK model using standard human parameters and a simple description of tissue binding provides a good description of human propofol kinetics. The major advantage of a

  4. Physiologically Based Pharmacokinetic (PBPK) Modeling of ... (United States)

    Background: Quantitative estimation of toxicokinetic variability in the human population is a persistent challenge in risk assessment of environmental chemicals. Traditionally, inter-individual differences in the population are accounted for by default assumptions or, in rare cases, are based on human toxicokinetic data.Objectives: To evaluate the utility of genetically diverse mouse strains for estimating toxicokinetic population variability for risk assessment, using trichloroethylene (TCE) metabolism as a case study. Methods: We used data on oxidative and glutathione conjugation metabolism of TCE in 16 inbred and one hybrid mouse strains to calibrate and extend existing physiologically-based pharmacokinetic (PBPK) models. We added one-compartment models for glutathione metabolites and a two-compartment model for dichloroacetic acid (DCA). A Bayesian population analysis of inter-strain variability was used to quantify variability in TCE metabolism. Results: Concentration-time profiles for TCE metabolism to oxidative and glutathione conjugation metabolites varied across strains. Median predictions for the metabolic flux through oxidation was less variable (5-fold range) than that through glutathione conjugation (10-fold range). For oxidative metabolites, median predictions of trichloroacetic acid production was less variable (2-fold range) than DCA production (5-fold range), although uncertainty bounds for DCA exceeded the predicted variability. Conclusions:

  5. Physiologically-based pharmacokinetic simulation modelling. (United States)

    Grass, George M; Sinko, Patrick J


    Drug selection is now widely viewed as an important and relatively new, yet largely unsolved, bottleneck in the drug discovery and development process. In order to achieve an efficient selection process, high quality, rapid, predictive and correlative ADME models are required in order for them to be confidently used to support critical financial decisions. Systems that can be relied upon to accurately predict performance in humans have not existed, and decisions have been made using tools whose capabilities could not be verified until candidates went to clinical trial, leading to the high failure rates historically observed. However, with the sequencing of the human genome, advances in proteomics, the anticipation of the identification of a vastly greater number of potential targets for drug discovery, and the potential of pharmacogenomics to require individualized evaluation of drug kinetics as well as drug effects, there is an urgent need for rapid and accurately computed pharmacokinetic properties.

  6. Clinical pharmacokinetic/pharmacodynamic and physiologically based pharmacokinetic modeling in new drug development: the capecitabine experience. (United States)

    Blesch, Karen S; Gieschke, Ronald; Tsukamoto, Yuko; Reigner, Bruno G; Burger, Hans U; Steimer, Jean-Louis


    Preclinical studies, along with Phase I, II, and III clinical trials demonstrate the pharmacokinetics, pharmacodynamics, safety and efficacy of a new drug under well controlled circumstances in relatively homogeneous populations. However, these types of studies generally do not answer important questions about variability in specific factors that predict pharmacokinetic and pharmacodynamic (PKPD) activity, in turn affecting safety and efficacy. Semi-physiological and clinical PKPD modeling and simulation offer the possibility of utilizing data obtained in the laboratory and the clinic to make accurate characterizations and predictions of PKPD activity in the target population, based on variability in predictive factors. Capecitabine is an orally administered pro-drug of 5-fluorouracil (5-FU), designed to exploit tissue-specific differences in metabolic enzyme activities in order to enhance efficacy and safety. It undergoes extensive metabolism in multiple physiologic compartments, and presents particular challenges for predicting pharmacokinetic and pharmacodynamic activity in humans. Clinical and physiologically based pharmacokinetic (PBPK) and pharmacodynamic models were developed to characterize the activity of capecitabine and its metabolites, and the clinical consequences under varying physiological conditions such as creatinine clearance or activity of key metabolic enzymes. The results of the modeling investigations were consistent with capecitabine's rational design as a triple pro-drug of 5-FU. This paper reviews and discusses the PKPD and PBPK modeling approaches used in capecitabine development to provide a more thorough understanding of what the key predictors of its PBPK activity are, and how variability in these predictors may affect its PKPD, and ultimately, clinical outcomes.

  7. Elucidating the Plasma and Liver Pharmacokinetics of Simeprevir in Special Populations Using Physiologically Based Pharmacokinetic Modelling. (United States)

    Snoeys, Jan; Beumont, Maria; Monshouwer, Mario; Ouwerkerk-Mahadevan, Sivi


    The disposition of simeprevir (SMV) in humans is characterised by cytochrome P450 3A4 metabolism and hepatic uptake by organic anion transporting polypeptide 1B1/3 (OATP1B1/3). This study was designed to investigate SMV plasma and liver exposure upon oral administration in subjects infected with hepatitis C virus (HCV), in subjects of Japanese or Chinese origin, subjects with organ impairment and subjects with OATP genetic polymorphisms, using physiologically based pharmacokinetic modelling. Simulations showed that compared with healthy Caucasian subjects, SMV plasma exposure was 2.4-, 1.7-, 2.2- and 2.0-fold higher, respectively, in HCV-infected Caucasian subjects, in healthy Japanese, healthy Chinese and subjects with severe renal impairment. Further simulations showed that compared with HCV-infected Caucasian subjects, SMV plasma exposure was 1.6-fold higher in HCV-infected Japanese subjects. In subjects with OATP1B1 genetic polymorphisms, no noteworthy changes in SMV pharmacokinetics were observed. Simulations suggested that liver concentrations in Caucasians with HCV are 18 times higher than plasma concentrations.

  8. Comparison of the use of a physiologically based pharmacokinetic model and a classical pharmacokinetic model for dioxin exposure assessments. (United States)

    Emond, Claude; Michalek, Joel E; Birnbaum, Linda S; DeVito, Michael J


    In epidemiologic studies, exposure assessments of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) assume a fixed elimination rate. Recent data suggest a dose-dependent elimination rate for TCDD. A physiologically based pharmacokinetic (PBPK) model, which uses a body-burden-dependent elimination rate, was developed previously in rodents to describe the pharmacokinetics of TCDD and has been extrapolated to human exposure for this study. Optimizations were performed using data from a random selection of veterans from the Ranch Hand cohort and data from a human volunteer who was exposed to TCDD. Assessment of this PBPK model used additional data from the Ranch Hand cohort and a clinical report of two women exposed to TCDD. This PBPK model suggests that previous exposure assessments may have significantly underestimated peak blood concentrations, resulting in potential exposure misclassifications. Application of a PBPK model that incorporates an inducible elimination of TCDD may improve the exposure assessments in epidemiologic studies of TCDD.

  9. A comprehensive physiologically based pharmacokinetic knowledgebase and web-based interface for rapid model ranking and querying (United States)

    Published physiologically based pharmacokinetic (PBPK) models from peer-reviewed articles are often well-parameterized, thoroughly-vetted, and can be utilized as excellent resources for the construction of models pertaining to related chemicals. Specifically, chemical-specific pa...

  10. A physiologically based pharmacokinetic (PB-PK) model for ethylene dibromide; relevance of extrahepatic metabolism

    NARCIS (Netherlands)

    Hissink, A.M.; Wormhoudt, L.W.; Sherratt, P.J.; Hayes, J.D.; Commandeur, J.N.M.; Vermeulen, N.P.E.; Bladeren, van P.J.


    A physiologically-based pharmacokinetic (PB-PK) model was developed for ethylene dibromide (1,2-dibromoethane, EDB) for rats and humans, partly based on previously published in vitro data (Ploemen et al., 1997). In the present study, this PB-PK model has been validated for the rat. In addition, new

  11. Human plasma concentrations of cytochrome P450 probes extrapolated from pharmacokinetics in cynomolgus monkeys using physiologically based pharmacokinetic modeling. (United States)

    Shida, Satomi; Utoh, Masahiro; Murayama, Norie; Shimizu, Makiko; Uno, Yasuhiro; Yamazaki, Hiroshi


    1. Cynomolgus monkeys are widely used in preclinical studies as non-human primate species. Pharmacokinetics of human cytochrome P450 probes determined in cynomolgus monkeys after single oral or intravenous administrations were extrapolated to give human plasma concentrations. 2. Plasma concentrations of slowly eliminated caffeine and R-/S-warfarin and rapidly eliminated omeprazole and midazolam previously observed in cynomolgus monkeys were scaled to human oral biomonitoring equivalents using known species allometric scaling factors and in vitro metabolic clearance data with a simple physiologically based pharmacokinetic (PBPK) model. Results of the simplified human PBPK models were consistent with reported experimental PK data in humans or with values simulated by a fully constructed population-based simulator (Simcyp). 3. Oral administrations of metoprolol and dextromethorphan (human P450 2D probes) in monkeys reportedly yielded plasma concentrations similar to their quantitative detection limits. Consequently, ratios of in vitro hepatic intrinsic clearances of metoprolol and dextromethorphan determined in monkeys and humans were used with simplified PBPK models to extrapolate intravenous PK in monkeys to oral PK in humans. 4. These results suggest that cynomolgus monkeys, despite their rapid clearance of some human P450 substrates, could be a suitable model for humans, especially when used in conjunction with simple PBPK models.

  12. Metoprolol Dose Equivalence in Adult Men and Women Based on Gender Differences: Pharmacokinetic Modeling and Simulations

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    Andy R. Eugene


    Full Text Available Recent meta-analyses and publications over the past 15 years have provided evidence showing there are considerable gender differences in the pharmacokinetics of metoprolol. Throughout this time, there have not been any research articles proposing a gender stratified dose-adjustment resulting in an equivalent total drug exposure. Metoprolol pharmacokinetic data was obtained from a previous publication. Data was modeled using nonlinear mixed effect modeling using the MONOLIX software package to quantify metoprolol concentration–time data. Gender-stratified dosing simulations were conducted to identify equivalent total drug exposure based on a 100 mg dose in adults. Based on the pharmacokinetic modeling and simulations, a 50 mg dose in adult women provides an approximately similar metoprolol drug exposure to a 100 mg dose in adult men.

  13. Virtual population pharmacokinetic using physiologically based pharmacokinetic model for evaluating bioequivalence of oral lacidipine formulations in dogs

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    Bin Yang


    Full Text Available The aim of the present study was to investigate virtual population pharmacokinetic using physiologically based pharmacokinetic (PBPK model for evaluating bioequivalence of oral lacidipine formulations in dogs. The dissolution behaviors of three lacidipine formulations including one commercial product and two self-made amorphous solid dispersions (ASDs capsules were determined in 0.07% Tween 80 media. A randomized 3-period crossover design in 6 healthy beagle dogs after oral administration of the three formulations at a single dose of 4 mg was conducted. The PBPK modeling was utilized for the virtual bioequivalence study. In vitro dissolution experiment showed that the dissolution behaviors of lacidipine amorphous solid dispersions (ASDs capsules, which was respectively prepared by HPMC-E5 or Soluplus, as polymer displayed similar curves compared with the reference formulation in 0.07% Tween 80 media. In vivo pharmacokinetics experiments showed that three formulations had comparable maximum plasma drug concentration (Cmax, and the time (Tmax to reach Cmax of lacidipine tablet, which was prepared by Soluplus, as polymer was slower than other two formulations in consistency with the in vitro dissolution rate. The 90% confidence interval (CI for the Cmax, AUC0–24 h and AUC0–∞ of the ratio of the test drug to the referencedrug exceeded the acceptable bioequivalence (BE limits (0.80–1.25. However, the 90% CI of the AUC0–24 h, AUC0–∞ and Cmax of the ratio of test to reference drug were within the BE limit, calculated using PBPK modeling when the virtual subjects reached 24 dogs. The results all demonstrated that virtual bioequivalence study can overcome the inequivalence caused by inter-subject variability of the 6 beagle dogs involved in in vivo experiments.

  14. Human plasma concentrations of five cytochrome P450 probes extrapolated from pharmacokinetics in dogs and minipigs using physiologically based pharmacokinetic modeling. (United States)

    Shida, Satomi; Yamazaki, Hiroshi


    The pharmacokinetics of cytochrome P450 probes in humans can be extrapolated from corresponding data in cynomolgus monkeys using simplified physiologically based pharmacokinetic (PBPK) modeling. In the current study, despite some species difference in drug clearances, this modeling methodology was adapted to estimate human plasma concentrations of P450 probes based on data from commonly used medium-sized experimental animals, namely dogs and minipigs. Using known species allometric scaling factors and in vitro metabolic clearance data, the observed plasma concentrations of slowly eliminated caffeine and warfarin and rapidly eliminated omeprazole, metoprolol and midazolam in two young dogs were scaled to human oral monitoring equivalents. Using the same approach, the previously reported pharmacokinetics of the five P450 probes in minipigs was also scaled to human monitoring equivalents. The human plasma concentration profiles of the five P450 probes estimated by the simplified human PBPK models based on observed/reported pharmacokinetics in dogs/minipigs were consistent with previously published pharmacokinetic data in humans. These results suggest that dogs and minipigs, in addition to monkeys, could be suitable models for humans during research into new drugs, especially when used in combination with simple PBPK models.

  15. A genetic algorithm based global search strategy for population pharmacokinetic/pharmacodynamic model selection. (United States)

    Sale, Mark; Sherer, Eric A


    The current algorithm for selecting a population pharmacokinetic/pharmacodynamic model is based on the well-established forward addition/backward elimination method. A central strength of this approach is the opportunity for a modeller to continuously examine the data and postulate new hypotheses to explain observed biases. This algorithm has served the modelling community well, but the model selection process has essentially remained unchanged for the last 30 years. During this time, more robust approaches to model selection have been made feasible by new technology and dramatic increases in computation speed. We review these methods, with emphasis on genetic algorithm approaches and discuss the role these methods may play in population pharmacokinetic/pharmacodynamic model selection.

  16. Physiologically based Pharmacokinetic Modeling of 1,4-Dioxane in Rats, Mice, and Humans

    Energy Technology Data Exchange (ETDEWEB)

    Sweeney, Lisa M.; Thrall, Karla D.; Poet, Torka S.; Corley, Rick; Weber, Thomas J.; Locey, B. J.; Clarkson, Jacquelyn; Sager, S.; Gargas, M. L.


    ABSTRACT 1,4-Dioxane (CAS No. 123-91-1) is used primarily as a solvent or as a solvent stabilizer. It can cause lung, liver and kidney damage at sufficiently high exposure levels. Two physiologically-based pharmacokinetic (PBPK) models of 1,4-dioxane and its major metabolite, hydroxyethoxyacetic acid (HEAA), were published in 1990. These models have uncertainties and deficiencies that could be addressed and the model strengthened for use in a contemporary cancer risk assessment for 1,4-dioxane. Studies were performed to fill data gaps and reduce uncertainties pertaining to the pharmacokinetics of 1,4-dioxane and HEAA in rats, mice, and humans. Three types of studies were performed:partition coefficient measurements, blood time course in mice, and in vitro pharmacokinetics using rat, mouse, and human hepatocytes. Updated PBPK models were developed based on these new data and previously available data. The optimized rate of metabolism for the mouse was significantly higher than the value previously estimated. The optimized rat kinetic parameters were similar to those in the 1990 models. Only two human studies were identified. Model predictions were consistent with one study, but did not fit the second as well. In addition, a rat nasal exposure was completed. The results confirmed water directly contacts rat nasal tissues during drinking water under bioassays. Consistent with previous PBPK models, nasal tissues were not specifically included in the model. Use of these models will reduce the uncertainty in future 1,4-dioxane risk assessments.

  17. Physiologically based pharmacokinetic modeling of 1,4-Dioxane in rats, mice, and humans. (United States)

    Sweeney, Lisa M; Thrall, Karla D; Poet, Torka S; Corley, Richard A; Weber, Thomas J; Locey, Betty J; Clarkson, Jacquelyn; Sager, Shawn; Gargas, Michael L


    1,4-Dioxane (CAS No. 123-91-1) is used primarily as a solvent or as a solvent stabilizer. It can cause lung, liver, and kidney damage at sufficiently high exposure levels. Two physiologically based pharmacokinetic (PBPK) models of 1,4-dioxane and its major metabolite, hydroxyethoxyacetic acid (HEAA), were published in 1990. These models have uncertainties and deficiencies that could be addressed and the model strengthened for use in a contemporary cancer risk assessment for 1,4-dioxane. Studies were performed to fill data gaps and reduce uncertainties pertaining to the pharmacokinetics of 1,4-dioxane and HEAA in rats, mice, and humans. Three types of studies were performed: partition coefficient measurements, blood time course in mice, and in vitro pharmacokinetics using rat, mouse, and human hepatocytes. Updated PBPK models were developed based on these new data and previously available data. The optimized rate of metabolism for the mouse was significantly higher than the value previously estimated. The optimized rat kinetic parameters were similar to those in the 1990 models. Only two human studies were identified. Model predictions were consistent with one study, but did not fit the second as well. In addition, a rat nasal exposure was completed. The results confirmed water directly contacts rat nasal tissues during drinking water under bioassay conditions. Consistent with previous PBPK models, nasal tissues were not specifically included in the model. Use of these models will reduce the uncertainty in future 1,4-dioxane risk assessments.

  18. Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulation Approaches: A Systematic Review of Published Models, Applications, and Model Verification. (United States)

    Sager, Jennifer E; Yu, Jingjing; Ragueneau-Majlessi, Isabelle; Isoherranen, Nina


    Modeling and simulation of drug disposition has emerged as an important tool in drug development, clinical study design and regulatory review, and the number of physiologically based pharmacokinetic (PBPK) modeling related publications and regulatory submissions have risen dramatically in recent years. However, the extent of use of PBPK modeling by researchers, and the public availability of models has not been systematically evaluated. This review evaluates PBPK-related publications to 1) identify the common applications of PBPK modeling; 2) determine ways in which models are developed; 3) establish how model quality is assessed; and 4) provide a list of publically available PBPK models for sensitive P450 and transporter substrates as well as selective inhibitors and inducers. PubMed searches were conducted using the terms "PBPK" and "physiologically based pharmacokinetic model" to collect published models. Only papers on PBPK modeling of pharmaceutical agents in humans published in English between 2008 and May 2015 were reviewed. A total of 366 PBPK-related articles met the search criteria, with the number of articles published per year rising steadily. Published models were most commonly used for drug-drug interaction predictions (28%), followed by interindividual variability and general clinical pharmacokinetic predictions (23%), formulation or absorption modeling (12%), and predicting age-related changes in pharmacokinetics and disposition (10%). In total, 106 models of sensitive substrates, inhibitors, and inducers were identified. An in-depth analysis of the model development and verification revealed a lack of consistency in model development and quality assessment practices, demonstrating a need for development of best-practice guidelines.

  19. Physiologically based pharmacokinetic modeling in drug discovery and development: a pharmaceutical industry perspective. (United States)

    Jones, H M; Chen, Y; Gibson, C; Heimbach, T; Parrott, N; Peters, S A; Snoeys, J; Upreti, V V; Zheng, M; Hall, S D


    The application of physiologically based pharmacokinetic (PBPK) modeling has developed rapidly within the pharmaceutical industry and is becoming an integral part of drug discovery and development. In this study, we provide a cross pharmaceutical industry position on "how PBPK modeling can be applied in industry" focusing on the strategies for application of PBPK at different stages, an associated perspective on the confidence and challenges, as well as guidance on interacting with regulatory agencies and internal best practices.

  20. Physiologically Based Pharmacokinetic Modeling for 1-Bromopropane in F344 Rats Using Gas Uptake Inhalation Experiments



    1-Bromopropane (1-BP) was introduced into the workplace as an alternative to ozone-depleting solvents and increasingly used in manufacturing industry. The potential exposure to 1-BP and the current reports of adverse effects associated with occupational exposure to high levels of 1-BP have increased the need to understand the mechanism of 1-BP toxicity in animal models as a mean of understanding risk in workers. Physiologically based pharmacokinetic (PBPK) model for 1-BP has been developed to...

  1. Development of a Physiologically-Based Pharmacokinetic Model for Preterm Neonates: Evaluation with In Vivo Data. (United States)

    Claassen, Karina; Thelen, Kirstin; Coboeken, Katrin; Gaub, Thomas; Lippert, Jorg; Allegaert, Karel; Willmann, Stefan


    Among pediatric patients, preterm neonates and newborns are the most vulnerable subpopulation. Rapid developmental changes of physiological factors affecting the pharmacokinetics of drug substances in newborns require extreme care in dose and dose regimen decisions. These decisions could be supported by in silico methods such as physiologically-based pharmacokinetic (PBPK) modeling. In a comprehensive literature search, the physiological information of preterm neonates that is required to establish a PBPK model has been summarized and implemented into the database of a generic PBPK software. Physiological parameters include the organ weights and blood flow rates, tissue composition, as well as ontogeny information about metabolic and elimination processes in the liver and kidney. The aim of this work is to evaluate the model's accuracy in predicting the pharmacokinetics following intravenous administration of two model drugs with distinct physicochemical properties and elimination pathways based on earlier reported in vivo data. To this end, PBPK models of amikacin and paracetamol have been set up to predict their plasma levels in preterm neonates. Predicted plasma concentration-time profiles were compared to experimentally obtained in vivo data. For both drugs, plasma concentration time profiles following single and multiple dosing were appropriately predicted for a large range gestational and postnatal ages. In summary, PBPK simulations in preterm neonates appear feasible and might become a useful tool in the future to support dosing decisions in this special patient population.


    Understanding the pharmacokinetics of a chemical¯its absorption, distribution, metabolism, and excretion in humans and laboratory animals ¯ is critical to the assessment of its human health risks. For trichloroethylene (TCE), numerous physiologically-based pharmacokinetic (PBPK)...

  3. Development of a Physiologically-Based Pharmacokinetic Model of the Rat Central Nervous System

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    Raj K. Singh Badhan


    Full Text Available Central nervous system (CNS drug disposition is dictated by a drug’s physicochemical properties and its ability to permeate physiological barriers. The blood–brain barrier (BBB, blood-cerebrospinal fluid barrier and centrally located drug transporter proteins influence drug disposition within the central nervous system. Attainment of adequate brain-to-plasma and cerebrospinal fluid-to-plasma partitioning is important in determining the efficacy of centrally acting therapeutics. We have developed a physiologically-based pharmacokinetic model of the rat CNS which incorporates brain interstitial fluid (ISF, choroidal epithelial and total cerebrospinal fluid (CSF compartments and accurately predicts CNS pharmacokinetics. The model yielded reasonable predictions of unbound brain-to-plasma partition ratio (Kpuu,brain and CSF:plasma ratio (CSF:Plasmau using a series of in vitro permeability and unbound fraction parameters. When using in vitro permeability data obtained from L-mdr1a cells to estimate rat in vivo permeability, the model successfully predicted, to within 4-fold, Kpuu,brain and CSF:Plasmau for 81.5% of compounds simulated. The model presented allows for simultaneous simulation and analysis of both brain biophase and CSF to accurately predict CNS pharmacokinetics from preclinical drug parameters routinely available during discovery and development pathways.

  4. Development of a Physiologically Based Pharmacokinetic Model for the Anesthetics Halothane, Isoflurane, and Desflurane in the Pig (SUS SCROFA) (United States)


    HALOTHANE, ISOFLURANE, AND DESFLURANE IN THE PIG ( SUS SCROFA ) / Allen Vinegar MANTECH-GEO CENTER JOINT VENTURE PO BOX 31009 ~ DAYTON, OH 45437-0009...Pharmacokinetic Model for the Anesthetics Contract F41624-96-C-9010 Halothane, Isoflurane, and Desfiurane in the Pig ( Sus Scrofa ) PE 62202F PR 7757 6. AUTHOR(S) TA...PFA) " CA Figure I - Physiologicallly Based Pharmacokinetic Model of the Pig ( Sus scrofa ). Abbreviations: CA, arterial concentration; CX, exhaled

  5. Simulation of the pharmacokinetics of bisoprolol in healthy adults and patients with impaired renal function using whole-body physiologically based pharmacokinetic modeling

    Institute of Scientific and Technical Information of China (English)

    Guo-fu LI; Kun WANG; Rui CHEN; Hao-ru ZHAO; Jin YANG; Qing-shan ZHENG


    Aim:To develop and evaluate a whole-body physiologically based pharmacokinetic (WB-PBPK) model of bisoprolol and to simulate its exposure and disposition in healthy adults and patients with renal function impairment.Methods:Bisoprolol dispositions in 14 tissue compartments were described by perfusion-limited compartments.Based the tissue composition equations and drug-specific properties such as log P,permeability,and plasma protein binding published in literatures,the absorption and whole-body distribution of bisoprolol was predicted using the ‘Advanced Compartmental Absorption Transit’ (ACAT)model and the whole-body disposition model,respectively.Renal and hepatic clearances were simulated using empirical scaling methods followed by incorporation into the WB-PBPK model.Model refinements were conducted after a comparison of the simulated concentration-time profiles and pharmacokinetic parameters with the observed data in healthy adults following intravenous and oral administration.Finally,the WB-PBPK model coupled with a Monte Carlo simulation was employed to predict the mean and variability of bisoprolol pharmacokinetics in virtual healthy subjects and patients.Results:The simulated and observed data after both intravenous and oral dosing showed good agreement for all of the dose levels in the reported normal adult population groups.The predicted pharmacokinetic parameters (AUC,Cmax,and Tmax) were reasonably consistent (<1.3-fold error) with the observed values after single oral administration of doses ranging from of 5 to 20 mg using the refined WB-PBPK model.The simulated plasma profiles after multiple oral administration of bisoprolol in healthy adults and patient with renal impairment matched well with the observed profiles.Conclusion:The WB-PBPK model successfully predicts the intravenous and oral pharmacokinetics of bisoprolol across multiple dose levels in diverse normal adult human populations and patients with renal insufficiency.

  6. Physiologically based pharmacokinetic modeling of PLGA nanoparticles with varied mPEG content

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    Avgoustakis K


    Full Text Available Mingguang Li1, Zoi Panagi2, Konstantinos Avgoustakis2, Joshua Reineke11Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, USA; 2Pharmaceutical Technology Laboratory, Department of Pharmacy, University of Patras, Rion, Patras, GreeceAbstract: Biodistribution of nanoparticles is dependent on their physicochemical properties (such as size, surface charge, and surface hydrophilicity. Clear and systematic understanding of nanoparticle properties' effects on their in vivo performance is of fundamental significance in nanoparticle design, development and optimization for medical applications, and toxicity evaluation. In the present study, a physiologically based pharmacokinetic model was utilized to interpret the effects of nanoparticle properties on previously published biodistribution data. Biodistribution data for five poly(lactic-co-glycolic acid (PLGA nanoparticle formulations prepared with varied content of monomethoxypoly (ethyleneglycol (mPEG (PLGA, PLGA-mPEG256, PLGA-mPEG153, PLGA-mPEG51, PLGA-mPEG34 were collected in mice after intravenous injection. A physiologically based pharmacokinetic model was developed and evaluated to simulate the mass-time profiles of nanoparticle distribution in tissues. In anticipation that the biodistribution of new nanoparticle formulations could be predicted from the physiologically based pharmacokinetic model, multivariate regression analysis was performed to build the relationship between nanoparticle properties (size, zeta potential, and number of PEG molecules per unit surface area and biodistribution parameters. Based on these relationships, characterized physicochemical properties of PLGA-mPEG495 nanoparticles (a sixth formulation were used to calculate (predict biodistribution profiles. For all five initial formulations, the developed model adequately simulates the experimental data indicating that the model is suitable for

  7. Physiologically-Based Pharmacokinetic/Toxicokinetic Modeling in Risk Assessment (United States)


    thyroid stroma, follicular membrane and lumen after perchlorate (C10 4 ) dosing (Chow and Woodbury, 1970). Electrical potential differences can be...concentration in blood. In addition, some of the chemical will be reabsorbed from bile and result in an increase of parent or metabolite(s) concentration...misleading as it is usually not suggested that there is an actual membrane barrier to the diffusion process. PBPK/PD models These models include a

  8. A physiologically based pharmacokinetic model for quinoxaline-2-carboxylic acid in rats, extrapolation to pigs. (United States)

    Yang, X; Zhou, Y-F; Yu, Y; Zhao, D-H; Shi, W; Fang, B-H; Liu, Y-H


    A multi-compartment physiologically based pharmacokinetic (PBPK) model to describe the disposition of cyadox (CYX) and its metabolite quinoxaline-2-carboxylic acid (QCA) after a single oral administration was developed in rats (200 mg/kg b.w. of CYX). Considering interspecies differences in physiology and physiochemistry, the model efficiency was validated by pharmacokinetic data set in swine. The model included six compartments that were blood, muscle, liver, kidney, adipose, and a combined compartment for the rest of tissues. The model was parameterized using rat plasma and tissue concentration data that were generated from this study. Model simulations were achieved using a commercially available software program (ACSLXL ibero version Results supported the validity of the model with simulated tissue concentrations within the range of the observations. The correlation coefficients of the predicted and experimentally determined values for plasma, liver, kidney, adipose, and muscles in rats were 0.98, 0.98, 0.98, 0.99, and 0.95, respectively. The rat model parameters were then extrapolated to pigs to estimate QCA disposition in tissues and validated by tissue concentration of QCA in swine. The correlation coefficients between the predicted and observed values were over 0.90. This model could provide a foundation for developing more reliable pig models once more data are available.

  9. A Review on Pharmacokinetic Modeling and the Effects of Environmental Stressors on Pharmacokinetics for Operational Medicine: Operational Pharmacokinetics (United States)


    demonstrates two general approaches to pharmacokinetic modeling: compartment- based modeling (Holz and Fahr 2001) and noncompartment-based modeling (Veng...comprehensive models (Holz and Fahr 2001; Aarons 2005). Mechanistic models can be further subdivided into compartments; designated as mammillary...order to understand their interaction. An integrated approach has also been taken to correlate the pharmacokinetics, pharmacodynamics and disease

  10. Semi-Mechanism-Based Population Pharmacokinetic Modeling of the Hedgehog Pathway Inhibitor Vismodegib. (United States)

    Lu, T; Wang, B; Gao, Y; Dresser, M; Graham, R A; Jin, J Y


    Vismodegib, approved for the treatment of advanced basal cell carcinoma, has shown unique pharmacokinetic (PK) nonlinearity and binding to α1-acid glycoprotein (AAG) in humans. A semi-mechanism-based population pharmacokinetic (PopPK) model was developed from a meta-dataset of 225 subjects enrolled in five clinical studies to quantitatively describe the clinical PK of vismodegib and identify sources of interindividual variability. Total and unbound vismodegib were analyzed simultaneously, together with time-varying AAG data. The PK of vismodegib was adequately described by a one-compartment model with first-order absorption, first-order elimination of unbound drug, and saturable binding to AAG with fast-equilibrium. The variability of total vismodegib concentration at steady-state was predominantly explained by the range of AAG level. The impact of AAG on unbound concentration was clinically insignificant. Various approaches were evaluated for model validation. The semi-mechanism-based PopPK model described herein provided insightful information on the nonlinear PK and has been utilized for various clinical applications.

  11. Setting safe acute exposure limits for halon replacement chemicals using physiologically based pharmacokinetic modeling. (United States)

    Vinegar, A; Jepson, G W; Cisneros, M; Rubenstein, R; Brock, W J


    Most proposed replacements for Halon 1301 as a fire suppressant are halogenated hydrocarbons. The acute toxic endpoint of concern for these agents is cardiac sensitization. An approach is described that links the cardiac endpoint as assessed in dogs to a target arterial concentration in humans. Linkage was made using a physiologically based pharmacokinetic (PBPK) model. Monte Carlo simulations, which account for population variability, were used to establish safe exposure times at different exposure concentrations for Halon 1301 (bromotrifluoromethane), CF(3)I (trifluoroiodomethane), HFC-125 (pentafluoroethane), HFC-227ea (1,1,1,2,3,3,3-heptafluoropropane), and HFC-236fa (1,1,1,3,3,3-hexafluoropropane). Application of the modeling technique described here not only makes use of the conservative cardiac sensitization endpoint, but also uses an understanding of the pharmacokinetics of the chemical agents to better establish standards for safe exposure. The combined application of cardiac sensitization data and physiologically based modeling provides a quantitative approach, which can facilitate the selection and effective use of halon replacement candidates.

  12. Physiologically-based pharmacokinetic model for Fentanyl in support of the development of Provisional Advisory Levels

    Energy Technology Data Exchange (ETDEWEB)

    Shankaran, Harish, E-mail: [Computational Biology and Bioinformatics Group, Pacific Northwest National Laboratory, Richland, WA 99352 (United States); Adeshina, Femi [National Homeland Security Research Center, United States Environmental Protection Agency, Washington, DC 20460 (United States); Teeguarden, Justin G. [Systems Toxicology Group, Pacific Northwest National Laboratory, Richland, WA 99352 (United States)


    Provisional Advisory Levels (PALs) are tiered exposure limits for toxic chemicals in air and drinking water that are developed to assist in emergency responses. Physiologically-based pharmacokinetic (PBPK) modeling can support this process by enabling extrapolations across doses, and exposure routes, thereby addressing gaps in the available toxicity data. Here, we describe the development of a PBPK model for Fentanyl – a synthetic opioid used clinically for pain management – to support the establishment of PALs. Starting from an existing model for intravenous Fentanyl, we first optimized distribution and clearance parameters using several additional IV datasets. We then calibrated the model using pharmacokinetic data for various formulations, and determined the absorbed fraction, F, and time taken for the absorbed amount to reach 90% of its final value, t90. For aerosolized pulmonary Fentanyl, F = 1 and t90 < 1 min indicating complete and rapid absorption. The F value ranged from 0.35 to 0.74 for oral and various transmucosal routes. Oral Fentanyl was absorbed the slowest (t90 ∼ 300 min); the absorption of intranasal Fentanyl was relatively rapid (t90 ∼ 20–40 min); and the various oral transmucosal routes had intermediate absorption rates (t90 ∼ 160–300 min). Based on these results, for inhalation exposures, we assumed that all of the Fentanyl inhaled from the air during each breath directly, and instantaneously enters the arterial circulation. We present model predictions of Fentanyl blood concentrations in oral and inhalation scenarios relevant for PAL development, and provide an analytical expression that can be used to extrapolate between oral and inhalation routes for the derivation of PALs. - Highlights: • We develop a Fentanyl PBPK model for relating external dose to internal levels. • We calibrate the model to oral and inhalation exposures using > 50 human datasets. • Model predictions are in good agreement with the available

  13. Development of a physiologically based pharmacokinetic model for flunixin in cattle (Bos taurus). (United States)

    Leavens, Teresa L; Tell, Lisa A; Kissell, Lindsey W; Smith, Geoffrey W; Smith, David J; Wagner, Sarah A; Shelver, Weilin L; Wu, Huali; Baynes, Ronald E; Riviere, Jim E


    Frequent violation of flunixin residues in tissues from cattle has been attributed to non-compliance with the USFDA-approved route of administration and withdrawal time. However, the effect of administration route and physiological differences among animals on tissue depletion has not been determined. The objective of this work was to develop a physiologically based pharmacokinetic (PBPK) model to predict plasma, liver and milk concentrations of flunixin in cattle following intravenous (i.v.), intramuscular (i.m.) or subcutaneous (s.c.) administration for use as a tool to determine factors that may affect the withdrawal time. The PBPK model included blood flow-limited distribution in all tissues and elimination in the liver, kidney and milk. Regeneration of parent flunixin due to enterohepatic recirculation and hydrolysis of conjugated metabolites was incorporated in the liver compartment. Values for physiological parameters were obtained from the literature, and partition coefficients for all tissues but liver and kidney were derived empirically. Liver and kidney partition coefficients and elimination parameters were estimated for 14 pharmacokinetic studies (including five crossover studies) from the literature or government sources in which flunixin was administered i.v., i.m. or s.c. Model simulations compared well with data for the matrices following all routes of administration. Influential model parameters included those that may be age or disease-dependent, such as clearance and rate of milk production. Based on the model, route of administration would not affect the estimated days to reach the tolerance concentration (0.125 mg kg(-1)) in the liver of treated cattle. The majority of USDA-reported violative residues in liver were below the upper uncertainty predictions based on estimated parameters, which suggests the need to consider variability due to disease and age in establishing withdrawal intervals for drugs used in food animals. The model predicted

  14. A Human Life-Stage Physiologically Based Pharmacokinetic and Pharmacodynamic Model for Chlorpyrifos: Development and Validation

    Energy Technology Data Exchange (ETDEWEB)

    Smith, Jordan N.; Hinderliter, Paul M.; Timchalk, Charles; Bartels, M. J.; Poet, Torka S.


    Sensitivity to chemicals in animals and humans are known to vary with age. Age-related changes in sensitivity to chlorpyrifos have been reported in animal models. A life-stage physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model was developed to computationally predict disposition of CPF and its metabolites, chlorpyrifos-oxon (the ultimate toxicant) and 3,5,6-trichloro-2-pyridinol (TCPy), as well as B-esterase inhibition by chlorpyrifos-oxon in humans. In this model, age-dependent body weight was calculated from a generalized Gompertz function, and compartments (liver, brain, fat, blood, diaphragm, rapid, and slow) were scaled based on body weight from polynomial functions on a fractional body weight basis. Blood flows among compartments were calculated as a constant flow per compartment volume. The life-stage PBPK/PD model was calibrated and tested against controlled adult human exposure studies. Model simulations suggest age-dependent pharmacokinetics and response may exist. At oral doses ≥ 0.55 mg/kg of chlorpyrifos (significantly higher than environmental exposure levels), 6 mo old children are predicted to have higher levels of chlorpyrifos-oxon in blood and higher levels of red blood cell cholinesterase inhibition compared to adults from equivalent oral doses of chlorpyrifos. At lower doses that are more relevant to environmental exposures, the model predicts that adults will have slightly higher levels of chlorpyrifos-oxon in blood and greater cholinesterase inhibition. This model provides a computational framework for age-comparative simulations that can be utilized to predict CPF disposition and biological response over various postnatal life-stages.

  15. Development of Multi-Route Physiologically-based Pharmacokinetic Models for Ethanol in the Adult, Pregnant, and Neonatal Rat (United States)

    Biofuel blends of 10% ethanol (EtOH) and gasoline are common in the United States, and higher EtOH concentrations are being considered (15-85%). Currently, no physiologically-based pharmacokinetic (PBPK) models are available to describe the kinetics of EtOH-based biofuels. PBPK...

  16. The use of in vitro metabolic parameters and physiologically based pharmacokinetic (PBPK) modeling to explore the risk assessment of trichloroethylene

    NARCIS (Netherlands)

    Hissink, E.M.; Bogaards, J.J.P.; Freidig, A.P.; Commandeur, J.N.M.; Vermeulen, N.P.E.; Bladeren, P.J. van


    A physiologically based pharmacokinetic (PBPK) model has been developed for trichloroethylene (1,1,2-trichloroethene, TRI) for rat and humans, based on in vitro metabolic parameters. These were obtained using individual cytochrome P450 and glutathione S-transferase enzymes. The main enzymes involved

  17. Estimating marbofloxacin withdrawal time in broiler chickens using a population physiologically based pharmacokinetics model. (United States)

    Yang, F; Yang, Y R; Wang, L; Huang, X H; Qiao, G; Zeng, Z L


    Residue depletion of marbofloxacin in broiler chicken after oral administration at 5 mg/kg/day for three consecutive days was studied in this study. The areas under the concentration-time curve from 0 h to ∞ (AUC0-∞ s) of marbofloxacin in tissues and plasma were used to calculate tissue/plasma partition coefficients (PX s). Based on PX s and the other parameters derived from published studies, a flow-limited physiologically based pharmacokinetics (PBPK) model was developed to predict marbofloxacin concentrations, which were then compared with those derived from the residue depletion study so as to validate this model. Considering individual difference in drug disposition, a Monte Carlo simulation included 1000 iterations was further incorporated into the validated model to generate a population PBPK model and to estimate the marbofloxacin residue withdrawal times in edible tissues. The withdrawal periods were compared to those derived from linear regression analysis. The PBPK model presented here successfully predicted the measured concentrations in all tissues. The withdrawal times in all edible tissues derived from the population PBPK model were longer than those from linear regression analysis, and based on the residues in kidney, a withdrawal time of 4 days was estimated for marbofloxacin after oral administration at 5 mg/kg/day for three consecutive days. It was shown that population PBPK model could be used to accurately predict marbofloxacin residue withdrawal time in edible tissues in broiler chickens.

  18. Physiologically Based Pharmacokinetic (PBPK model for biodistribution of radiolabeled peptides in patients with neuroendocrine tumours

    Directory of Open Access Journals (Sweden)

    Viktor Popov


    Full Text Available Objective(s: The objectives of this work was to assess the benefits of the application of Physiologically Based Pharmacokinetic (PBPK models in patients with different neuroendocrine tumours (NET who were treatedwith Lu-177 DOTATATE. The model utilises clinical data on biodistribution of radiolabeled peptides (RLPs obtained by whole body scintigraphy (WBS of the patients.Methods: The blood flow restricted (perfusion rate limited type of the PBPK model for biodistribution of radiolabeled peptides (RLPs in individual human organs is based on the multi-compartment approach, which takes into account the main physiological processes in the organism: absorption, distribution, metabolism and excretion (ADME. The approachcalibrates the PBPK model for each patient in order to increase the accuracy of the dose estimation. Datasets obtained using WBS in four patients have been used to obtain the unknown model parameters. The scintigraphic data were acquired using a double head gamma camera in patients with different neuroendocrine tumours who were treated with Lu-177 DOTATATE. The activity administered to each patient was 7400MBq.Results: Satisfactory agreement of the model predictions with the data obtained from the WBS for each patient has been achieved. Conclusion: The study indicates that the PBPK model can be used for more accurate calculation of biodistribution and absorbed doses in patients. This approach is the first attempt of utilizing scintigraphic data in PBPK models, which was obtained during Lu-177 peptide therapy of patients with NET.

  19. Ubiquity: a framework for physiological/mechanism-based pharmacokinetic/pharmacodynamic model development and deployment. (United States)

    Harrold, John M; Abraham, Anson K


    Practitioners of pharmacokinetic/pharmacodynamic modeling routinely employ various software packages that enable them to fit differential equation based mechanistic or empirical models to biological/pharmacological data. The availability and choice of different analytical tools, while enabling, can also pose a significant challenge in terms of both, implementation and transferability. A package has been developed that addresses these issues by creating a simple text-based format, which provides methods to reduce coding complexity and enables the modeler to describe the components of the model based on the underlying physiochemical processes. A Perl script builds the system for multiple formats (ADAPT, MATLAB, Berkeley Madonna, etc.), enabling analysis across several software packages and reducing the chance for transcription error. Workflows can then be built around this package, which can increase efficiency and model availability. As a proof of concept, tools are included that allow models constructed in this format to be run with MATLAB both at the scripting level and through a generic graphical application that can be compiled and run as a stand-alone application.

  20. A physiologically based pharmacokinetic (PB/PK) model for multiple exposure routes for soman in multiple species

    NARCIS (Netherlands)

    Sweeney, R.E.; Langenberg, J.P.; Maxwell, D.M.


    A physiologically based pharmacokinetic (PB/PK) model has been developed in advanced computer simulation language (ACSL) to describe blood and tissue concentration-time profiles of the C(±)P(-) stereoisomers of soman after inhalation, subcutaneous and intravenous exposures at low (0.8-1.0 × LD50), m

  1. Mechanism-Based Pharmacokinetic-Pharmacodynamic Modeling of the Dopamine D-2 Receptor Occupancy of Olanzapine in Rats

    NARCIS (Netherlands)

    Johnson, Martin; Kozielska, Magdalena; Reddy, Venkatesh Pilla; Vermeulen, An; Li, Cheryl; Grimwood, Sarah; de Greef, Rik; Groothuis, Geny M. M.; Danhof, Meindert; Proost, Johannes H.


    A mechanism-based PK-PD model was developed to predict the time course of dopamine D-2 receptor occupancy (D2RO) in rat striatum following administration of olanzapine, an atypical antipsychotic drug. A population approach was utilized to quantify both the pharmacokinetics and pharmacodynamics of ol

  2. Physiologically based pharmacokinetic modeling for 1-bromopropane in F344 rats using gas uptake inhalation experiments. (United States)

    Garner, C Edwin; Liang, Shenxuan; Yin, Lei; Yu, Xiaozhong


    1-Bromopropane (1-BP) was introduced into the workplace as an alternative to ozone-depleting solvents and increasingly used in manufacturing industry. The potential exposure to 1-BP and the current reports of adverse effects associated with occupational exposure to high levels of 1-BP have increased the need to understand the mechanism of 1-BP toxicity in animal models as a mean of understanding risk in workers. Physiologically based pharmacokinetic (PBPK) model for 1-BP has been developed to examine 2 metabolic pathway assumptions for gas-uptake inhalation study. Based on previous gas-uptake experiments in the Fischer 344 rat, the PBPK model was developed by simulating the 1-BP concentration in a closed chamber. In the model, we tested the hypothesis that metabolism responsibilities were shared by the p450 CYP2E1 and glutathione (GSH) conjugation. The results showed that 2 metabolic pathways adequately simulated 1-BP closed chamber concentration. Furthermore, the above model was tested by simulating the gas-uptake data of the female rats pretreated with 1-aminobenzotrizole, a general P450 suicide inhibitor, or d,l-buthionine (S,R)-sulfoximine, an inhibitor of GSH synthesis, prior to exposure to 800 ppm 1-BP. The comparative investigation on the metabolic pathway of 1-BP through the PBPK modeling in both sexes provides critical information for understanding the role of p450 and GSH in the metabolism of 1-BP and eventually helps to quantitatively extrapolate current animal studies to human.

  3. Reconstructing Organophosphorus Pesticide Doses Using the Reversed Dosimetry Approach in a Simple Physiologically-Based Pharmacokinetic Model

    Directory of Open Access Journals (Sweden)

    Chensheng Lu


    Full Text Available We illustrated the development of a simple pharmacokinetic (SPK model aiming to estimate the absorbed chlorpyrifos doses using urinary biomarker data, 3,5,6-trichlorpyridinol as the model input. The effectiveness of the SPK model in the pesticide risk assessment was evaluated by comparing dose estimates using different urinary composite data. The dose estimates resulting from the first morning voids appeared to be lower than but not significantly different to those using before bedtime, lunch or dinner voids. We found similar trend for dose estimates using three different urinary composite data. However, the dose estimates using the SPK model for individual children were significantly higher than those from the conventional physiologically based pharmacokinetic (PBPK modeling using aggregate environmental measurements of chlorpyrifos as the model inputs. The use of urinary data in the SPK model intuitively provided a plausible alternative to the conventional PBPK model in reconstructing the absorbed chlorpyrifos dose.

  4. A physiologically based pharmacokinetic model to predict the pharmacokinetics of highly protein-bound drugs and the impact of errors in plasma protein binding. (United States)

    Ye, Min; Nagar, Swati; Korzekwa, Ken


    Predicting the pharmacokinetics of highly protein-bound drugs is difficult. Also, since historical plasma protein binding data were often collected using unbuffered plasma, the resulting inaccurate binding data could contribute to incorrect predictions. This study uses a generic physiologically based pharmacokinetic (PBPK) model to predict human plasma concentration-time profiles for 22 highly protein-bound drugs. Tissue distribution was estimated from in vitro drug lipophilicity data, plasma protein binding and the blood: plasma ratio. Clearance was predicted with a well-stirred liver model. Underestimated hepatic clearance for acidic and neutral compounds was corrected by an empirical scaling factor. Predicted values (pharmacokinetic parameters, plasma concentration-time profile) were compared with observed data to evaluate the model accuracy. Of the 22 drugs, less than a 2-fold error was obtained for the terminal elimination half-life (t1/2 , 100% of drugs), peak plasma concentration (Cmax , 100%), area under the plasma concentration-time curve (AUC0-t , 95.4%), clearance (CLh , 95.4%), mean residence time (MRT, 95.4%) and steady state volume (Vss , 90.9%). The impact of fup errors on CLh and Vss prediction was evaluated. Errors in fup resulted in proportional errors in clearance prediction for low-clearance compounds, and in Vss prediction for high-volume neutral drugs. For high-volume basic drugs, errors in fup did not propagate to errors in Vss prediction. This is due to the cancellation of errors in the calculations for tissue partitioning of basic drugs. Overall, plasma profiles were well simulated with the present PBPK model. Copyright © 2016 John Wiley & Sons, Ltd.

  5. A physiologically based pharmacokinetic model for ionic silver and silver nanoparticles

    Directory of Open Access Journals (Sweden)

    Bachler G


    Full Text Available Gerald Bachler, Natalie von Goetz, Konrad Hungerbühler ETH Zurich, Institute for Chemical and Bioengineering, Zurich, Switzerland Abstract: Silver is a strong antibiotic that is increasingly incorporated into consumer products as a bulk, salt, or nanosilver, thus potentially causing side-effects related to human exposure. However, the fate and behavior of (nanosilver in the human body is presently not well understood. In order to aggregate the existing experimental information, a physiologically based pharmacokinetic model (PBPK was developed in this study for ionic silver and nanosilver. The structure of the model was established on the basis of toxicokinetic data from intravenous studies. The number of calibrated parameters was minimized in order to enhance the predictive capability of the model. We validated the model structure for both silver forms by reproducing exposure conditions (dermal, oral, and inhalation of in vivo experiments and comparing simulated and experimentally assessed organ concentrations. Therefore, the percutaneous, intestinal, or pulmonary absorption fraction was estimated based on the blood silver concentration of the respective experimental data set. In all of the cases examined, the model could successfully predict the biodistribution of ionic silver and 15–150 nm silver nanoparticles, which were not coated with substances designed to prolong the circulatory time (eg, polyethylene glycol. Furthermore, the results of our model indicate that: (1 within the application domain of our model, the particle size and coating had a minor influence on the biodistribution; (2 in vivo, it is more likely that silver nanoparticles are directly stored as insoluble salt particles than dissolve into Ag+; and (3 compartments of the mononuclear phagocytic system play a minor role in exposure levels that are relevant for human consumers. We also give an example of how the model can be used in exposure and risk assessments based on five

  6. Use of partition coefficients in flow-limited physiologically-based pharmacokinetic modeling. (United States)

    Thompson, Matthew D; Beard, Daniel A; Wu, Fan


    Permeability-limited two-subcompartment and flow-limited, well-stirred tank tissue compartment models are routinely used in physiologically-based pharmacokinetic modeling. Here, the permeability-limited two-subcompartment model is used to derive a general flow-limited case of a two-subcompartment model with the well-stirred tank being a specific case where tissue fractional blood volume approaches zero. The general flow-limited two-subcompartment model provides a clear distinction between two partition coefficients typically used in PBPK: a biophysical partition coefficient and a well-stirred partition coefficient. Case studies using diazepam and cotinine demonstrate that, when the well-stirred tank is used with a priori predicted biophysical partition coefficients, simulations overestimate or underestimate total organ drug concentration relative to flow-limited two-subcompartment model behavior in tissues with higher fractional blood volumes. However, whole-body simulations show predicted drug concentrations in plasma and lower fractional blood volume tissues are relatively unaffected. These findings point to the importance of accurately determining tissue fractional blood volume for flow-limited PBPK modeling. Simulations using biophysical and well-stirred partition coefficients optimized with flow-limited two-subcompartment and well-stirred models, respectively, lead to nearly identical fits to tissue drug distribution data. Therefore, results of whole-body PBPK modeling with diazepam and cotinine indicate both flow-limited models are appropriate PBPK tissue models as long as the correct partition coefficient is used: the biophysical partition coefficient is for use with two-subcompartment models and the well-stirred partition coefficient is for use with the well-stirred tank model.

  7. Physiologically Based Pharmacokinetic Modeling: Methodology, Applications, and Limitations with a Focus on Its Role in Pediatric Drug Development

    Directory of Open Access Journals (Sweden)

    Feras Khalil


    Full Text Available The concept of physiologically based pharmacokinetic (PBPK modeling was introduced years ago, but it has not been practiced significantly. However, interest in and implementation of this modeling technique have grown, as evidenced by the increased number of publications in this field. This paper demonstrates briefly the methodology, applications, and limitations of PBPK modeling with special attention given to discuss the use of PBPK models in pediatric drug development and some examples described in detail. Although PBPK models do have some limitations, the potential benefit from PBPK modeling technique is huge. PBPK models can be applied to investigate drug pharmacokinetics under different physiological and pathological conditions or in different age groups, to support decision-making during drug discovery, to provide, perhaps most important, data that can save time and resources, especially in early drug development phases and in pediatric clinical trials, and potentially to help clinical trials become more “confirmatory” rather than “exploratory”.

  8. Validation of human physiologically based pharmacokinetic model for vinyl acetate against human nasal dosimetry data. (United States)

    Hinderliter, P M; Thrall, K D; Corley, R A; Bloemen, L J; Bogdanffy, M S


    Vinyl acetate has been shown to induce nasal lesions in rodents in inhalation bioassays. A physiologically based pharmacokinetic (PBPK) model for vinyl acetate has been used in human risk assessment, but previous in vivo validation was conducted only in rats. Controlled human exposures to vinyl acetate were conducted to provide validation data for the application of the model in humans. Five volunteers were exposed to 1, 5, and 10 ppm 13C1,13C2 vinyl acetate via inhalation. A probe inserted into the nasopharyngeal region sampled both 13C1,13C2 vinyl acetate and the major metabolite 13C1,13C2 acetaldehyde during rest and light exercise. Nasopharyngeal air concentrations were analyzed in real time by ion trap mass spectrometry (MS/MS). Experimental concentrations of both vinyl acetate and acetaldehyde were then compared to predicted concentrations calculated from the previously published human model. Model predictions of vinyl acetate nasal extraction compared favorably with measured values of vinyl acetate, as did predictions of nasopharyngeal acetaldehyde when compared to measured acetaldehyde. The results showed that the current PBPK model structure and parameterization are appropriate for vinyl acetate. These analyses were conducted from 1 to 10 ppm vinyl acetate, a range relevant to workplace exposure standards but which would not be expected to saturate vinyl acetate metabolism. Risk assessment based on this model further concluded that 24 h per day exposures up to 1 ppm do not present concern regarding cancer or non-cancer toxicity. Validation of the vinyl acetate human PBPK model provides support for these conclusions.

  9. Physiologically based pharmacokinetic modeling using microsoft excel and visual basic for applications. (United States)

    Marino, Dale J


    Abstract Physiologically based pharmacokinetic (PBPK) models are mathematical descriptions depicting the relationship between external exposure and internal dose. These models have found great utility for interspecies extrapolation. However, specialized computer software packages, which are not widely distributed, have typically been used for model development and utilization. A few physiological models have been reported using more widely available software packages (e.g., Microsoft Excel), but these tend to include less complex processes and dose metrics. To ascertain the capability of Microsoft Excel and Visual Basis for Applications (VBA) for PBPK modeling, models for styrene, vinyl chloride, and methylene chloride were coded in Advanced Continuous Simulation Language (ACSL), Excel, and VBA, and simulation results were compared. For styrene, differences between ACSL and Excel or VBA compartment concentrations and rates of change were less than +/-7.5E-10 using the same numerical integration technique and time step. Differences using VBA fixed step or ACSL Gear's methods were generally <1.00E-03, although larger differences involving very small values were noted after exposure transitions. For vinyl chloride and methylene chloride, Excel and VBA PBPK model dose metrics differed by no more than -0.013% or -0.23%, respectively, from ACSL results. These differences are likely attributable to different step sizes rather than different numerical integration techniques. These results indicate that Microsoft Excel and VBA can be useful tools for utilizing PBPK models, and given the availability of these software programs, it is hoped that this effort will help facilitate the use and investigation of PBPK modeling.

  10. Update on a Pharmacokinetic-Centric Alternative Tier II Program for MMT—Part II: Physiologically Based Pharmacokinetic Modeling and Manganese Risk Assessment

    Directory of Open Access Journals (Sweden)

    Michael D. Taylor


    Full Text Available Recently, a variety of physiologically based pharmacokinetic (PBPK models have been developed for the essential element manganese. This paper reviews the development of PBPK models (e.g., adult, pregnant, lactating, and neonatal rats, nonhuman primates, and adult, pregnant, lactating, and neonatal humans and relevant risk assessment applications. Each PBPK model incorporates critical features including dose-dependent saturable tissue capacities and asymmetrical diffusional flux of manganese into brain and other tissues. Varied influx and efflux diffusion rate and binding constants for different brain regions account for the differential increases in regional brain manganese concentrations observed experimentally. We also present novel PBPK simulations to predict manganese tissue concentrations in fetal, neonatal, pregnant, or aged individuals, as well as individuals with liver disease or chronic manganese inhalation. The results of these simulations could help guide risk assessors in the application of uncertainty factors as they establish exposure guidelines for the general public or workers.

  11. Physiologically Based Pharmacokinetic Modeling Framework for Quantitative Prediction of an Herb–Drug Interaction (United States)

    Brantley, S J; Gufford, B T; Dua, R; Fediuk, D J; Graf, T N; Scarlett, Y V; Frederick, K S; Fisher, M B; Oberlies, N H; Paine, M F


    Herb–drug interaction predictions remain challenging. Physiologically based pharmacokinetic (PBPK) modeling was used to improve prediction accuracy of potential herb–drug interactions using the semipurified milk thistle preparation, silibinin, as an exemplar herbal product. Interactions between silibinin constituents and the probe substrates warfarin (CYP2C9) and midazolam (CYP3A) were simulated. A low silibinin dose (160 mg/day × 14 days) was predicted to increase midazolam area under the curve (AUC) by 1%, which was corroborated with external data; a higher dose (1,650 mg/day × 7 days) was predicted to increase midazolam and (S)-warfarin AUC by 5% and 4%, respectively. A proof-of-concept clinical study confirmed minimal interaction between high-dose silibinin and both midazolam and (S)-warfarin (9 and 13% increase in AUC, respectively). Unexpectedly, (R)-warfarin AUC decreased (by 15%), but this is unlikely to be clinically important. Application of this PBPK modeling framework to other herb–drug interactions could facilitate development of guidelines for quantitative prediction of clinically relevant interactions. PMID:24670388

  12. Predicting lung dosimetry of inhaled particleborne benzo[a]pyrene using physiologically based pharmacokinetic modeling (United States)

    Campbell, Jerry; Franzen, Allison; Van Landingham, Cynthia; Lumpkin, Michael; Crowell, Susan; Meredith, Clive; Loccisano, Anne; Gentry, Robinan; Clewell, Harvey


    Abstract Benzo[a]pyrene (BaP) is a by-product of incomplete combustion of fossil fuels and plant/wood products, including tobacco. A physiologically based pharmacokinetic (PBPK) model for BaP for the rat was extended to simulate inhalation exposures to BaP in rats and humans including particle deposition and dissolution of absorbed BaP and renal elimination of 3-hydroxy benzo[a]pyrene (3-OH BaP) in humans. The clearance of particle-associated BaP from lung based on existing data in rats and dogs suggest that the process is bi-phasic. An initial rapid clearance was represented by BaP released from particles followed by a slower first-order clearance that follows particle kinetics. Parameter values for BaP-particle dissociation were estimated using inhalation data from isolated/ventilated/perfused rat lungs and optimized in the extended inhalation model using available rat data. Simulations of acute inhalation exposures in rats identified specific data needs including systemic elimination of BaP metabolites, diffusion-limited transfer rates of BaP from lung tissue to blood and the quantitative role of macrophage-mediated and ciliated clearance mechanisms. The updated BaP model provides very good prediction of the urinary 3-OH BaP concentrations and the relative difference between measured 3-OH BaP in nonsmokers versus smokers. This PBPK model for inhaled BaP is a preliminary tool for quantifying lung BaP dosimetry in rat and humans and was used to prioritize data needs that would provide significant model refinement and robust internal dosimetry capabilities. PMID:27569524

  13. Development of Physiologically Based Pharmacokinetic Model (PBPK) of BMP2 in Mice. (United States)

    Utturkar, Aditya; Paul, Bikram; Akkiraju, Hemanth; Bonor, Jeremy; Dhurjati, Prasad; Nohe, Anja


    Bone Morphogenetic protein 2 holds great promise for potential applications in the clinic. It is a potent growth factor for the use in the cervical spine surgery (FDA approved 2002) and has been marketed as "Infuse" for treating open tibial shaft fractures (FDA approved 2004). However, its use is limited by several significant side effects that maybe due to its potency and effect on different stem cell populations in the spine. BMP2 is expressed throughout the human body in several tissues and at a very high concentration in the blood. BMP receptors, especially BMP receptor type Ia, is ubiquitously expressed in most tissues. Currently, it is difficult to determine how BMP2 is physiologically distributed in mice or humans and no quantitative models are available. A Physiologically-Based Pharmaco-Kinetic (PBPK) model has been developed to determine steady-state distribution of BMP2 in mice. The multi-compartmental PBPK model represents relevant organ/tissues with physiological accuracy. The organs/tissue compartments chosen were brain, lung, heart, liver, pancreas, kidney, uterus, bone and fat. A blood compartment maintained connectivity among the various organs. Four processes characterized the change in the concentration of the protein in every compartment: blood flow in, blood flow out, protein turnover and receptor binding in the organ. The unique aspects of the model are the determination of elimination using receptor kinetics and generation using protein turnover. The model also predicts steady state concentrations of BMP2 in tissues in mice and may be used for possible scale-up of dosage regimens in humans.

  14. A general model-based design of experiments approach to achieve practical identifiability of pharmacokinetic and pharmacodynamic models. (United States)

    Galvanin, Federico; Ballan, Carlo C; Barolo, Massimiliano; Bezzo, Fabrizio


    The use of pharmacokinetic (PK) and pharmacodynamic (PD) models is a common and widespread practice in the preliminary stages of drug development. However, PK-PD models may be affected by structural identifiability issues intrinsically related to their mathematical formulation. A preliminary structural identifiability analysis is usually carried out to check if the set of model parameters can be uniquely determined from experimental observations under the ideal assumptions of noise-free data and no model uncertainty. However, even for structurally identifiable models, real-life experimental conditions and model uncertainty may strongly affect the practical possibility to estimate the model parameters in a statistically sound way. A systematic procedure coupling the numerical assessment of structural identifiability with advanced model-based design of experiments formulations is presented in this paper. The objective is to propose a general approach to design experiments in an optimal way, detecting a proper set of experimental settings that ensure the practical identifiability of PK-PD models. Two simulated case studies based on in vitro bacterial growth and killing models are presented to demonstrate the applicability and generality of the methodology to tackle model identifiability issues effectively, through the design of feasible and highly informative experiments.

  15. Physiologically based pharmacokinetic modeling of zinc oxide nanoparticles and zinc nitrate in mice

    Directory of Open Access Journals (Sweden)

    Chen WY


    Full Text Available Wei-Yu Chen,1 Yi-Hsien Cheng,2 Nan-Hung Hsieh,3 Bo-Chun Wu,2 Wei-Chun Chou,4 Chia-Chi Ho,4 Jen-Kun Chen,5 Chung-Min Liao,2,* Pinpin Lin4,* 1Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, 2Department of Bioenvironmental Systems Engineering, National Taiwan University, Taipei, 3Institute of Labor, Occupational Safety and Health, Ministry of Labor, New Taipei City, 4National Institute of Environmental Health Sciences, 5Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Zhunan, Taiwan *These authors contributed equally to this work Abstract: Zinc oxide nanoparticles (ZnO NPs have been widely used in consumer products, therapeutic agents, and drug delivery systems. However, the fate and behavior of ZnO NPs in living organisms are not well described. The purpose of this study was to develop a physiologically based pharmacokinetic model to describe the dynamic interactions of 65ZnO NPs in mice. We estimated key physicochemical parameters of partition coefficients and excretion or elimination rates, based on our previously published data quantifying the biodistributions of 10 nm and 71 nm 65ZnO NPs and zinc nitrate (65Zn(NO32 in various mice tissues. The time-dependent partition coefficients and excretion or elimination rates were used to construct our physiologically based pharmacokinetic model. In general, tissue partition coefficients of 65ZnO NPs were greater than those of 65Zn(NO32, particularly the lung partition coefficient of 10 nm 65ZnO NPs. Sensitivity analysis revealed that 71 nm 65ZnO NPs and 65Zn(NO32 were sensitive to excretion and elimination rates in the liver and gastrointestinal tract. Although the partition coefficient of the brain was relative low, it increased time-dependently for 65ZnO NPs and 65Zn(NO32. The simulation of 65Zn(NO32 was well fitted with the experimental data. However, replacing partition coefficients of 65ZnO NPs with

  16. Integration of Life-Stage Physiologically Based Pharmacokinetic Models with Adverse Outcome Pathways and Environmental Exposure Models to Screen for Environmental Hazards (United States)

    A Life-stage Physiologically-Based Pharmacokinetic (PBPK) model was developed to include descriptions of several life-stage events such as pregnancy, fetal development, the neonate and child growth. The overall modeling strategy was used for in vitro to in vivo (IVIVE) extrapolat...

  17. Metabolism and physiologically based pharmacokinetic modeling of flumioxazin in pregnant animals

    Energy Technology Data Exchange (ETDEWEB)

    Takaku, Tomoyuki, E-mail:; Nagahori, Hirohisa; Sogame, Yoshihisa


    A physiologically based pharmacokinetic (PBPK) model was developed to predict the concentration of flumioxazin, in the blood and fetus of pregnant humans during a theoretical accidental intake (1000 mg/kg). The data on flumioxazin concentration in pregnant rats (30 mg/kg po) was used to develop the PBPK model in pregnant rats using physiological parameters and chemical specific parameters. The rat PBPK model developed was extrapolated to a human model. Liver microsomes of female rats and a mixed gender of humans were used for the in vitro metabolism study. To determine the % of flumioxazin absorbed after administration at a dose of 1000 mg/kg assuming maximum accidental intake, the biliary excretion study of [phenyl-U-{sup 14}C]flumioxazin was conducted in bile duct-cannulated female rats (Crl:CD (SD)) to collect and analyze the bile, urine, feces, gastrointestinal tract, and residual carcass. The % of flumioxazin absorbed at a dose of 1000 mg/kg in rats was low (12.3%) by summing up {sup 14}C of the urine, bile, and residual carcass. The pregnant human model that was developed demonstrated that the maximum flumioxazin concentration in the blood and fetus of a pregnant human at a dose of 1000 mg/kg po was 0.86 μg/mL and 0.68 μg/mL, respectively, which is much lower than K{sub m} (202.4 μg/mL). Because the metabolism was not saturated and the absorption rate was low at a dose of 1000 mg/kg, the calculated flumioxazin concentration in pregnant humans was thought to be relatively low, considering the flumioxazin concentration in pregnant rats at a dose of 30 mg/kg. For the safety assessment of flumioxazin, these results would be useful for further in vitro toxicology experiments. - Highlights: • A PBPK model of flumioxazin in pregnant humans was developed. • Simulated flumioxazin concentration in pregnant humans was relatively low. • The results would be useful for further in vitro toxicology experiments.

  18. Reduction of a Whole-Body Physiologically Based Pharmacokinetic Model to Stabilise the Bayesian Analysis of Clinical Data. (United States)

    Wendling, Thierry; Tsamandouras, Nikolaos; Dumitras, Swati; Pigeolet, Etienne; Ogungbenro, Kayode; Aarons, Leon


    Whole-body physiologically based pharmacokinetic (PBPK) models are increasingly used in drug development for their ability to predict drug concentrations in clinically relevant tissues and to extrapolate across species, experimental conditions and sub-populations. A whole-body PBPK model can be fitted to clinical data using a Bayesian population approach. However, the analysis might be time consuming and numerically unstable if prior information on the model parameters is too vague given the complexity of the system. We suggest an approach where (i) a whole-body PBPK model is formally reduced using a Bayesian proper lumping method to retain the mechanistic interpretation of the system and account for parameter uncertainty, (ii) the simplified model is fitted to clinical data using Markov Chain Monte Carlo techniques and (iii) the optimised reduced PBPK model is used for extrapolation. A previously developed 16-compartment whole-body PBPK model for mavoglurant was reduced to 7 compartments while preserving plasma concentration-time profiles (median and variance) and giving emphasis to the brain (target site) and the liver (elimination site). The reduced model was numerically more stable than the whole-body model for the Bayesian analysis of mavoglurant pharmacokinetic data in healthy adult volunteers. Finally, the reduced yet mechanistic model could easily be scaled from adults to children and predict mavoglurant pharmacokinetics in children aged from 3 to 11 years with similar performance compared with the whole-body model. This study is a first example of the practicality of formal reduction of complex mechanistic models for Bayesian inference in drug development.

  19. Human plasma concentrations of herbicidal carbamate molinate extrapolated from the pharmacokinetics established in in vivo experiments with chimeric mice with humanized liver and physiologically based pharmacokinetic modeling. (United States)

    Yamashita, Masanao; Suemizu, Hiroshi; Murayama, Norie; Nishiyama, Sayako; Shimizu, Makiko; Yamazaki, Hiroshi


    To predict concentrations in humans of the herbicidal carbamate molinate, used exclusively in rice cultivation, a forward dosimetry approach was carried out using data from lowest-observed-adverse-effect-level doses orally administered to rats, wild type mice, and chimeric mice with humanized liver and from in vitro human and rodent experiments. Human liver microsomes preferentially mediated hydroxylation of molinate, but rat livers additionally produced molinate sulfoxide and an unidentified metabolite. Adjusted animal biomonitoring equivalents for molinate and its primary sulfoxide from animal studies were scaled to human biomonitoring equivalents using known species allometric scaling factors and human metabolic data with a simple physiologically based pharmacokinetic (PBPK) model. The slower disposition of molinate and accumulation of molinate sulfoxide in humans were estimated by modeling after single and multiple doses compared with elimination in rodents. The results from simplified PBPK modeling in combination with chimeric mice with humanized liver suggest that ratios of estimated parameters of molinate sulfoxide exposure in humans to those in rats were three times as many as general safety factor of 10 for species difference in toxicokinetics. Thus, careful regulatory decision is needed when evaluating the human risk resulting from exposure to low doses of molinate and related carbamates based on data obtained from rats.

  20. Prediction of pharmacokinetics and drug-drug interaction potential using physiologically based pharmacokinetic (PBPK) modeling approach: A case study of caffeine and ciprofloxacin (United States)

    Park, Min-Ho; Shin, Seok-Ho; Byeon, Jin-Ju; Lee, Gwan-Ho; Yu, Byung-Yong


    Over the last decade, physiologically based pharmacokinetics (PBPK) application has been extended significantly not only to predicting preclinical/human PK but also to evaluating the drug-drug interaction (DDI) liability at the drug discovery or development stage. Herein, we describe a case study to illustrate the use of PBPK approach in predicting human PK as well as DDI using in silico, in vivo and in vitro derived parameters. This case was composed of five steps such as: simulation, verification, understanding of parameter sensitivity, optimization of the parameter and final evaluation. Caffeine and ciprofloxacin were used as tool compounds to demonstrate the “fit for purpose” application of PBPK modeling and simulation for this study. Compared to caffeine, the PBPK modeling for ciprofloxacin was challenging due to several factors including solubility, permeability, clearance and tissue distribution etc. Therefore, intensive parameter sensitivity analysis (PSA) was conducted to optimize the PBPK model for ciprofloxacin. Overall, the increase in Cmax of caffeine by ciprofloxacin was not significant. However, the increase in AUC was observed and was proportional to the administered dose of ciprofloxacin. The predicted DDI and PK results were comparable to observed clinical data published in the literatures. This approach would be helpful in identifying potential key factors that could lead to significant impact on PBPK modeling and simulation for challenging compounds. PMID:28066147

  1. Scale-up of a physiologically-based pharmacokinetic model to predict the disposition of monoclonal antibodies in monkeys. (United States)

    Glassman, Patrick M; Chen, Yang; Balthasar, Joseph P


    Preclinical assessment of monoclonal antibody (mAb) disposition during drug development often includes investigations in non-human primate models. In many cases, mAb exhibit non-linear disposition that relates to mAb-target binding [i.e., target-mediated disposition (TMD)]. The goal of this work was to develop a physiologically-based pharmacokinetic (PBPK) model to predict non-linear mAb disposition in plasma and in tissues in monkeys. Physiological parameters for monkeys were collected from several sources, and plasma data for several mAbs associated with linear pharmacokinetics were digitized from prior literature reports. The digitized data displayed great variability; therefore, parameters describing inter-antibody variability in the rates of pinocytosis and convection were estimated. For prediction of the disposition of individual antibodies, we incorporated tissue concentrations of target proteins, where concentrations were estimated based on categorical immunohistochemistry scores, and with assumed localization of target within the interstitial space of each organ. Kinetics of target-mAb binding and target turnover, in the presence or absence of mAb, were implemented. The model was then employed to predict concentration versus time data, via Monte Carlo simulation, for two mAb that have been shown to exhibit TMD (2F8 and tocilizumab). Model predictions, performed a priori with no parameter fitting, were found to provide good prediction of dose-dependencies in plasma clearance, the areas under plasma concentration versu time curves, and the time-course of plasma concentration data. This PBPK model may find utility in predicting plasma and tissue concentration versus time data and, potentially, the time-course of receptor occupancy (i.e., mAb-target binding) to support the design and interpretation of preclinical pharmacokinetic-pharmacodynamic investigations in non-human primates.


    A physiologically-based pharmacokinetic (PBPK) model for a mixture of N-methyl carbamate pesticides was developed based on single chemical models. The model was used to compare urinary metabolite concentrations to levels from National Health and Nutrition Examination Survey (NHA...

  3. An Extended Minimal Physiologically Based Pharmacokinetic Model: Evaluation of Type II Diabetes Mellitus and Diabetic Nephropathy on Human IgG Pharmacokinetics in Rats. (United States)

    Chadha, Gurkishan S; Morris, Marilyn E


    Although many studies have evaluated the effects of type 2 diabetes mellitus (T2DM) on the pharmacokinetics (PK) of low molecular weight molecules, there is limited information regarding effects on monoclonal antibodies. Our previous studies have reported significant increases in total (2-4 fold) and renal (100-300 fold) clearance of human IgG, an antibody isotype, in Zucker diabetic fatty (ZDF) rats. Pioglitazone treatment incompletely reversed the disease-related PK changes. The objective of this study was to construct a mechanistic model for simultaneous fitting plasma and urine data, to yield physiologically relevant PK parameters. We propose an extended minimal physiologically based PK (mPBPK) model specifically for IgG by classifying organs as either leaky or tight vascular tissues, and adding a kidney compartment. The model incorporates convection as the primary mechanism of IgG movement from plasma into tissues, interstitial fluid (ISF) in extravascular distribution space, and glomerular filtration rate (GFR), sieving coefficient and fraction reabsorbed in the kidney. The model captured the plasma and urine PK profiles well, and simulated concentrations in ISF. The model estimated a 2-4 fold increase in nonrenal clearance from plasma and 30-120 fold increase in renal clearance with T2DM, consistent with the experimental findings, and these differences in renal clearance were related to changes in GFR, sieving coefficient, and proximal tubular reabsorption. In conclusion, the mPBPK model offers a more relevant approach for analyzing plasma and urine IgG concentration-time data than conventional models and provides insight regarding alterations in distributional and elimination parameters occurring with T2DM.

  4. A Novel Method for Assessing Drug Degradation Product Safety Using Physiologically-Based Pharmacokinetic Models and Stochastic Risk Assessment. (United States)

    Nguyen, Hoa Q; Stamatis, Stephen D; Kirsch, Lee E


    Patient safety risk due to toxic degradation products is a potentially critical quality issue for a small group of useful drug substances. Although the pharmacokinetics of toxic drug degradation products may impact product safety, these data are frequently unavailable. The objective of this study is to incorporate the prediction capability of physiologically based pharmacokinetic (PBPK) models into a rational drug degradation product risk assessment procedure using a series of model drug degradants (substituted anilines). The PBPK models were parameterized using a combination of experimental and literature data and computational methods. The impact of model parameter uncertainty was incorporated into stochastic risk assessment procedure for estimating human safe exposure levels based on the novel use of a statistical metric called "PROB" for comparing probability that a human toxicity-target tissue exposure exceeds the rat exposure level at a critical no-observed-adverse-effect level. When compared with traditional risk assessment calculations, this novel PBPK approach appeared to provide a rational basis for drug instability risk assessment by focusing on target tissue exposure and leveraging physiological, biochemical, biophysical knowledge of compounds and species.

  5. Mechanism-based pharmacokinetic-pharmacodynamic modeling of concentration-dependent hysteresis and biphasic electroencephalogram effects of alphaxalone in rats. (United States)

    Visser, S A G; Smulders, C J G M; Reijers, B P R; Van der Graaf, P H; Peletier, L A; Danhof, M


    The neuroactive steroid alphaxalone reveals a complex biphasic concentration-effect relationship using the 11.5 to 30 Hz frequency band of the electroencephalogram (EEG) as biomarker. The purpose of the present investigation was to develop a mechanism-based pharmacokinetic-pharmacodynamic model to describe this observation. The proposed model is based on receptor theory and aims to separate the drug-receptor interaction from the transduction of the initial stimulus into the observed biphasic response. Individual concentration-time courses of alphaxalone were obtained in combination with continuous recording of the EEG parameter. Alphaxalone was administered intravenously in various dosages. The pharmacokinetics were described by a two-compartment model, and parameter estimates for clearance, intercompartmental clearance, volume of distribution 1 and 2 were 158 +/- 29 ml. min(-1). kg(-1), 143 +/- 31 ml. min(-1). kg(-1), 122 +/- 20 ml. kg(-1) and 606 +/- 48 ml. kg(-1), respectively. Concentration-effect relationships exhibited a biphasic pattern and delay in onset of effect. The hysteresis was described on the basis of an effect-compartment model with C(max) as covariate. The pharmacodynamic model consisted of a receptor model, featuring a monophasic saturable receptor activation model in combination with a biphasic stimulus-response model. The in vivo affinity (K(PD)) was estimated at 432 +/- 26 ng. ml(-1). Unique parameter estimates were obtained that were independent of the dose and the duration of the infusion. In conclusion, we have shown that this mechanism-based approach, which separates drug- and system-related properties in vivo, was successfully applied for the characterization of the biphasic effect versus time patterns of alphaxalone. The model should be of use in the characterization of other biphasic responses.

  6. Prediction of drug-drug interactions between various antidepressants and ritonavir using a physiologically based pharmacokinetic model

    Directory of Open Access Journals (Sweden)

    M Siccardi


    Full Text Available Depression can impact on the treatment of HIV infection, and effective treatment of depressive conditions can have a beneficial effect improving adherence. However antidepressant treatment requires long-term maintenance, and is prone to pharmacokinetic drug-drug interactions (DDI with antiretrovirals. The aim of this study was to predict the magnitude of DDI between ritonavir (RTV and the most commonly prescribed antidepressants using a physiologically based pharmacokinetic (PBPK model simulating virtual clinical trials. In vitro data describing the physiochemical properties, absorption, metabolism, induction and inhibitory potential of RTV and five antidepressants were obtained from published literature. Interactions between RTV and antidepressants were evaluated using the full PBPK model implemented in the Simcyp Population-based Simulator (Version 11.1, Simcyp Limited, UK and virtual clinical studies were simulated on 50 Caucasian subjects receiving 100mg bid of RTV for 21 days plus sertraline (100mg qd, citalopram (40mg qd, fluoxetine (20mg qd, venlafaxine (25mg qd and then from day 14–21. Simulated pharmacokinetic parameters were compared with observed values available in the literature. The simulated PK parameters of RTV, sertraline, citalopram, fluoxetine, mirtazepine and venlafaxine given alone at standard dosage were similar to reference values obtain from published clinical studies. The effect of simulated RTV co-administration on sertaline, fluoxetine and venlaflaxine was an AUC decrease of 40%, 26% and 6%, respectively and on mirtazepine and citalopram, an AUC increase of 60% and 20% respectively. The magnitude of the simulated DDI between RTV and the antidepressants was overall weak to moderate according to the classification of the FDA. The modest magnitude of these drug-drug interactions could be explained by the fact that antidepressants are substrates of multiple isoforms thus metabolism can still occur through CYPs that are

  7. Application of physiologically based pharmacokinetic modeling in predicting drug–drug interactions for sarpogrelate hydrochloride in humans

    Directory of Open Access Journals (Sweden)

    Min JS


    Full Text Available Jee Sun Min,1 Doyun Kim,1 Jung Bae Park,1 Hyunjin Heo,1 Soo Hyeon Bae,2 Jae Hong Seo,1 Euichaul Oh,1 Soo Kyung Bae1 1Integrated Research Institute of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea, Bucheon, 2Department of Pharmacology, College of Medicine, The Catholic University of Korea, Seocho-gu, Seoul, South Korea Background: Evaluating the potential risk of metabolic drug–drug interactions (DDIs is clinically important. Objective: To develop a physiologically based pharmacokinetic (PBPK model for sarpogrelate hydrochloride and its active metabolite, (R,S-1-{2-[2-(3-methoxyphenylethyl]-phenoxy}-3-(dimethylamino-2-propanol (M-1, in order to predict DDIs between sarpogrelate and the clinically relevant cytochrome P450 (CYP 2D6 substrates, metoprolol, desipramine, dextromethorphan, imipramine, and tolterodine. Methods: The PBPK model was developed, incorporating the physicochemical and pharmacokinetic properties of sarpogrelate hydrochloride, and M-1 based on the findings from in vitro and in vivo studies. Subsequently, the model was verified by comparing the predicted concentration-time profiles and pharmacokinetic parameters of sarpogrelate and M-1 to the observed clinical data. Finally, the verified model was used to simulate clinical DDIs between sarpogrelate hydrochloride and sensitive CYP2D6 substrates. The predictive performance of the model was assessed by comparing predicted results to observed data after coadministering sarpogrelate hydrochloride and metoprolol. Results: The developed PBPK model accurately predicted sarpogrelate and M-1 plasma concentration profiles after single or multiple doses of sarpogrelate hydrochloride. The simulated ratios of area under the curve and maximum plasma concentration of metoprolol in the presence of sarpogrelate hydrochloride to baseline were in good agreement with the observed ratios. The predicted fold-increases in the area under the curve ratios of metoprolol

  8. An Age-Dependent Physiologically-Based Pharmacokinetic/Pharmacodynamic Model for the Organophosphorus Insecticide Chlorpyrifos in the Preweanling Rat

    Energy Technology Data Exchange (ETDEWEB)

    Timchalk, Chuck; Kousba, Ahmed A.; Poet, Torka S.


    Juvenile rats are more susceptible than adults to the acute toxicity of organophosphorus insecticides like chlorpyrifos (CPF). Age- and dose-dependent differences in metabolism may be responsible. Of importance is CYP450 activation and detoxification of CPF to chlorpyrifos-oxon (CPF-oxon) and trichloropyridinol (TCP), as well as B-esterase (cholinesterase; ChE) and A-esterase (PON-1) detoxification of CPF-oxon to TCP. In the current study, a modified physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model incorporating age-dependent changes in CYP450, PON-1, and tissue ChE levels for rats was developed. In this model, age was used as a dependent function to estimate body weight which was then used to allometrically scale both metabolism and tissue ChE levels. Model simulations suggest that preweanling rats are particularly sensitive to CPF toxicity, with levels of CPF-oxon in blood and brain disproportionately increasing, relative to the response in adult rats. This age-dependent non-linear increase in CPF-oxon concentration may potentially result from the depletion of non-target B-esterases, and a lower PON-1 metabolic capacity in younger animals. These results indicate that the PBPK/PD model behaves consistently with the general understanding of CPF toxicity, pharmacokinetics and tissue ChE inhibition in neonatal and adult rats. Hence, this model represents an important starting point for developing a computational model to assess the neurotoxic potential of environmentally relevant organophosphate exposures in infants and children.

  9. Use of novel inhalation kinetic studies to refine physiologically-based-pharmacokinetic models for ethanol in non-pregnant and pregnant rats (United States)

    Ethanol (EtOH) exposure induces a variety of concentration-dependent neurological and developmental effects in the rat. Physiologically-based pharmacokinetic (PBPK) models have been used to predict the inhalation exposure concentrations necessary to produce blood EtOH concentrat...

  10. Providing a theoretical basis for nanotoxicity risk analysis departing from traditional physiologically-based pharmacokinetic (PBPK) modeling (United States)

    Yamamoto, Dirk P.

    The same novel properties of engineered nanoparticles that make them attractive may also present unique exposure risks. But, the traditional physiologically-based pharmacokinetic (PBPK) modeling assumption of instantaneous equilibration likely does not apply to nanoparticles. This simulation-based research begins with development of a model that includes diffusion, active transport, and carrier mediated transport. An eigenvalue analysis methodology was developed to examine model behavior to focus future research. Simulations using the physico-chemical properties of size, shape, surface coating, and surface charge were performed and an equation was determined which estimates area under the curve for arterial blood concentration, which is a surrogate of nanoparticle dose. Results show that the cellular transport processes modeled in this research greatly affect the biokinetics of nanoparticles. Evidence suggests that the equation used to estimate area under the curve for arterial blood concentration can be written in terms of nanoparticle size only. The new paradigm established by this research leverages traditional in vitro, in vivo, and PBPK modeling, but includes area under the curve to bridge animal testing results to humans. This new paradigm allows toxicologists and policymakers to then assess risk to a given exposure and assist in setting appropriate exposure limits for nanoparticles. This research provides critical understanding of nanoparticle biokinetics and allows estimation of total exposure at any toxicological endpoint in the body. This effort is a significant contribution as it highlights future research needs and demonstrates how modeling can be used as a tool to advance nanoparticle risk assessment.

  11. Prediction of clinical response based on pharmacokinetic/pharmacodynamic models of 5-hydroxytryptamine reuptake inhibitors in mice

    DEFF Research Database (Denmark)

    Kreilgaard, Mads; Smith, D. G.; Brennum, L. T.;


    Bridging the gap between preclinical research and clinical trials is vital for drug development. Predicting clinically relevant steady-state drug concentrations (Css) in serum from preclinical animal models may facilitate this transition. Here we used a pharmacokinetic/pharmacodynamic (PK/PD) mod...

  12. Mathematical modeling and simulation in animal health - Part II: principles, methods, applications, and value of physiologically based pharmacokinetic modeling in veterinary medicine and food safety assessment. (United States)

    Lin, Z; Gehring, R; Mochel, J P; Lavé, T; Riviere, J E


    This review provides a tutorial for individuals interested in quantitative veterinary pharmacology and toxicology and offers a basis for establishing guidelines for physiologically based pharmacokinetic (PBPK) model development and application in veterinary medicine. This is important as the application of PBPK modeling in veterinary medicine has evolved over the past two decades. PBPK models can be used to predict drug tissue residues and withdrawal times in food-producing animals, to estimate chemical concentrations at the site of action and target organ toxicity to aid risk assessment of environmental contaminants and/or drugs in both domestic animals and wildlife, as well as to help design therapeutic regimens for veterinary drugs. This review provides a comprehensive summary of PBPK modeling principles, model development methodology, and the current applications in veterinary medicine, with a focus on predictions of drug tissue residues and withdrawal times in food-producing animals. The advantages and disadvantages of PBPK modeling compared to other pharmacokinetic modeling approaches (i.e., classical compartmental/noncompartmental modeling, nonlinear mixed-effects modeling, and interspecies allometric scaling) are further presented. The review finally discusses contemporary challenges and our perspectives on model documentation, evaluation criteria, quality improvement, and offers solutions to increase model acceptance and applications in veterinary pharmacology and toxicology.

  13. Development of a Physiologically Based Pharmacokinetic and Pharmacodynamic Model to Determine Dosimetry and Cholinesterase Inhibition for a Binary Mixture of Chlorpyrifos and Diazinon in the Rat

    Energy Technology Data Exchange (ETDEWEB)

    Timchalk, Chuck; Poet, Torka S.


    Physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) models have been developed and validated for the organophosphorus (OP) insecticides chlorpyrifos (CPF) and diazinon (DZN). Based on similar pharmacokinetic and mode of action properties it is anticipated that these OPs could interact at a number of important metabolic steps including: CYP450 mediated activation/detoxification, and blood/tissue cholinesterase (ChE) binding/inhibition. We developed a binary PBPK/PD model for CPF, DZN and their metabolites based on previously published models for the individual insecticides. The metabolic interactions (CYP450) between CPF and DZN were evaluated in vitro and suggests that CPF is more substantially metabolized to its oxon metabolite than is DZN. These data are consistent with their observed in vivo relative potency (CPF>DZN). Each insecticide inhibited the other’s in vitro metabolism in a concentration-dependent manner. The PBPK model code used to described the metabolism of CPF and DZN was modified to reflect the type of inhibition kinetics (i.e. competitive vs. non-competitive). The binary model was then evaluated against previously published rodent dosimetry and ChE inhibition data for the mixture. The PBPK/PD model simulations of the acute oral exposure to single- (15 mg/kg) vs. binary-mixtures (15+15 mg/kg) of CFP and DZN at this lower dose resulted in no differences in the predicted pharmacokinetics of either the parent OPs or their respective metabolites; whereas, a binary oral dose of CPF+DZN at 60+60 mg/kg did result in observable changes in the DZN pharmacokinetics. Cmax was more reasonably fit by modifying the absorption parameters. It is anticipated that at low environmentally relevant binary doses, most likely to be encountered in occupational or environmental related exposures, that the pharmacokinetics are expected to be linear, and ChE inhibition dose-additive.

  14. Pharmacokinetic modelling of microencapsulated metronidazole

    Institute of Scientific and Technical Information of China (English)

    Mahmood AHMAD; Khalid PERVAIZ; Ghulam MURTAZA; Munaza RAMZAN


    The aim of present study is to develop a pharmacokinetic model for microencapsulated metronidazole to predict drug absorption pattern in healthy human and validate this model internally. Metronidazole was microencapsulated into ethylcellulose shells followed by the conversion of these microcapsules into tablets.tablets (T1: fast release, T2: moderate release, T3: slow release and reference) were administered to twenty four healthy human volunteers and serial blood samples were collected for 12 hours followed by their analysis using RP-HPLC. Drug release data were analyzed by various model dependent and independent approaches. Drug absorbed (%) was determined by Wagner-Nelson method from plasma concentration profile. Internal predictability was checked from Cmax and AUC. Optimum dissolution profile was observed in double distilled water and 50coefficient, R2 = 0.900 9, 0.942 6, 0.901 5 and 0.932 for T1, T2, T3 and reference, respectively). Internal predictability was found less than 10%. Good correlation coefficients and low prediction errors elaborate the validity of this mathematical in-vitro in-vivo correlation model as a predictive tool for the determination of pharmaenkinetics from dissolution data.

  15. Report from the EMA workshop on qualification and reporting of physiologically based pharmacokinetic (PBPK) modeling and simulation (United States)


    On Nov 21, 2016, the European Medicines Agency (EMA) hosted a workshop to discuss its draft guideline on qualification and reporting of physiologically based pharmacokinetic (PBPK) analysis.1 Published on July 21, 2016, the draft PBPK guideline is currently under the period of public comments. PMID:28035755

  16. Physiologically based pharmacokinetic model of amphotericin B disposition in rats following administration of deoxycholate formulation (Fungizone®): pooled analysis of published data. (United States)

    Kagan, Leonid; Gershkovich, Pavel; Wasan, Kishor M; Mager, Donald E


    The time course of tissue distribution of amphotericin B (AmB) has not been sufficiently characterized despite its therapeutic importance and an apparent disconnect between plasma pharmacokinetics and clinical outcomes. The goals of this work were to develop and evaluate a physiologically based pharmacokinetic (PBPK) model to characterize the disposition properties of AmB administered as deoxycholate formulation in healthy rats and to examine the utility of the PBPK model for interspecies scaling of AmB pharmacokinetics. AmB plasma and tissue concentration-time data, following single and multiple intravenous administration of Fungizone® to rats, from several publications were combined for construction of the model. Physiological parameters were fixed to literature values. Various structural models for single organs were evaluated, and the whole-body PBPK model included liver, spleen, kidney, lung, heart, gastrointestinal tract, plasma, and remainder compartments. The final model resulted in a good simultaneous description of both single and multiple dose data sets. Incorporation of three subcompartments for spleen and kidney tissues was required for capturing a prolonged half-life in these organs. The predictive performance of the final PBPK model was assessed by evaluating its utility in predicting pharmacokinetics of AmB in mice and humans. Clearance and permeability-surface area terms were scaled with body weight. The model demonstrated good predictions of plasma AmB concentration-time profiles for both species. This modeling framework represents an important basis that may be further utilized for characterization of formulation- and disease-related factors in AmB pharmacokinetics and pharmacodynamics.

  17. A mechanism-based pharmacokinetic/pharmacodynamic model for CYP3A1/2 induction by dexamethasone in rats

    Institute of Scientific and Technical Information of China (English)

    Liang LI; Zai-quan LI; Chen-hui DENG; Miao-ran NING; Han-qing LI; Shan-shan BI; Tian-yan ZHOU; Wei LU


    To develop a pharmacokinetic/pharmacodynamic (PK/PD) model describing the receptor/gene-mediated induction of CYP3A1/2 by dexamethasone (DEX) in rats.Methods:A group of male Sprague-Dawley rats receiving DEX (100 mg/kg,ip) were sacrificed at various time points up to 60 h post- treatment.Their blood sample and liver were collected.The plasma concentration of DEX was determined with a reverse phase HPLC method.CYP3A1/2 mRNA,protein levels and enzyme activity were measured using RT-PCR,ELISA and the testosterone substrate assay,respectively.Data analyses were performed using a first-order conditional estimate (FOCE) with INTERACTION method in NONMEM version 7.1.2.Results:A two-compartment model with zero-order absorption was applied to describe the pharmacokinetic characteristics of DEX.Systemic clearance,the apparent volume of distribution and the duration of zero-order absorption were calculated to be 172.7 mL·kg-1.h-1,657.4 mL/kg and 10.47 h,respectively.An indirect response model with a series of transit compartments was developed to describe the induction of CYP3A1/2 via PXR transactivation by DEX.The maximum induction of CYP3A1 and CYP3A2 mRNA levels was achieved,showing nearly 21.29- and 8.67-fold increases relative to the basal levels,respectively.The CYP3A1 and CYP3A2 protein levels were increased by 8.02-fold and 2.49-fold,respectively.The total enzyme activities of CYP3A1/2 were shown to increase by up to 2.79-fold,with a lag time of 40 h from the Tmax of the DEX plasma concentration.The final PK/PD model was able to recapitulate the delayed induction of CYP3A1/2 mRNA,protein and enzyme activity by DEX.Conclusion:A mechanism-based PK/PD model was developed to characterize the complex concentration-induction response relationship between DEX and CYP3A1/2 and to resolve the drug- and system-specific PK/PD parameters for the course of induction.

  18. Human biofluid concentrations of mono(2-ethylhexyl)phthalate extrapolated from pharmacokinetics in chimeric mice with humanized liver administered with di(2-ethylhexyl)phthalate and physiologically based pharmacokinetic modeling. (United States)

    Adachi, Koichiro; Suemizu, Hiroshi; Murayama, Norie; Shimizu, Makiko; Yamazaki, Hiroshi


    Di(2-ethylhexyl)phthalate (DEHP) is a reproductive toxicant in male rodents. The aim of the current study was to extrapolate the pharmacokinetics and toxicokinetics of mono(2-ethylhexyl)phthalate (MEHP, a primary metabolite of DEHP) in humans by using data from oral administration of DEHP to chimeric mice transplanted with human hepatocytes. MEHP and its glucuronide were detected in plasma from control mice and chimeric mice after single oral doses of 250mg DEHP/kg body weight. Biphasic plasma concentration-time curves of MEHP and its glucuronide were seen only in control mice. MEHP and its glucuronide were extensively excreted in urine within 24h in mice with humanized liver. In contrast, fecal excretion levels of MEHP glucuronide were high in control mice compared with those with humanized liver. Adjusted animal biomonitoring equivalents from chimeric mice studies were scaled to human biomonitoring equivalents using known species allometric scaling factors and in vitro metabolic clearance data with a simple physiologically based pharmacokinetic (PBPK) model. Estimated urine MEHP concentrations in humans were consistent with reported concentrations. This research illustrates how chimeric mice transplanted with human hepatocytes in combination with a simple PBPK model can assist evaluations of pharmacokinetics or toxicokinetics of the primary or secondary metabolites of DEHP.

  19. Comparative activity of pradofloxacin and marbofloxacin against coagulase-positive staphylococci in a pharmacokinetic-pharmacodynamic model based on canine pharmacokinetics. (United States)

    Körber-Irrgang, B; Wetzstein, H-G; Bagel-Trah, S; Hafner, D; Kresken, M


    Pradofloxacin (PRA), a novel veterinary 8-cyano-fluoroquinolone (FQ), is active against Staphylococcus pseudintermedius, the primary cause of canine pyoderma. An in vitro pharmacokinetic-pharmacodynamic model was used to compare the activities of PRA and marbofloxacin (MAR) against three clinical isolates of S. pseudintermedius and reference strain Staphylococcus aureus ATCC 6538. Experiments were performed involving populations of 10(10) CFU corresponding to an inoculum density of approximately 5 × 10(7) CFU/mL. The time course of free drug concentrations in canine serum was modelled, resulting from once daily standard oral dosing of 3 mg of PRA/kg and 2 mg of MAR/kg. In addition, experimentally high doses of 6 mg of PRA/kg and 16 mg of MAR/kg were tested against the least susceptible strain. Viable counts were monitored over 24 h. At concentrations associated with standard doses, PRA caused a faster and more sustained killing than MAR of all strains. The ratios of free drug under the concentration-time curve for 24 h over MIC and the maximum concentration of free drug over MIC were at least 90 and 26, and 8.5 and 2.1 for PRA and MAR, respectively. At experimentally high doses, PRA was superior to MAR in terms of immediate killing. Subpopulations with reduced susceptibility to either FQ did not emerge. We conclude that PRA is likely to be an efficacious therapy of canine staphylococcal infections.

  20. Proposed mechanistic description of dose-dependent BDE-47 urinary elimination in mice using a physiologically based pharmacokinetic model

    Energy Technology Data Exchange (ETDEWEB)

    Emond, Claude, E-mail: [BioSimulation Consulting Inc., Newark, DE (United States); Departments of Environmental and Occupational Health, Medicine Faculty, University of Montreal, Montreal, Quebec (Canada); Sanders, J. Michael, E-mail: [National Cancer Institute, Research Triangle Park, NC (United States); Wikoff, Daniele, E-mail: [ToxStrategies, Austin, TX (United States); Birnbaum, Linda S., E-mail: [National Cancer Institute, Research Triangle Park, NC (United States)


    Polybrominated diphenyl ethers (PBDEs) have been used in a wide variety of consumer applications as additive flame retardants. In North America, scientists have noted continuing increases in the levels of PBDE congeners measured in human serum. Some recent studies have found that PBDEs are associated with adverse health effects in humans, in experimental animals, and wildlife. This laboratory previously demonstrated that urinary elimination of 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47) is saturable at high doses in mice; however, this dose-dependent urinary elimination has not been observed in adult rats or immature mice. Thus, the primary objective of this study was to examine the mechanism of urinary elimination of BDE-47 in adult mice using a physiologically based pharmacokinetic (PBPK) model. To support this objective, additional laboratory data were collected to evaluate the predictions of the PBPK model using novel information from adult multi-drug resistance 1a/b knockout mice. Using the PBPK model, the roles of mouse major urinary protein (a blood protein carrier) and P-glycoprotein (an apical membrane transporter in proximal tubule cells in the kidneys, brain, intestines, and liver) were investigated in BDE-47 elimination. The resulting model and new data supported the major role of m-MUP in excretion of BDE-47 in the urine of adult mice, and a lesser role of P-gp as a transporter of BDE-47 in mice. This work expands the knowledge of BDE-47 kinetics between species and provides information for determining the relevancy of these data for human risk assessment purposes. - Highlights: • We report the first study on PBPK model on flame retardant in mice for BDE-47. • We examine mechanism of urinary elimination of BDE-47 in mice using a PBPK model. • We investigated roles of m-MUP and P-gp as transporters in urinary elimination.

  1. Development of a mechanism-based pharmacokinetic/pharmacodynamic model to characterize the thermoregulatory effects of serotonergic drugs in mice

    Directory of Open Access Journals (Sweden)

    Xi-Ling Jiang


    Full Text Available We have shown recently that concurrent harmaline, a monoamine oxidase-A inhibitor (MAOI, potentiates serotonin (5-HT receptor agonist 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT-induced hyperthermia. The objective of this study was to develop an integrated pharmacokinetic/pharmacodynamic (PK/PD model to characterize and predict the thermoregulatory effects of such serotonergic drugs in mice. Physiological thermoregulation was described by a mechanism-based indirect-response model with adaptive feedback control. Harmaline-induced hypothermia and 5-MeO-DMT–elicited hyperthermia were attributable to the loss of heat through the activation of 5-HT1A receptor and thermogenesis via the stimulation of 5-HT2A receptor, respectively. Thus serotonergic 5-MeO-DMT–induced hyperthermia was readily distinguished from handling/injection stress-provoked hyperthermic effects. This PK/PD model was able to simultaneously describe all experimental data including the impact of drug-metabolizing enzyme status on 5-MeO-DMT and harmaline PK properties, and drug- and stress-induced simple hypo/hyperthermic and complex biphasic effects. Furthermore, the modeling results revealed a 4-fold decrease of apparent SC50 value (1.88–0.496 µmol/L for 5-MeO-DMT when harmaline was co-administered, providing a quantitative assessment for the impact of concurrent MAOI harmaline on 5-MeO-DMT–induced hyperthermia. In addition, the hyperpyrexia caused by toxic dose combinations of harmaline and 5-MeO-DMT were linked to the increased systemic exposure to harmaline rather than 5-MeO-DMT, although the body temperature profiles were mispredicted by the model. The results indicate that current PK/PD model may be used as a new conceptual framework to define the impact of serotonergic agents and stress factors on thermoregulation.

  2. A model-based meta-analysis of monoclonal antibody pharmacokinetics to guide optimal first-in-human study design. (United States)

    Davda, Jasmine P; Dodds, Michael G; Gibbs, Megan A; Wisdom, Wendy; Gibbs, John


    The objectives of this retrospective analysis were (1) to characterize the population pharmacokinetics (popPK) of four different monoclonal antibodies (mAbs) in a combined analysis of individual data collected during first-in-human (FIH) studies and (2) to provide a scientific rationale for prospective design of FIH studies with mAbs. The data set was composed of 171 subjects contributing a total of 2716 mAb serum concentrations, following intravenous (IV) and subcutaneous (SC) doses. mAb PK was described by an open 2-compartment model with first-order elimination from the central compartment and a depot compartment with first-order absorption. Parameter values obtained from the popPK model were further used to generate optimal sampling times for a single dose study. A robust fit to the combined data from four mAbs was obtained using the 2-compartment model. Population parameter estimates for systemic clearance and central volume of distribution were 0.20 L/day and 3.6 L with intersubject variability of 31% and 34%, respectively. The random residual error was 14%. Differences (> 2-fold) in PK parameters were not apparent across mAbs. Rich designs (22 samples/subject), minimal designs for popPK (5 samples/subject), and optimal designs for non-compartmental analysis (NCA) and popPK (10 samples/subject) were examined by stochastic simulation and estimation. Single-dose PK studies for linear mAbs executed using the optimal designs are expected to yield high-quality model estimates, and accurate capture of NCA estimations. This model-based meta-analysis has determined typical popPK values for four mAbs with linear elimination and enabled prospective optimization of FIH study designs, potentially improving the efficiency of FIH studies for this class of therapeutics.

  3. Prediction of Deoxypodophyllotoxin Disposition in Mouse, Rat, Monkey and Dog by Physiologically-based Pharmacokinetic Model and the Extrapolation to Human

    Directory of Open Access Journals (Sweden)

    Yang Chen


    Full Text Available Deoxypodophyllotoxin (DPT is a potential anti-tumor candidate prior to its clinical phase. The aim of the study was to develop a physiologically-based pharmacokinetic (PBPK model consisting of 13 tissue compartments to predict DPT disposition in mouse, rat, monkey and dog based on in vitro and in silico inputs. Since large interspecies difference was found in unbound fraction of DPT in plasma, we assumed that Kt:pl,u (unbound tissue-to-plasma concentration ratio was identical across species. The predictions of our model were then validated by in vivo data of corresponding preclinical species, along with visual predictive checks. Reasonable matches were found between observed and predicted plasma concentrations and pharmacokinetic parameters in all four animal species. The prediction in the related seven tissues of mouse was also desirable. We also attempted to predict human pharmacokinetic profile by both the developed PBPK model and interspecies allometric scaling across mouse, rat and monkey, while dog was excluded from the scaling. The two approaches reached similar results. We hope the study will help in the efficacy and safety assessment of DPT in future clinical studies and provide a reference to the preclinical screening of similar compounds by PBPK model.

  4. Physiologically based pharmacokinetic-pharmacodynamic modeling to predict concentrations and actions of sodium-dependent glucose transporter 2 inhibitor canagliflozin in human intestines and renal tubules. (United States)

    Mori, Kazumi; Saito, Ryuta; Nakamaru, Yoshinobu; Shimizu, Makiko; Yamazaki, Hiroshi


    Canagliflozin is a recently developed sodium-glucose cotransporter (SGLT) 2 inhibitor that promotes renal glucose excretion and is considered to inhibit renal SGLT2 from the luminal side of proximal tubules. Canagliflozin reportedly inhibits SGLT1 weakly and suppresses postprandial plasma glucose, suggesting that it also inhibits intestinal SGLT1. However, it is difficult to measure the drug concentrations of these assumed sites of action directly. The pharmacokinetic-pharmacodynamic (PK/PD) relationships of canagliflozin remain poorly characterized. Therefore, a physiologically based pharmacokinetic (PBPK) model of canagliflozin was developed based on clinical data from healthy volunteers and it was used to simulate luminal concentrations in intestines and renal tubules. In small intestine simulations, the inhibition ratios for SGLT1 were predicted to be 40%-60% after the oral administration of clinical doses (100-300 mg/day). In contrast, inhibition ratios of canagliflozin for renal SGLT2 and SGLT1 were predicted to be approximately 100% and 0.2%-0.4%, respectively. These analyses suggest that canagliflozin only inhibits SGLT2 in the kidney. Using the simulated proximal tubule luminal concentrations of canagliflozin, the urinary glucose excretion rates in canagliflozin-treated diabetic patients were accurately predicted using the renal glucose reabsorption model as a PD model. Because the simulation of canagliflozin pharmacokinetics was successful, this PBPK methodology was further validated by successfully simulating the pharmacokinetics of dapagliflozin, another SGLT2 inhibitor. The present results suggest the utility of this PBPK/PD model for predicting canagliflozin concentrations at target sites and help to elucidate the pharmacological effects of SGLT1/2 inhibition in humans. Copyright © 2016 John Wiley & Sons, Ltd.

  5. Use of Physiologically-Based Pharmacokinetic Modeling to Simulate the Profiles of 3-Hydroxybenzo(a)pyrene in Workers Exposed to Polycyclic Aromatic Hydrocarbons


    Roberto Heredia Ortiz; Anne Maître; Damien Barbeau; Michel Lafontaine; Michèle Bouchard


    Biomathematical modeling has become an important tool to assess xenobiotic exposure in humans. In the present study, we have used a human physiologically-based pharmacokinetic (PBPK) model and an simple compartmental toxicokinetic model of benzo(a)pyrene (BaP) kinetics and its 3-hydroxybenzo(a)pyrene (3-OHBaP) metabolite to reproduce the time-course of this biomarker of exposure in the urine of industrially exposed workers and in turn predict the most plausible exposure scenarios. The models ...

  6. Prediction and evaluation of route dependent dosimetry of BPA in rats at different life stages using a physiologically based pharmacokinetic model

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Xiaoxia, E-mail:; Doerge, Daniel R.; Fisher, Jeffrey W.


    Bisphenol A (BPA) has received considerable attention throughout the last decade due to its widespread use in consumer products. For the first time a physiologically based pharmacokinetic (PBPK) model was developed in neonatal and adult rats to quantitatively evaluate age-dependent pharmacokinetics of BPA and its phase II metabolites. The PBPK model was calibrated in adult rats using studies on BPA metabolism and excretion in the liver and gastrointestinal tract, and pharmacokinetic data with BPA in adult rats. For immature rats the hepatic and gastrointestinal metabolism of BPA was inferred from studies on the maturation of phase II enzymes coupled with serum time course data in pups. The calibrated model predicted the measured serum concentrations of BPA and BPA conjugates after administration of 100 μg/kg of d6-BPA in adult rats (oral gavage and intravenous administration) and postnatal days 3, 10, and 21 pups (oral gavage). The observed age-dependent BPA serum concentrations were partially attributed to the immature metabolic capacity of pups. A comparison of the dosimetry of BPA across immature rats and monkeys suggests that dose adjustments would be necessary to extrapolate toxicity studies from neonatal rats to infant humans. - Highlights: • A PBPK model predicts the kinetics of bisphenol A (BPA) in young and adult rats. • BPA metabolism within enterocytes is required for fitting of oral BPA kinetic data. • BPA dosimetry in young rats is different than adult rats and young monkeys.

  7. A Physiologically Based Pharmacokinetic Model for the Oxime TMB-4: Simulation of Rodent and Human Data (United States)


    values) (Voicu et al. 2010). Medically, oximes are administered to counteract organophosphate (OP) poisoning . OPs form serine-conjugated phosphonates...AH, Warnet JM (2011) Does modulation of organic cation transporters improve pralidoxime activity in an animal model of organophosphate poisoning ...model structure for the organophosphate diisopropylfluorophosphate, the model includes key sites of acetylcholinesterase inhibition (brain and diaphragm

  8. Estimation of placental and lactational transfer and tissue distribution of atrazine and its main metabolites in rodent dams, fetuses, and neonates with physiologically based pharmacokinetic modeling

    Energy Technology Data Exchange (ETDEWEB)

    Lin, Zhoumeng [Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602 (United States); Interdisciplinary Toxicology Program, University of Georgia, Athens, GA 30602 (United States); Fisher, Jeffrey W. [Division of Biochemical Toxicology, National Center for Toxicological Research, Food and Drug Administration, Jefferson, AR 72079 (United States); Wang, Ran [Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS 39762 (United States); Institute of Food Safety, Jiangsu Academy of Agricultural Sciences, Nanjing 210014 (China); Ross, Matthew K. [Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS 39762 (United States); Filipov, Nikolay M., E-mail: [Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602 (United States); Interdisciplinary Toxicology Program, University of Georgia, Athens, GA 30602 (United States)


    Atrazine (ATR) is a widely used chlorotriazine herbicide, a ubiquitous environmental contaminant, and a potential developmental toxicant. To quantitatively evaluate placental/lactational transfer and fetal/neonatal tissue dosimetry of ATR and its major metabolites, physiologically based pharmacokinetic models were developed for rat dams, fetuses and neonates. These models were calibrated using pharmacokinetic data from rat dams repeatedly exposed (oral gavage; 5 mg/kg) to ATR followed by model evaluation against other available rat data. Model simulations corresponded well to the majority of available experimental data and suggest that: (1) the fetus is exposed to both ATR and its major metabolite didealkylatrazine (DACT) at levels similar to maternal plasma levels, (2) the neonate is exposed mostly to DACT at levels two-thirds lower than maternal plasma or fetal levels, while lactational exposure to ATR is minimal, and (3) gestational carryover of DACT greatly affects its neonatal dosimetry up until mid-lactation. To test the model's cross-species extrapolation capability, a pharmacokinetic study was conducted with pregnant C57BL/6 mice exposed (oral gavage; 5 mg/kg) to ATR from gestational day 12 to 18. By using mouse-specific parameters, the model predictions fitted well with the measured data, including placental ATR/DACT levels. However, fetal concentrations of DACT were overestimated by the model (10-fold). This overestimation suggests that only around 10% of the DACT that reaches the fetus is tissue-bound. These rodent models could be used in fetal/neonatal tissue dosimetry predictions to help design/interpret early life toxicity/pharmacokinetic studies with ATR and as a foundation for scaling to humans. - Highlights: • We developed PBPK models for atrazine in rat dams, fetuses, and neonates. • We conducted pharmacokinetic (PK) study with atrazine in pregnant mice. • Model predictions were in good agreement with experimental rat and mouse PK data

  9. Bioelectrical impedance modelling of gentamicin pharmacokinetic parameters. (United States)

    Zarowitz, B J; Pilla, A M; Peterson, E L


    1. Bioelectrical impedance analysis was used to develop descriptive models of gentamicin pharmacokinetic parameters in 30 adult in-patients receiving therapy with gentamicin. 2. Serial blood samples obtained from each subject at steady state were analyzed and used to derive gentamicin pharmacokinetic parameters. 3. Multiple regression equations were developed for clearance, elimination rate constant and volume of distribution at steady state and were all statistically significant at P less than 0.05. 4. Clinical validation of this innovative technique is warranted before clinical use is recommended.

  10. Application of physiologically based pharmacokinetic (PBPK) model of trichloroethylene in rats for estimation of internal dose (United States)

    Potential human health risk from chemical exposure must often be assessed for conditions for which suitable human or animal data are not available, requiring extrapolation across duration and concentration. The default method for exposure-duration adjustment is based on Haber's r...

  11. Human Blood Concentrations of Cotinine, a Biomonitoring Marker for Tobacco Smoke, Extrapolated from Nicotine Metabolism in Rats and Humans and Physiologically Based Pharmacokinetic Modeling

    Directory of Open Access Journals (Sweden)

    Masato Kitajima


    Full Text Available The present study defined a simplified physiologically based pharmacokinetic (PBPK model for nicotine and its primary metabolite cotinine in humans, based on metabolic parameters determined in vitro using relevant liver microsomes, coefficients derived in silico, physiological parameters derived from the literature, and an established rat PBPK model. The model consists of an absorption compartment, a metabolizing compartment, and a central compartment for nicotine and three equivalent compartments for cotinine. Evaluation of a rat model was performed by making comparisons with predicted concentrations in blood and in vivo experimental pharmacokinetic values obtained from rats after oral treatment with nicotine (1.0 mg/kg, a no-observed-adverse-effect level for 14 days. Elimination rates of nicotine in vitro were established from data from rat liver microsomes and from human pooled liver microsomes. Human biomonitoring data (17 ng nicotine and 150 ng cotinine per mL plasma 1 h after smoking from pooled five male Japanese smokers (daily intake of 43 mg nicotine by smoking revealed that these blood concentrations could be calculated using a human PBPK model. These results indicate that a simplified PBPK model for nicotine/cotinine is useful for a forward dosimetry approach in humans and for estimating blood concentrations of other related compounds resulting from exposure to low chemical doses.

  12. Use of physiologically based pharmacokinetic models coupled with pharmacodynamic models to assess the clinical relevance of current bioequivalence criteria for generic drug products containing Ibuprofen. (United States)

    Cristofoletti, Rodrigo; Dressman, Jennifer B


    Physiologically based pharmacokinetic models coupled with pharmacodynamic (PBPK/PD) models can be useful to identify whether current bioequivalence criteria is overly conservative or venturesome for different drugs. A PBPK model constructed with Simcyp Simulator(®) using reported biopharmaceutics parameters for ibuprofen was coupled with two published PD models: one for antipyresis and one for dental pain relief. Using products with doses of 400 mg and 10 mg/kg as "reference (R)" drug products, virtual products with doses of 280 mg and 7 mg/kg, respectively, could be interpreted as representing bioinequivalent test (T) drug products, as the point estimate for the ratios T/R are well below the bioequivalence limits. Despite being bioinequivalent in terms of PK, these lower doses were shown to be therapeutically equivalent to the higher doses because of the flat dose-response relationship of ibuprofen. Sensitivity analysis of the PBPK/PD models demonstrated that gastric emptying time, dissolution rate and small intestine pH are variables that influence ibuprofen PK, but do not seem to significantly affect its PD. It was concluded that current bioequivalent guidance might be unnecessarily restrictive for ibuprofen products.

  13. Mechanism-based pharmacokinetic-pharmacodynamic modeling of salvianolic acid A effects on plasma xanthine oxidase activity and uric acid levels in acute myocardial infarction rats. (United States)

    Wang, Haidong; Li, Xi; Zhang, Wenting; Liu, Yao; Wang, Shijun; Liu, Xiaoquan; He, Hua


    1. Salvianolic acid A (SalA) was found to attenuate plasma uric acid (UA) concentration and xanthine oxidase (XO) activity in acute myocardial infraction (AMI) rats, which was characterized with developed mechanism-based pharmacokinetic-pharmacodynamic (PK-PD) model. 2. AMI was induced in rats by coronary artery ligation. Surviving AMI rats received a single intravenous dose of 5 mg/kg of SalA and normal saline. The plasma SalA concentrations were determined by HPLC-MS/MS method. The plasma UA concentrations were determined by HPLC method and plasma XO activity were measured spectrophotometrically. An integrated mathematical model characterized the relationship between plasma UA and SalA. 3. Pharmacokinetics was described using two-compartment model for SalA with linear metabolic process. In post-AMI rats, XO activity and UA concentrations were increased, while SalA dosing palliated this increase. These effects were well captured by using two series of transduction models, simulating the delay of inhibition on XO driven by SalA and UA elevation resulted from the multiple factors, respectively. 4. The effect was well described by the developed PK-PD model, indicating that SalA can exert cardiovascular protective effects by decreasing elevated plasma UA levels induced by AMI.

  14. A physiologically based pharmacokinetic/pharmacodynamic model for carbofuran in Sprague-Dawley rats using the exposure-related dose estimating model. (United States)

    Zhang, Xiaofei; Tsang, Andy M; Okino, Miles S; Power, Frederick W; Knaak, James B; Harrison, Lynda S; Dary, Curtis C


    Carbofuran (2,3-dihydro-2,2-dimethyl-7-benzofuranyl-N-methylcarbamate), a broad spectrum N-methyl carbamate insecticide, and its metabolite, 3-hydroxycarbofuran, exert their toxicity by reversibly inhibiting acetylcholinesterase (AChE). To characterize AChE inhibition from carbofuran exposure, a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model was developed in the Exposure-Related Dose Estimating Model (ERDEM) platform for the Sprague-Dawley (SD) rat. Experimental estimates of physiological, biochemical, and physicochemical model parameters were obtained or based on data from the open literature. The PBPK/PD model structure included carbofuran metabolism in the liver to 16 known metabolites, enterohepatic circulation of glucuronic acid conjugates, and excretion in urine and feces. Bolus doses by ingestion of 50 microg/kg and 0.5 mg/kg carbofuran were simulated for the blood and brain AChE activity. The carbofuran ERDEM simulated a half-life of 5.2 h for urinary clearance, and the experimental AChE activity data were reproduced for the blood and brain. Thirty model parameters were found influential to the model outputs and were chosen for perturbation in Monte Carlo simulations to evaluate the impact of their variability on the model predictions. Results of the simulation runs indicated that the minimum AChE activity in the blood ranged from 29.3 to 79.0% (as 5th and 95th percentiles) of the control level with a mean of 55.9% (standard deviation = 15.1%) compared to an experimental value of 63%. The constructed PBPK/PD model for carbofuran in the SD rat provides a foundation for extrapolating to a human model that can be used for future risk assessment.

  15. Evaluation of Drug-Drug Interaction Potential Between Sacubitril/Valsartan (LCZ696) and Statins Using a Physiologically Based Pharmacokinetic Model. (United States)

    Lin, Wen; Ji, Tao; Einolf, Heidi; Ayalasomayajula, Surya; Lin, Tsu-Han; Hanna, Imad; Heimbach, Tycho; Breen, Christopher; Jarugula, Venkateswar; He, Handan


    Sacubitril/valsartan (LCZ696) has been approved for the treatment of heart failure. Sacubitril is an in vitro inhibitor of organic anion-transporting polypeptides (OATPs). In clinical studies, LCZ696 increased atorvastatin Cmax by 1.7-fold and area under the plasma concentration-time curve by 1.3-fold, but had little or no effect on simvastatin or simvastatin acid exposure. A physiologically based pharmacokinetics modeling approach was applied to explore the underlying mechanisms behind the statin-specific LCZ696 drug interaction observations. The model incorporated OATP-mediated clearance (CLint,T) for simvastatin and simvastatin acid to successfully describe the pharmacokinetic profiles of either analyte in the absence or presence of LCZ696. Moreover, the model successfully described the clinically observed drug effect with atorvastatin. The simulations clarified the critical parameters responsible for the observation of a low, yet clinically relevant, drug-drug interaction DDI between sacubitril and atorvastatin and the lack of effect with simvastatin acid. Atorvastatin is administered in its active form and rapidly achieves Cmax that coincide with the low Cmax of sacubitril. In contrast, simvastatin requires a hydrolysis step to the acid form and therefore is not present at the site of interactions at sacubitril concentrations that are inhibitory. Similar models were used to evaluate the drug-drug interaction risk for additional OATP-transported statins which predicted to maximally result in a 1.5-fold exposure increase.

  16. A Detailed Physiologically Based Model to Simulate the Pharmacokinetics and Hormonal Pharmacodynamics of Enalapril on the Circulating Endocrine Renin-Angiotensin-Aldosterone System (United States)

    Claassen, Karina; Willmann, Stefan; Eissing, Thomas; Preusser, Tobias; Block, Michael


    The renin-angiotensin-aldosterone system (RAAS) plays a key role in the pathogenesis of cardiovascular disorders including hypertension and is one of the most important targets for drugs. A whole body physiologically based pharmacokinetic (wb PBPK) model integrating this hormone circulation system and its inhibition can be used to explore the influence of drugs that interfere with this system, and thus to improve the understanding of interactions between drugs and the target system. In this study, we describe the development of a mechanistic RAAS model and exemplify drug action by a simulation of enalapril administration. Enalapril and its metabolite enalaprilat are potent inhibitors of the angiotensin-converting-enzyme (ACE). To this end, a coupled dynamic parent-metabolite PBPK model was developed and linked with the RAAS model that consists of seven coupled PBPK models for aldosterone, ACE, angiotensin 1, angiotensin 2, angiotensin 2 receptor type 1, renin, and prorenin. The results indicate that the model represents the interactions in the RAAS in response to the pharmacokinetics (PK) and pharmacodynamics (PD) of enalapril and enalaprilat in an accurate manner. The full set of RAAS-hormone profiles and interactions are consistently described at pre- and post-administration steady state as well as during their dynamic transition and show a good agreement with literature data. The model allows a simultaneous representation of the parent-metabolite conversion to the active form as well as the effect of the drug on the hormone levels, offering a detailed mechanistic insight into the hormone cascade and its inhibition. This model constitutes a first major step to establish a PBPK-PD-model including the PK and the mode of action (MoA) of a drug acting on a dynamic RAAS that can be further used to link to clinical endpoints such as blood pressure. PMID:23404365

  17. Semiphysiologically based pharmacokinetic model for midazolam and CYP3A mediated metabolite 1-OH-midazolam in morbidly obese and weight loss surgery patients. (United States)

    Brill, M J E; Välitalo, P A J; Darwich, A S; van Ramshorst, B; van Dongen, H P A; Rostami-Hodjegan, A; Danhof, M; Knibbe, C A J


    This study aimed to describe the pharmacokinetics of midazolam and its cytochrome P450 3A (CYP3A) mediated metabolite 1-OH-midazolam in morbidly obese patients receiving oral and i.v. midazolam before (n = 20) and one year after weight loss surgery (n = 18), thereby providing insight into the influence of weight loss surgery on CYP3A activity in the gut wall and liver. In a semiphysiologically based pharmacokinetic (semi-PBPK) model in which different blood flow scenarios were evaluated, intrinsic hepatic clearance of midazolam (CLint,H) was 2 (95% CI 1.40-1.64) times higher compared to morbidly obese patients before surgery (P Midazolam gut wall clearance (CLint,G) was slightly lower in patients after surgery (P > 0.05), with low values for both groups. The results of the semi-PBPK model suggest that, in patients after weight loss surgery, CYP3A hepatic metabolizing capacity seems to recover compared to morbidly obese patients, whereas CYP3A mediated CLint,G was low for both populations and showed large interindividual variability.

  18. Pooled model-based approach to compare the pharmacokinetics of entecavir between Japanese and non-Japanese chronic hepatitis B patients. (United States)

    Yoshitsugu, Hiroyuki; Sakurai, Takao; Ishikawa, Hiroki; Roy, Amit; Bifano, Marc; Pfister, Marc; Seriu, Taku; Hiraoka, Masaki


    This study evaluated the population pharmacokinetics (PK) of entecavir in Japanese patients with chronic hepatitis B infection enrolled in 2 Japanese phase IIb clinical trials and compared them to non-Japanese patients enrolled in global phase II trials. The objectives were to identify significant and clinically meaningful covariate effects on entecavir population pharmacokinetic parameters and assess whether differences exist between Japanese and non-Japanese patients. A total of 843 observations were obtained from 142 patients who received once daily administration of entecavir at 0.1, 0.5, and 1.0 mg doses in the 2 Japanese studies. Consistent with findings in non-Japanese patients, creatinine clearance estimated with ideal body weight (ICrCL) was found to be statistically significant for clearance in a 2-compartment model. Also, the entecavir dose was identified as a covariate on intercompartmental clearance. Age, gender, and hepatic function were not identified as covariate for clearance. The estimated population average of oral clearance in a typical patient with a reference ICrCL value of 100 mL/min was 26.4 L/h (interindividual variability: 19.4%). This model-based analysis indicates that the PK of entecavir are similar in Japanese and non-Japanese chronic hepatitis B patients.

  19. A model to resolve organochlorine pharmacokinetics in migrating humpback whales. (United States)

    Cropp, Roger; Nash, Susan Bengtson; Hawker, Darryl


    Humpback whales are iconic mammals at the top of the Antarctic food chain. Their large reserves of lipid-rich tissues such as blubber predispose them to accumulation of lipophilic contaminants throughout their lifetime. Changes in the volume and distribution of lipids in humpback whales, particularly during migration, could play an important role in the pharmacokinetics of lipophilic contaminants such as the organochlorine pesticide hexachlorobenzene (HCB). Previous models have examined constant feeding and nonmigratory scenarios. In the present study, the authors develop a novel heuristic model to investigate HCB dynamics in a humpback whale and its environment by coupling an ecosystem nutrient-phytoplankton-zooplankton-detritus (NPZD) model, a dynamic energy budget (DEB) model, and a physiologically based pharmacokinetic (PBPK) model. The model takes into account the seasonal feeding pattern of whales, their energy requirements, and fluctuating contaminant burdens in the supporting plankton food chain. It is applied to a male whale from weaning to maturity, spanning 20 migration and feeding cycles. The model is initialized with environmental HCB burdens similar to those measured in the Southern Ocean and predicts blubber HCB concentrations consistent with empirical concentrations observed in a southern hemisphere population of male, migrating humpback whales. Results show for the first time some important details of the relationship between energy budgets and organochlorine pharmacokinetics.

  20. Physiologically Based Pharmacokinetic Modeling of Tamoxifen and its Metabolites in Women of Different CYP2D6 Phenotypes Provides New Insight into the Tamoxifen Mass Balance (United States)

    Dickschen, Kristin; Willmann, Stefan; Thelen, Kirstin; Lippert, Jörg; Hempel, Georg; Eissing, Thomas


    Tamoxifen is a first-line endocrine agent in the mechanism-based treatment of estrogen receptor positive (ER+) mammary carcinoma and applied to breast cancer patients all over the world. Endoxifen is a secondary and highly active metabolite of tamoxifen that is formed among others by the polymorphic cytochrome P450 2D6 (CYP2D6). It is widely accepted that CYP2D6 poor metabolizers exert a pronounced decrease in endoxifen steady-state plasma concentrations compared to CYP2D6 extensive metabolizers. Nevertheless, an in-depth understanding of the chain of cause and effect between CYP2D6 genotype, endoxifen steady-state plasma concentration, and subsequent tamoxifen treatment benefit still remains to be evolved. In this study, physiologically based pharmacokinetic (PBPK)-modeling was applied to mechanistically investigate the impact of CYP2D6 phenotype on endoxifen formation in female breast cancer patients undergoing tamoxifen therapy. A PBPK-model of tamoxifen and its pharmacologically important metabolites N-desmethyltamoxifen (NDM-TAM), 4-hydroxytamoxifen (4-OH-TAM), and endoxifen was developed and validated. This model is able to simulate the pharmacokinetics (PK) after single and repeated oral tamoxifen doses in female breast cancer patients in dependence of the CYP2D6 phenotype. A detailed model-based analysis of the mass balance offered support for a recent hypothesis stating a more prominent role for endoxifen formation from 4-OH-TAM. In the future this model provides a good basis to further investigate the linkage of PK, mode of action, and treatment outcome in dependence of factors such as phenotype, ethnicity, or co-treatment with CYP2D6 inhibitors. PMID:22661948

  1. Neural network modelling of antifungal activity of a series of oxazole derivatives based on in silico pharmacokinetic parameters

    Directory of Open Access Journals (Sweden)

    Kovačević Strahinja Z.


    Full Text Available In the present paper, the antifungal activity of a series of benzoxazole and oxazolo[ 4,5-b]pyridine derivatives was evaluated against Candida albicans by using quantitative structure-activity relationships chemometric methodology with artificial neural network (ANN regression approach. In vitro antifungal activity of the tested compounds was presented by minimum inhibitory concentration expressed as log(1/cMIC. In silico pharmacokinetic parameters related to absorption, distribution, metabolism and excretion (ADME were calculated for all studied compounds by using PreADMET software. A feedforward back-propagation ANN with gradient descent learning algorithm was applied for modelling of the relationship between ADME descriptors (blood-brain barrier penetration, plasma protein binding, Madin-Darby cell permeability and Caco-2 cell permeability and experimental log(1/cMIC values. A 4-6-1 ANN was developed with the optimum momentum and learning rates of 0.3 and 0.05, respectively. An excellent correlation between experimental antifungal activity and values predicted by the ANN was obtained with a correlation coefficient of 0.9536. [Projekat Ministarstva nauke Republike Srbije, br. 172012 i br. 172014

  2. Metabolite Kinetics: The Segregated Flow Model for Intestinal and Whole Body Physiologically Based Pharmacokinetic Modeling to Describe Intestinal and Hepatic Glucuronidation of Morphine in Rats In Vivo. (United States)

    Yang, Qi Joy; Fan, Jianghong; Chen, Shu; Liu, Lutan; Sun, Huadong; Pang, K Sandy


    We used the intestinal segregated flow model (SFM) versus the traditional model (TM), nested within physiologically based pharmacokinetic (PBPK) models, to describe the biliary and urinary excretion of morphine 3β-glucuronide (MG) after intravenous and intraduodenal dosing of morphine in rats in vivo. The SFM model describes a partial (5%-30%) intestinal blood flow perfusing the transporter- and enzyme-rich enterocyte region, whereas the TM describes 100% flow perfusing the intestine as a whole. For the SFM, drugs entering from the circulation are expected to be metabolized to lesser extents by the intestine due to the segregated flow, reflecting the phenomenon of shunting and route-dependent intestinal metabolism. The poor permeability of MG crossing the liver or intestinal basolateral membranes mandates that most of MG that is excreted into bile is hepatically formed, whereas MG that is excreted into urine originates from both intestine and liver metabolism, since MG is effluxed back to blood. The ratio of MG amounts in urine/bile [Formula: see text] for intraduodenal/intravenous dosing is expected to exceed unity for the SFM but approximates unity for the TM. Compartmental analysis of morphine and MG data, without consideration of the permeability of MG and where MG is formed, suggests the ratio to be 1 and failed to describe the kinetics of MG. The observed intraduodenal/intravenous ratio of [Formula: see text] (2.55 at 4 hours) was better predicted by the SFM-PBPK (2.59 at 4 hours) and not the TM-PBPK (1.0), supporting the view that the SFM is superior for the description of intestinal-liver metabolism of morphine to MG. The SFM-PBPK model predicts an appreciable contribution of the intestine to first pass M metabolism.

  3. A semi-physiologically based pharmacokinetic pharmacodynamic model for glycyrrhizin-induced pseudoaldosteronism and prediction of the dose limit causing hypokalemia in a virtual elderly population.

    Directory of Open Access Journals (Sweden)

    Ruijuan Xu

    Full Text Available Glycyrrhizin (GL is a widely used food additive which can cause severe pseudoaldosteronism at high doses or after a long period of consumption. The aim of the present study was to develop a physiologically based pharmacokinetic (PBPK pharmacodynamic (PD model for GL-induced pseudoaldosteronism to improve the safe use of GL. Since the major metabolite of GL, glycyrrhetic acid (GA, is largely responsible for pseudoaldosteronism via inhibition of the kidney enzyme 11β-hydroxysteroiddehydrogenase 2 (11β-HSD 2, a semi-PBPK model was first developed in rat to predict the systemic pharmacokinetics of and the kidney exposure to GA. A human PBPK model was then developed using parameters either from the rat model or from in vitro studies in combination with essential scaling factors. Kidney exposure to GA was further linked to an Imax model in the 11β-HSD 2 module of the PD model to predict the urinary excretion of cortisol and cortisone. Subsequently, activation of the mineralocorticoid receptor in the renin-angiotensin-aldosterone-electrolyte system was associated with an increased cortisol level. Experimental data for various scenarios were used to optimize and validate the model which was finally able to predict the plasma levels of angiotensin II, aldosterone, potassium and sodium. The Monte Carlo method was applied to predict the probability distribution of the individual dose limits of GL causing pseudoaldosteronism in the elderly according to the distribution of sensitivity factors using serum potassium as an indicator. The critical value of the dose limit was found to be 101 mg with a probability of 3.07%.

  4. Rabbit as an animal model for intravitreal pharmacokinetics: Clinical predictability and quality of the published data. (United States)

    Del Amo, Eva M; Urtti, Arto


    Intravitreal administration is the method of choice in drug delivery to the retina and/or choroid. Rabbit is the most commonly used animal species in intravitreal pharmacokinetics, but it has been criticized as being a poor model of human eye. The critique is based on some anatomical differences, properties of the vitreous humor, and observed differences in drug concentrations in the anterior chamber after intravitreal injections. We have systematically analyzed all published information on intravitreal pharmacokinetics in the rabbit and human eye. The analysis revealed major problems in the design of the pharmacokinetic studies. In this review we provide advice for study design. Overall, the pharmacokinetic parameters (clearance, volume of distribution, half-life) in the human and rabbit eye have good correlation and comparable absolute values. Therefore, reliable rabbit-to-man translation of intravitreal pharmacokinetics should be feasible. The relevant anatomical and physiological parameters in rabbit and man show only small differences. Furthermore, the claimed discrepancy between drug concentrations in the human and rabbit aqueous humor is not supported by the data analysis. Based on the available and properly conducted pharmacokinetic studies, the differences in the vitreous structure in rabbits and human patients do not lead to significant pharmacokinetic differences. This review is the first step towards inter-species translation of intravitreal pharmacokinetics. More information is still needed to dissect the roles of drug delivery systems, disease states, age and ocular manipulation on the intravitreal pharmacokinetics in rabbit and man. Anyway, the published data and the derived pharmacokinetic parameters indicate that the rabbit is a useful animal model in intravitreal pharmacokinetics.

  5. Population Physiologically-Based Pharmacokinetic Modeling for the Human Lactational Transfer of PCB 153 with Consideration of Worldwide Human Biomonitoring Results

    Energy Technology Data Exchange (ETDEWEB)

    Redding, Laurel E.; Sohn, Michael D.; McKone, Thomas E.; Wang, Shu-Li; Hsieh, Dennis P. H.; Yang, Raymond S. H.


    We developed a physiologically based pharmacokinetic model of PCB 153 in women, and predict its transfer via lactation to infants. The model is the first human, population-scale lactational model for PCB 153. Data in the literature provided estimates for model development and for performance assessment. Physiological parameters were taken from a cohort in Taiwan and from reference values in the literature. We estimated partition coefficients based on chemical structure and the lipid content in various body tissues. Using exposure data in Japan, we predicted acquired body burden of PCB 153 at an average childbearing age of 25 years and compare predictions to measurements from studies in multiple countries. Forward-model predictions agree well with human biomonitoring measurements, as represented by summary statistics and uncertainty estimates. The model successfully describes the range of possible PCB 153 dispositions in maternal milk, suggesting a promising option for back estimating doses for various populations. One example of reverse dosimetry modeling was attempted using our PBPK model for possible exposure scenarios in Canadian Inuits who had the highest level of PCB 153 in their milk in the world.

  6. Investigation of an alternative generic model for predicting pharmacokinetic changes during physiological stress. (United States)

    Peng, Henry T; Edginton, Andrea N; Cheung, Bob


    Physiologically based pharmacokinetic models were developed using MATLAB Simulink® and PK-Sim®. We compared the capability and usefulness of these two models by simulating pharmacokinetic changes of midazolam under exercise and heat stress to verify the usefulness of MATLAB Simulink® as a generic PBPK modeling software. Although both models show good agreement with experimental data obtained under resting condition, their predictions of pharmacokinetics changes are less accurate in the stressful conditions. However, MATLAB Simulink® may be more flexible to include physiologically based processes such as oral absorption and simulate various stress parameters such as stress intensity, duration and timing of drug administration to improve model performance. Further work will be conducted to modify algorithms in our generic model developed using MATLAB Simulink® and to investigate pharmacokinetics under other physiological stress such as trauma.

  7. Population pharmacokinetic model for cancer chemoprevention with sulindac in healthy subjects. (United States)

    Berg, Alexander K; Mandrekar, Sumithra J; Ziegler, Katie L Allen; Carlson, Elsa C; Szabo, Eva; Ames, Mathew M; Boring, Daniel; Limburg, Paul J; Reid, Joel M


    Sulindac is a prescription-based non-steroidal anti-inflammatory drug (NSAID) that continues to be actively investigated as a candidate cancer chemoprevention agent. To further current understanding of sulindac bioavailability, metabolism, and disposition, we developed a population pharmacokinetic model for the parent compound and its active metabolites, sulindac sulfide, and exisulind. This analysis was based on data from 24 healthy subjects who participated in a bioequivalence study comparing two formulations of sulindac. The complex disposition of sulindac and its metabolites was described by a seven-compartment model featuring enterohepatic recirculation and is the first reported population pharmacokinetic model for sulindac. The derived model was used to explore effects of clinical variables on sulindac pharmacokinetics and revealed that body weight, creatinine clearance, and gender were significantly correlated with pharmacokinetic parameters. Moreover, the model quantifies the relative bioavailability of the sulindac formulations and illustrates the utility of population pharmacokinetics in bioequivalence assessment. This novel population pharmacokinetic model provides new insights regarding the factors that may affect the pharmacokinetics of sulindac and the exisulind and sulindac sulfide metabolites in generally healthy subjects, which have implications for future chemoprevention trial design for this widely available agent.

  8. Parameter Estimation of Population Pharmacokinetic Models with Stochastic Differential Equations: Implementation of an Estimation Algorithm

    Directory of Open Access Journals (Sweden)

    Fang-Rong Yan


    Full Text Available Population pharmacokinetic (PPK models play a pivotal role in quantitative pharmacology study, which are classically analyzed by nonlinear mixed-effects models based on ordinary differential equations. This paper describes the implementation of SDEs in population pharmacokinetic models, where parameters are estimated by a novel approximation of likelihood function. This approximation is constructed by combining the MCMC method used in nonlinear mixed-effects modeling with the extended Kalman filter used in SDE models. The analysis and simulation results show that the performance of the approximation of likelihood function for mixed-effects SDEs model and analysis of population pharmacokinetic data is reliable. The results suggest that the proposed method is feasible for the analysis of population pharmacokinetic data.

  9. The calculation of human toxicity thresholds of 2,3,7,8-TCDD; A Physiologically Based Pharmacokinetic modeling approach

    NARCIS (Netherlands)

    Zeilmaker MJ; van Eijkeren JCH; LBO


    Dit rapport beschrijft de toepassing van een 'Physiologically Based PharmacoKinetic' model (PBPK model) bij het berekenen van de verwachte 'No Adverse Effect Level' van 2,3,7,8-TetraChloroDibenzo-p-Dioxine (TCDD) bij de mens. Het model houdt rekening met variabiliteit en onzeker

  10. Performance Assessment and Translation of Physiologically Based Pharmacokinetic Models from acslX™ to Berkeley Madonna™, MATLAB®, and R language: Oxytetracycline and Gold Nanoparticles as Case Examples. (United States)

    Lin, Zhoumeng; Jaberi-Douraki, Majid; He, Chunla; Jin, Shiqiang; Yang, Raymond S H; Fisher, Jeffrey W; Riviere, Jim E


    Many physiologically based pharmacokinetic (PBPK) models for environmental chemicals, drugs, and nanomaterials have been developed to aid risk and safety assessments using acslXTM. However, acslXTM has been rendered sunset since November 2015. Alternative modeling tools and tutorials are needed for future PBPK applications. This forum article aimed to: (1) demonstrate the performance of four PBPK modeling software packages (acslXTM, Berkeley MadonnaTM, MATLAB®, and R language) tested using two existing models (oxytetracycline and gold nanoparticles); (2) provide a tutorial of PBPK model code conversion from acslXTM to Berkeley MadonnaTM, MATLAB®, and R language; (3) discuss the advantages and disadvantages of each software package in the implementation of PBPK models in toxicology, and (4) share our perspective about future direction in this field. Simulation results of plasma/tissue concentrations/amounts of oxytetracycline and gold from different models were compared visually and statistically with linear regression analyses. Simulation results from the original models were correlated well with results from the recoded models, with time-concentration/amount curves nearly superimposable and determination coefficients of 0.86-1.00. Step-by-step explanations of the recoding of the models in different software programs are provided in the Supplementary Data. In summary, this article presents a tutorial of PBPK model code conversion for a small molecule and a nanoparticle among four software packages, and a performance comparison of these software packages in PBPK model implementation. This tutorial helps beginners learn PBPK modeling, provides suggestions for selecting a suitable tool for future projects, and may lead to the transition from acslXTM to alternative modeling tools.

  11. Incorporation of Therapeutic Interventions in Physiologically Based Pharmacokinetic Modeling of Human Clinical Case Reports of Accidental or Intentional Overdosing with Ethylene Glycol

    Energy Technology Data Exchange (ETDEWEB)

    Corley, Rick A.; McMartin, K. E.


    Ethylene glycol is a high production volume chemical used in the manufacture of resins and fibers, antifreeze, deicing fluids, heat transfer and hydraulic fluids. Although occupational uses of ethylene glycol have not been associated with adverse effects, there are case reports where humans have either intentionally or accidentally ingested large quantities of ethylene glycol, primarily from antifreeze. The acute toxicity of ethylene glycol in humans and animals and can proceed through three stages, each associated with a different metabolite: central nervous system depression (ethylene glycol), cardiopulmonary effects associated with metabolic acidosis (glycolic acid) and ultimately renal toxicity (oxalic acid), depending upon the total amounts consumed and effectiveness of therapeutic interventions. A physiologically based pharmacokinetic (PBPK) model developed in a companion paper (Corley et al., 2004) was refined in this study to include clinically relevant treatment regimens for ethylene glycol poisoning such as hemodialysis or metabolic inhibition with either ethanol or fomepizole. Such modifications enabled the model to describe several human case reports which included analysis of ethylene glycol and/or glycolic acid. Such data and model simulations provide important confirmation that the PBPK model developed previously can adequately describe the pharmacokinetics of ethylene glycol in humans following low, occupational or environmentally relevant inhalation exposures, as well as massive oral doses even under conditions where treatments have been employed that markedly affect the disposition of ethylene glycol and glycolic acid. By integrating the case report data sets with controlled studies in this PBPK model, it was demonstrated that fomepizole, if administered early enough in a clinical situation, can be more effective than ethanol or hemodialysis in preventing the metabolism of ethylene glycol to more toxic metabolites. Hemodialysis remains an

  12. Use of Physiologically-Based Pharmacokinetic Modeling to Simulate the Profiles of 3-Hydroxybenzo(a)pyrene in Workers Exposed to Polycyclic Aromatic Hydrocarbons (United States)

    Heredia Ortiz, Roberto; Maître, Anne; Barbeau, Damien; Lafontaine, Michel; Bouchard, Michèle


    Biomathematical modeling has become an important tool to assess xenobiotic exposure in humans. In the present study, we have used a human physiologically-based pharmacokinetic (PBPK) model and an simple compartmental toxicokinetic model of benzo(a)pyrene (BaP) kinetics and its 3-hydroxybenzo(a)pyrene (3-OHBaP) metabolite to reproduce the time-course of this biomarker of exposure in the urine of industrially exposed workers and in turn predict the most plausible exposure scenarios. The models were constructed from in vivo experimental data in rats and then extrapolated from animals to humans after assessing and adjusting the most sensitive model parameters as well as species specific physiological parameters. Repeated urinary voids from workers exposed to polycyclic aromatic hydrocarbons (PAHs) have been collected over the course of a typical workweek and during subsequent days off work; urinary concentrations of 3-OHBaP were then determined. Based on the information obtained for each worker (BaP air concentration, daily shift hours, tasks, protective equipment), the time courses of 3-OHBaP in the urine of the different workers have been simulated using the PBPK and toxicokinetic models, considering the various possible exposure routes, oral, dermal and inhalation. Both models were equally able to closely reproduce the observed time course of 3-OHBaP in the urine of workers and predicted similar exposure scenarios. Simulations of various scenarios suggest that the workers under study were exposed mainly by the dermal route. Comparison of measured air concentration levels of BaP with simulated values needed to obtain a good approximation of observed time course further pointed out that inhalation was not the main route of exposure for most of the studied workers. Both kinetic models appear as a useful tool to interpret biomonitoring data of PAH exposure on the basis of 3-OHBaP levels. PMID:25032692

  13. Application of pharmacokinetics local model to evaluate renal function

    Institute of Scientific and Technical Information of China (English)


    The pharmacokinetics local model was used to evaluate renal function.Some typical kinds of renal function cases, normal or disorder, were selected to be imaged with SPECT and those data measured were treated by the pharmacokinetics local model computer program (PLM).The results indicated that parameters, including peak value, peak time, inflexion time, half-excretion time, and kinetic equation played and importantrole in judging renal function.The fact confirms that local model isvery useful in evaluating renal function.

  14. Gene therapy: a pharmacokinetic/pharmacodynamic modelling overview. (United States)

    Parra-Guillén, Zinnia P; González-Aseguinolaza, Gloria; Berraondo, Pedro; Trocóniz, Iñaki F


    Since gene therapy started over 20 years ago, more than one-thousand clinical trials have been carried out. Nonviral vectors present interesting properties for their clinical application, but their efficiency in vivo is relatively low, and further improvements in these vectors are needed. Elucidating how nonviral vectors behave at the intracellular level is enlightening for vector improvement and optimization. Model-based approach is a powerful tool to understand and describe the different processes that gene transfer systems should overcome inside the body. Model-based approach allows for proposing and predicting the effect of parameter changes on the overall gene therapy response, as well as the known application of the pharmacokinetic/pharmacodynamic modelling in conventional therapies. The objective of this paper is to critically review the works in which the time-course of naked or formulated DNA have been quantitatively studied or modelled.

  15. The Application of Global Sensitivity Analysis in the Development of a Physiologically Based Pharmacokinetic Model for m-Xylene and Ethanol Co-Exposure in Humans

    Directory of Open Access Journals (Sweden)

    George D Loizou


    Full Text Available Global sensitivity analysis (SA was used during the development phase of a binary chemical physiologically based pharmacokinetic (PBPK model used for the analysis of m-xylene and ethanol co-exposure in humans. SA was used to identify those parameters which had the most significant impact on variability of venous blood and exhaled m-xylene and urinary excretion of the major metabolite of m-xylene metabolism, 3-methyl hippuric acid. This information informed the selection of parameters for estimation/calibration by fitting to measured biological monitoring (BM data in a Bayesian framework using Markov chain Monte Carlo (MCMC simulation. Data generated in controlled human studies were shown to be useful for investigating the structure and quantitative outputs of PBPK models as well as the biological plausibility and variability of parameters for which measured values were not available. This approach ensured that a priori knowledge in the form of prior distributions was ascribed only to those parameters that were identified as having the greatest impact on variability. This is an efficient approach which helps reduce computational cost.

  16. A Systematic Analysis of the Sensitivity of Plasma Pharmacokinetics to Detect Differences in the Pulmonary Performance of Inhaled Fluticasone Propionate Products Using a Model-Based Simulation Approach


    Weber, Benjamin; Hochhaus, Guenther


    The role of plasma pharmacokinetics (PK) for assessing bioequivalence at the target site, the lung, for orally inhaled drugs remains unclear. A validated semi-mechanistic model, considering the presence of mucociliary clearance in central lung regions, was expanded for quantifying the sensitivity of PK studies in detecting differences in the pulmonary performance (total lung deposition, central-to-peripheral lung deposition ratio, and pulmonary dissolution characteristics) between test (T) an...

  17. Influence of obesity on propofol pharmacokinetics : derivation of a pharmacokinetic model

    NARCIS (Netherlands)

    Cortinez, L. I.; Anderson, B. J.; Penna, A.; Olivares, L.; Munoz, H. R.; Holford, N. H. G.; Struys, M. M. R. F.; Sepulveda, P.


    The objective of this study was to develop a pharmacokinetic (PK) model to characterize the influence of obesity on propofol PK parameters. Nineteen obese ASA II patients undergoing bariatric surgery were studied. Patients received propofol 2 mg kg(-1) bolus dose followed by a 5-20-40-120 min, 10-8-

  18. Using Physiologically-Based Pharmacokinetic Models to Incorporate Chemical and Non-Chemical Stressors into Cumulative Risk Assessment: A Case Study of Pesticide Exposures

    Directory of Open Access Journals (Sweden)

    Jonathan I. Levy


    Full Text Available Cumulative risk assessment has been proposed as an approach to evaluate the health risks associated with simultaneous exposure to multiple chemical and non-chemical stressors. Physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD models can allow for the inclusion and evaluation of multiple stressors, including non-chemical stressors, but studies have not leveraged PBPK/PD models to jointly consider these disparate exposures in a cumulative risk context. In this study, we focused on exposures to organophosphate (OP pesticides for children in urban low-income environments, where these children would be simultaneously exposed to other pesticides (including pyrethroids and non-chemical stressors that may modify the effects of these exposures (including diet. We developed a methodological framework to evaluate chemical and non-chemical stressor impacts on OPs, utilizing an existing PBPK/PD model for chlorpyrifos. We evaluated population-specific stressors that would influence OP doses or acetylcholinesterase (AChE inhibition, the relevant PD outcome. We incorporated the impact of simultaneous exposure to pyrethroids and dietary factors on OP dose through the compartments of metabolism and PD outcome within the PBPK model, and simulated combinations of stressors across multiple exposure ranges and potential body weights. Our analyses demonstrated that both chemical and non-chemical stressors can influence the health implications of OP exposures, with up to 5-fold variability in AChE inhibition across combinations of stressor values for a given OP dose. We demonstrate an approach for modeling OP risks in the presence of other population-specific environmental stressors, providing insight about co-exposures and variability factors that most impact OP health risks and contribute to children’s cumulative health risk from pesticides. More generally, this framework can be used to inform cumulative risk assessment for any compound impacted by

  19. Dynamically simulating the interaction of midazolam and the CYP3A4 inhibitor itraconazole using individual coupled whole-body physiologically-based pharmacokinetic (WB-PBPK models

    Directory of Open Access Journals (Sweden)

    Jang In-Jin


    Full Text Available Abstract Background Drug-drug interactions resulting from the inhibition of an enzymatic process can have serious implications for clinical drug therapy. Quantification of the drugs internal exposure increase upon administration with an inhibitor requires understanding to avoid the drug reaching toxic thresholds. In this study, we aim to predict the effect of the CYP3A4 inhibitors, itraconazole (ITZ and its primary metabolite, hydroxyitraconazole (OH-ITZ on the pharmacokinetics of the anesthetic, midazolam (MDZ and its metabolites, 1' hydroxymidazolam (1OH-MDZ and 1' hydroxymidazolam glucuronide (1OH-MDZ-Glu using mechanistic whole body physiologically-based pharmacokinetic simulation models. The model is build on MDZ, 1OH-MDZ and 1OH-MDZ-Glu plasma concentration time data experimentally determined in 19 CYP3A5 genotyped adult male individuals, who received MDZ intravenously in a basal state. The model is then used to predict MDZ, 1OH-MDZ and 1OH-MDZ-Glu concentrations in an CYP3A-inhibited state following ITZ administration. Results For the basal state model, three linked WB-PBPK models (MDZ, 1OH-MDZ, 1OH-MDZ-Glu for each individual were elimination optimized that resulted in MDZ and metabolite plasma concentration time curves that matched individual observed clinical data. In vivo Km and Vmax optimized values for MDZ hydroxylation were similar to literature based in vitro measures. With the addition of the ITZ/OH-ITZ model to each individual coupled MDZ + metabolite model, the plasma concentration time curves were predicted to greatly increase the exposure of MDZ as well as to both increase exposure and significantly alter the plasma concentration time curves of the MDZ metabolites in comparison to the basal state curves. As compared to the observed clinical data, the inhibited state curves were generally well described although the simulated concentrations tended to exceed the experimental data between approximately 6 to 12 hours following

  20. Physiologically-based pharmacokinetic modeling of tamoxifen and its metabolites in women of different CYP2D6 phenotypes provides new insight into the tamoxifen mass balance

    Directory of Open Access Journals (Sweden)

    Kristin eDickschen


    Full Text Available Tamoxifen is a first-line endocrine agent in the mechanism-based treatment of estrogen receptor positive (ER+ mammary carcinoma and applied to breast cancer patients all over the world. Endoxifen is a secondary and highly active metabolite of tamoxifen that is formed among others by the polymorphic cytochrome P450 2D6 (CYP2D6. It is widely accepted that CYP2D6 poor metabolizers (PM exert a pronounced decrease in endoxifen steady-state plasma concentrations compared to CYP2D6 extensive metabolizers (EM. Nevertheless, an in-depth understanding of the chain of cause and effect between CYP2D6 genotype, endoxifen steady-state plasma concentration, and subsequent tamoxifen treatment benefit still remains to be evolved.In this context, physiologically-based pharmacokinetic (PBPK-modeling provides a useful tool to mechanistically investigate the impact of CYP2D6 phenotype on endoxifen formation in female breast cancer patients undergoing tamoxifen therapy.It has long been thought that only a minor percentage of endoxifen is formed via 4-hydroxytamoxifen. However, the current investigation supports very recently published data that postulates a contribution of 4-hydroxytamoxifen above 20 % to total endoxifen formation. The developed PBPK-model describes tamoxifen PK in rats and humans. Moreover, tamoxifen metabolism in dependence of CYP2D6 phenotype in populations of European female individuals is well described, thus providing a good basis to further investigate the linkage of PK, mode of action, and treatment outcome in dependence of factors such as phenotype, ethnicity or co-treatment with CYP2D6 inhibitors.

  1. Modeling in biopharmaceutics, pharmacokinetics and pharmacodynamics homogeneous and heterogeneous approaches

    CERN Document Server

    Macheras, Panos


    The state of the art in Biopharmaceutics, Pharmacokinetics, and Pharmacodynamics Modeling is presented in this new second edition book. It shows how advanced physical and mathematical methods can expand classical models in order to cover heterogeneous drug-biological processes and therapeutic effects in the body. The book is divided into four parts; the first deals with the fundamental principles of fractals, diffusion and nonlinear dynamics; the second with drug dissolution, release, and absorption; the third with epirical, compartmental, and stochastic pharmacokinetic models, with two new chapters, one on fractional pharmacokinetics and one on bioequivalence; and the fourth mainly with classical and nonclassical aspects of pharmacodynamics. The classical models that have relevance and application to these sciences are also considered throughout. This second edition has new information on reaction limited models of dissolution, non binary biopharmaceutic classification system, time varying models, and interf...

  2. The In Vivo Quantitation of Diazinon, chlorpyrifos, and Their Major Metabolites in Rat Blood for the Refinement of a Physiologically-Based Pharmacokinetic/Pharmacodynamic Models

    Energy Technology Data Exchange (ETDEWEB)

    Busby, A.; Kousba, A.; Timchalk, C.


    Chlorpyrifos (CPF)(O,O-diethyl-O-[3,5,6-trichloro-2-pyridyl]-phosphorothioate, CAS 2921-88-2), and diazinon (DZN)(O,O-diethyl-O-2-isopropyl-4-methyl-6-pyrimidyl thiophosphate, CAS 333-41-5) are commonly encountered organophosphorus insecticides whose oxon metabolites (CPF-oxon and DZN-oxon) have the ability to strongly inhibit acetylcholinesterase, an enzyme responsible for the breakdown of acetylcholine at nerve synapses. Chlorpyrifos-oxon and DZN-oxon are highly unstable compounds that degrade via hepatic, peripheral blood, and intestinal metabolism to the more stable metabolites, TCP (3,5,6-trichloro-2-pyridinol, CAS not assigned) and IMHP (2-isopropyl-6-methyl-4-pyrimidinol, CAS 2814-20-2), respectively. Studies have been performed to understand and model the chronic and acute toxic effects of CPF and DZN individually but little is known about their combined effects. The purpose of this study was to improve physiologically based pharmacokinetic/ pharmacodynamic (PBPK/PD) computational models by quantifying concentrations of CPF and DZN and their metabolites TCP and IMHP in whole rat blood, following exposure to the chemicals individually or as a mixture. Male Sprague-Dawley rats were orally dosed with 60 mg/kg of CPF, DZN, or a mixture of these two pesticides. When administered individually DZN and CPF were seen to reach their maximum concentration at ~3 hours post-dosing. When given as a mixture, both DZN and CPF peak blood concentrations were not achieved until ~6 hours post-dosing and the calculated blood area under the curve (AUC) for both chemicals exceeded those calculated following the single dose. Blood concentrations of IMHP and TCP correlated with these findings. It is proposed that the higher AUC obtained for both CPF and DZN as a mixture resulted from competition for the same metabolic enzyme systems.

  3. A Systematic Analysis of the Sensitivity of Plasma Pharmacokinetics to Detect Differences in the Pulmonary Performance of Inhaled Fluticasone Propionate Products Using a Model-Based Simulation Approach. (United States)

    Weber, Benjamin; Hochhaus, Guenther


    The role of plasma pharmacokinetics (PK) for assessing bioequivalence at the target site, the lung, for orally inhaled drugs remains unclear. A validated semi-mechanistic model, considering the presence of mucociliary clearance in central lung regions, was expanded for quantifying the sensitivity of PK studies in detecting differences in the pulmonary performance (total lung deposition, central-to-peripheral lung deposition ratio, and pulmonary dissolution characteristics) between test (T) and reference (R) inhaled fluticasone propionate (FP) products. PK bioequivalence trials for inhaled FP were simulated based on this PK model for a varying number of subjects and T products. The statistical power to conclude bioequivalence when T and R products are identical was demonstrated to be 90% for approximately 50 subjects. Furthermore, the simulations demonstrated that PK metrics (area under the concentration time curve (AUC) and C max) are capable of detecting differences between T and R formulations of inhaled FP products when the products differ by more than 20%, 30%, and 25% for total lung deposition, central-to-peripheral lung deposition ratio, and pulmonary dissolution characteristics, respectively. These results were derived using a rather conservative risk assessment approach with an error rate of <10%. The simulations thus indicated that PK studies might be a viable alternative to clinical studies comparing pulmonary efficacy biomarkers for slowly dissolving inhaled drugs. PK trials for pulmonary efficacy equivalence testing should be complemented by in vitro studies to avoid false positive bioequivalence assessments that are theoretically possible for some specific scenarios. Moreover, a user-friendly web application for simulating such PK equivalence trials with inhaled FP is provided.

  4. In vitro-in vivo Pharmacokinetic correlation model for quality assurance of antiretroviral drugs

    Directory of Open Access Journals (Sweden)

    Ricardo Rojas Gómez


    Full Text Available Introduction: The in vitro-in vivo pharmacokinetic correlation models (IVIVC are a fundamental part of the drug discovery and development process. The ability to accurately predict the in vivo pharmacokinetic profile of a drug based on in vitro observations can have several applications during a successful development process. Objective: To develop a comprehensive model to predict the in vivo absorption of antiretroviral drugs based on permeability studies, in vitro and in vivo solubility and demonstrate its correlation with the pharmacokinetic profile in humans. Methods: Analytical tools to test the biopharmaceutical properties of stavudine, lamivudine y zidovudine were developed. The kinetics of dissolution, permeability in caco-2 cells and pharmacokinetics of absorption in rabbits and healthy volunteers were evaluated. Results: The cumulative areas under the curve (AUC obtained in the permeability study with Caco-2 cells, the dissolution study and the pharmacokinetics in rabbits correlated with the cumulative AUC values in humans. These results demonstrated a direct relation between in vitro data and absorption, both in humans and in the in vivo model. Conclusions: The analytical methods and procedures applied to the development of an IVIVC model showed a strong correlation among themselves. These IVIVC models are proposed as alternative and cost/effective methods to evaluate the biopharmaceutical properties that determine the bioavailability of a drug and their application includes the development process, quality assurance, bioequivalence studies and pharmacosurveillance. 

  5. Pharmacokinetics of Remifentanil: a three-compartmental modeling approach (United States)

    Cascone, Sara; Lamberti, Gaetano; Titomanlio, Giuseppe; Piazza, Ornella

    Remifentanil is a new opioid derivative drug characterized by a fast onset and by a short time of action, since it is rapidly degraded by esterases in blood and other tissues. Its pharmacokinetic and pharmacodynamics properties make remifentanil a very interesting molecule in the field of 0anesthesia. However a complete and versatile pharmacokinetic description of remifentanil still lacks. In this work a three-compartmental model has been developed to describe the pharmacokinetics of remifentanil both in the case in which it is administered by intravenous constant-rate infusion and by bolus injection. The model curves have been compared with experimental data published in scientific papers and the model parameters have been optimized to describe both ways of administration. The ad hoc model is adaptable and potentially useful for predictive purposes. PMID:24251247

  6. Population pharmacokinetic and pharmacodynamic modeling and simulation of the investigational anticancer agent indisulam

    NARCIS (Netherlands)

    Zandvliet, A.S.


    Indisulam is an investigational anticancer agent that is currently being evaluated in phase II clinical studies. The aim of this thesis was to develop a mechanism-based pharmacokinetic and pharmacodynamic model for indisulam-induced myelosuppression and to apply this model as a tool for treatment op

  7. Integrated semi-physiological pharmacokinetic model for both sunitinib and its active metabolite SU12662

    NARCIS (Netherlands)

    Yu, H.; Steeghs, N.; Kloth, J.S.; Wit, D. de; Hasselt, J.G. van; Erp, N. van; Beijnen, J.H.; Schellens, J.H.; Mathijssen, R.H.; Huitema, A.D.


    AIMS: Previously published pharmacokinetic (PK) models for sunitinib and its active metabolite SU12662 were based on a limited dataset or lacked important elements such as correlations between sunitinib and its metabolite. The current study aimed to develop an improved PK model that circumvented the

  8. Two-Compartment Pharmacokinetic Models for Chemical Engineers (United States)

    Kanneganti, Kumud; Simon, Laurent


    The transport of potassium permanganate between two continuous-stirred vessels was investigated to help chemical and biomedical engineering students understand two-compartment pharmacokinetic models. Concepts of modeling, mass balance, parameter estimation and Laplace transform were applied to the two-unit process. A good agreement was achieved…

  9. Nephrectomized and hepatectomized animal models as tools in preclinical pharmacokinetics. (United States)

    Vestergaard, Bill; Agersø, Henrik; Lykkesfeldt, Jens


    Early understanding of the pharmacokinetics and metabolic patterns of new drug candidates is essential for selection of optimal candidates to move further in to the drug development process. In vitro methodologies can be used to investigate metabolic patterns, but in general, they lack several aspects of the whole-body physiology. In contrast, the complexity of intact animals does not necessarily allow individual processes to be identified. Animal models lacking a major excretion organ can be used to investigate these individual metabolic processes. Animal models of nephrectomy and hepatectomy have considerable potential as tools in preclinical pharmacokinetics to assess organs of importance for drug clearance and thereby knowledge of potential metabolic processes to manipulate to improve pharmacokinetic properties of the molecules. Detailed knowledge of anatomy and surgical techniques is crucial to successfully establish the models, and a well-balanced anaesthesia and adequate monitoring of the animals are also of major importance. An obvious drawback of animal models lacking an organ is the disruption of normal homoeostasis and the induction of dramatic and ultimately mortal systemic changes in the animals. Refining of the surgical techniques and the post-operative supportive care of the animals can increase the value of these models by minimizing the systemic changes induced, and thorough validation of nephrectomy and hepatectomy models is needed before use of such models as a tool in preclinical pharmacokinetics. The present MiniReview discusses pros and cons of the available techniques associated with establishing nephrectomy and hepatectomy models.


    Deltamethrin (DLT) is a Type II pyrethroid insecticide widely used in agriculture and public health. DLT is a potent neurotoxin that is primarily cleared from the body by metabolism. To better understand the dosimetry of DLT in the central nervous system, a physiologically based ...

  11. The effect of azithromycin on ivermectin pharmacokinetics--a population pharmacokinetic model analysis.

    Directory of Open Access Journals (Sweden)

    Ahmed El-Tahtawy

    Full Text Available BACKGROUND: A recent drug interaction study reported that when azithromycin was administered with the combination of ivermectin and albendazole, there were modest increases in ivermectin pharmacokinetic parameters. Data from this study were reanalyzed to further explore this observation. A compartmental model was developed and 1,000 interaction studies were simulated to explore extreme high ivermectin values that might occur. METHODS AND FINDINGS: A two-compartment pharmacokinetic model with first-order elimination and absorption was developed. The chosen final model had 7 fixed-effect parameters and 8 random-effect parameters. Because some of the modeling parameters and their variances were not distributed normally, a second mixture model was developed to further explore these data. The mixture model had two additional fixed parameters and identified two populations, A (55% of subjects, where there was no change in bioavailability, and B (45% of subjects, where ivermectin bioavailability was increased 37%. Simulations of the data using both models were similar, and showed that the highest ivermectin concentrations fell in the range of 115-201 ng/mL. CONCLUSIONS: This is the first pharmacokinetic model of ivermectin. It demonstrates the utility of two modeling approaches to explore drug interactions, especially where there may be population heterogeneity. The mechanism for the interaction was identified (an increase in bioavailability in one subpopulation. Simulations show that the maximum ivermectin exposures that might be observed during co-administration with azithromycin are below those previously shown to be safe and well tolerated. These analyses support further study of co-administration of azithromycin with the widely used agents ivermectin and albendazole, under field conditions in disease control programs.

  12. Providing a Theoretical Basis for Nanotoxicity Risk Analysis Departing from Traditional Physiologically-Based Pharmacokinetic (PBPK) Modeling (United States)


    perfused tissue representation in STELLA R⃝ 131 Aspt u14SPT to Venous Cvspt P Qspt Arterial to SPT Vspt Cspt Ca Slowly Perfused Tissue - 15 - (a...5 - Cintra 5/Pintra2extra) Active Transp 5 =Vmaxe2i× Cextra 5 / (Kme2i + Cextra 5) 153 SPT ODEs Aspt u14SPT to Venous Cvspt P Qspt Arterial to SPT...Kme2i Vintraspt Cintra 6 Pintra2extra Vmaxi2e Kmi2e SPT - 16 - (b) SPT expanded Figure 74. SPT IE and expanded models in STELLA R⃝ SPT IE. d( Aspt u14

  13. PKreport: report generation for checking population pharmacokinetic model assumptions

    Directory of Open Access Journals (Sweden)

    Li Jun


    Full Text Available Abstract Background Graphics play an important and unique role in population pharmacokinetic (PopPK model building by exploring hidden structure among data before modeling, evaluating model fit, and validating results after modeling. Results The work described in this paper is about a new R package called PKreport, which is able to generate a collection of plots and statistics for testing model assumptions, visualizing data and diagnosing models. The metric system is utilized as the currency for communicating between data sets and the package to generate special-purpose plots. It provides ways to match output from diverse software such as NONMEM, Monolix, R nlme package, etc. The package is implemented with S4 class hierarchy, and offers an efficient way to access the output from NONMEM 7. The final reports take advantage of the web browser as user interface to manage and visualize plots. Conclusions PKreport provides 1 a flexible and efficient R class to store and retrieve NONMEM 7 output, 2 automate plots for users to visualize data and models, 3 automatically generated R scripts that are used to create the plots; 4 an archive-oriented management tool for users to store, retrieve and modify figures, 5 high-quality graphs based on the R packages, lattice and ggplot2. The general architecture, running environment and statistical methods can be readily extended with R class hierarchy. PKreport is free to download at

  14. PKgraph: an R package for graphically diagnosing population pharmacokinetic models. (United States)

    Sun, Xiaoyong; Wu, Kai; Cook, Dianne


    Population pharmacokinetic (PopPK) modeling has become increasing important in drug development because it handles unbalanced design, sparse data and the study of individual variation. However, the increased complexity of the model makes it more of a challenge to diagnose the fit. Graphics can play an important and unique role in PopPK model diagnostics. The software described in this paper, PKgraph, provides a graphical user interface for PopPK model diagnosis. It also provides an integrated and comprehensive platform for the analysis of pharmacokinetic data including exploratory data analysis, goodness of model fit, model validation and model comparison. Results from a variety of modeling fitting software, including NONMEM, Monolix, SAS and R, can be used. PKgraph is programmed in R, and uses the R packages lattice, ggplot2 for static graphics, and rggobi for interactive graphics.

  15. Pharmacokinetic Modeling of Intranasal Scopolamine in Plasma Saliva and Urine (United States)

    Wu, L.; Tam, V. H.; Chow, D. S. L.; Putcha, L.


    An intranasal gel dosage formulation of scopolamine (INSCOP) was developed for the treatment of Space Motion Sickness (SMS). The bioavailability and pharmacokinetics (PK) were evaluated under IND (Investigational New Drug) guidelines. The aim of the project was to develop a PK model that can predict the relationships among plasma, saliva and urinary scopolamine concentrations using data collected from the IND clinical trial protocol with INSCOP. Twelve healthy human subjects were administered at three dose levels (0.1, 0.2 and 0.4 mg) of INSCOP. Serial blood, saliva and urine samples were collected between 5 min to 24 h after dosing and scopolamine concentrations were measured by using a validated LC-MS-MS assay. PK compartmental models, using actual dosing and sampling time, were established using Phoenix (version 1.2). Model selection was based on a likelihood ratio test on the difference of criteria (-2LL (i.e. log-likelihood ratio test)) and comparison of the quality of fit plots. The results: Predictable correlations among scopolamine concentrations in compartments of plasma, saliva and urine were established, and for the first time the model satisfactorily predicted the population and individual PK of INSCOP in plasma, saliva and urine. The model can be utilized to predict the INSCOP plasma concentration by saliva and urine data, and it will be useful for monitoring the PK of scopolamine in space and other remote environments using non-invasive sampling of saliva and/or urine.

  16. Modeling in biopharmaceutics, pharmacokinetics, and pharmacodynamics homogeneous and heterogeneous approaches

    CERN Document Server

    Macheras, Panos


    The state of the art in Biopharmaceutics, Pharmacokinetics, and Pharmacodynamics Modeling is presented in this book. It shows how advanced physical and mathematical methods can expand classical models in order to cover heterogeneous drug-biological processes and therapeutic effects in the body. The book is divided into four parts; the first deals with the fundamental principles of fractals, diffusion and nonlinear dynamics; the second with drug dissolution, release, and absorption; the third with empirical, compartmental, and stochastic pharmacokinetic models, and the fourth mainly with nonclassical aspects of pharmacodynamics. The classical models that have relevance and application to these sciences are also considered throughout. Many examples are used to illustrate the intrinsic complexity of drug administration related phenomena in the human, justifying the use of advanced modeling methods. This timely and useful book will appeal to graduate students and researchers in pharmacology, pharmaceutical scienc...

  17. Characterization of preclinical in vitro and in vivo ADME properties and prediction of human PK using a physiologically based pharmacokinetic model for YQA-14, a new dopamine D3 receptor antagonist candidate for treatment of drug addiction. (United States)

    Liu, Fei; Zhuang, Xiaomei; Yang, Cuiping; Li, Zheng; Xiong, Shan; Zhang, Zhiwei; Li, Jin; Lu, Chuang; Zhang, Zhenqing


    YQA-14 is a novel and selective dopamine D3 receptor antagonist, with potential for the treatment of drug addiction. However, earlier compounds in its structural class tend to have poor oral bioavailability. The objectives of this study were to characterize the preclinical absorption, distribution, metabolism and excretion (ADME) properties and pharmacokinetics (PK) of YQA-14, then to simulate the clinical PK of YQA-14 using a physiologically based pharmacokinetics (PBPK) model to assess the likelihood of developing YQA-14 as a clinical candidate. For human PK prediction, PBPK models were first built in preclinical species, rats and dogs, for validation purposes. The model was then modified by input of human in vitro ADME data obtained from in vitro studies. The study data showed that YQA-14 is a basic lipophilic compound, with rapid absorption (Tmax ~ 1 h) in both rats and dogs. Liver microsomal clearances and in vivo clearances were moderate in rats and dogs consistent with the moderate bioavailability observed in both species. The PBPK models built for rats and dogs simulated the observed PK data well in both species. The PBPK model refined with human data predicted that YQA-14 would have a clearance of 8.0 ml/min/kg, a volume distribution of 1.7 l/kg and a bioavailability of 16.9%. These acceptable PK properties make YQA-14 an improved candidate for further research and development as a potential dopamine D3R antagonism for the treatment of drug addiction in the clinic.

  18. Development of a Rat Plasma and Brain Extracellular Fluid Pharmacokinetic Model for Bupropion and Hydroxybupropion Based on Microdialysis Sampling, and Application to Predict Human Brain Concentrations. (United States)

    Cremers, Thomas I F H; Flik, Gunnar; Folgering, Joost H A; Rollema, Hans; Stratford, Robert E


    Administration of bupropion [(±)-2-(tert-butylamino)-1-(3-chlorophenyl)propan-1-one] and its preformed active metabolite, hydroxybupropion [(±)-1-(3-chlorophenyl)-2-[(1-hydroxy-2-methyl-2-propanyl)amino]-1-propanone], to rats with measurement of unbound concentrations by quantitative microdialysis sampling of plasma and brain extracellular fluid was used to develop a compartmental pharmacokinetics model to describe the blood-brain barrier transport of both substances. The population model revealed rapid equilibration of both entities across the blood-brain barrier, with resultant steady-state brain extracellular fluid/plasma unbound concentration ratio estimates of 1.9 and 1.7 for bupropion and hydroxybupropion, respectively, which is thus indicative of a net uptake asymmetry. An overshoot of the brain extracellular fluid/plasma unbound concentration ratio at early time points was observed with bupropion; this was modeled as a time-dependent uptake clearance of the drug across the blood-brain barrier. Translation of the model was used to predict bupropion and hydroxybupropion exposure in human brain extracellular fluid after twice-daily administration of 150 mg bupropion. Predicted concentrations indicate that preferential inhibition of the dopamine and norepinephrine transporters by the metabolite, with little to no contribution by bupropion, would be expected at this therapeutic dose. Therefore, these results extend nuclear imaging studies on dopamine transporter occupancy and suggest that inhibition of both transporters contributes significantly to bupropion's therapeutic efficacy.

  19. Dose Assessment of Cefquinome by Pharmacokinetic/Pharmacodynamic Modeling in Mouse Model of Staphylococcus aureus Mastitis (United States)

    Yu, Yang; Zhou, Yu-Feng; Li, Xiao; Chen, Mei-Ren; Qiao, Gui-Lin; Sun, Jian; Liao, Xiao-Ping; Liu, Ya-Hong


    This work aimed to characterize the mammary gland pharmacokinetics of cefquinome after an intramammary administration and integrate pharmacokinetic/pharmacodynamic model. The pharmacokinetic profiles of cefquinome in gland tissue were measured using high performance liquid chromatograph. Therapeutic regimens covered various dosages ranging from 25 to 800 μg/gland and multiple dosing intervals of 8, 12, and 24 h. The in vivo bacterial killing activity elevated when dosage increased or when dosing intervals were shortened. The best antibacterial effect was demonstrated by a mean 1.5 log10CFU/gland visible count reduction. On the other hand, the results showed that the percentage of time duration of drug concentration exceeding the MIC during a dose interval (%T > MIC) was generally 100% because of the influence of drug distribution caused by the blood-milk barrier. Therefore, pharmacokinetic/pharmacodynamic parameter of the ratio of area under the concentration-time curve over 24 h to the MIC (AUC0-24/MIC) was used to describe the efficacy of cefquinome instead of %T > MIC. When the magnitude of AUC0-24/MIC exceeding 16571.55 h⋅mL/g, considerable activity of about 1.5 log10CFU/g gland bacterial count reduction was observed in vivo. Based on the Monte Carlo simulation, the clinical recommended regimen of three infusions of 75 mg per quarter every 12 h can achieve a 76.67% cure rate in clinical treatment of bovine mastitis caused by Staphylococcus aureus infection. PMID:27774090

  20. Population Pharmacokinetic Model for Cancer Chemoprevention With Sulindac in Healthy Subjects


    Berg, Alexander K.; Mandrekar, Sumithra J.; Ziegler, Katie L. Allen; Carlson, Elsa C.; Szabo, Eva; Ames, Mathew M.; Boring, Daniel; Limburg, Paul J.; Reid, Joel M.


    Sulindac is a prescription-based non-steroidal anti-inflammatory drug (NSAID) that continues to be actively investigated as a candidate cancer chemoprevention agent. To further current understanding of sulindac bioavailability, metabolism, and disposition, we developed a population pharmacokinetic model for the parent compound and its active metabolites, sulindac sulfide, and exisulind. This analysis was based on data from 24 healthy subjects who participated in a bioequivalence study compari...

  1. Application of pharmacokinetic/pharmacodynamic modelling and simulation for the prediction of target attainment of ceftobiprole against meticillin-resistant Staphylococcus aureus using minimum inhibitory concentration and time-kill curve based approaches. (United States)

    Barbour, April M; Schmidt, Stephan; Zhuang, Luning; Rand, Kenneth; Derendorf, Hartmut


    The purpose of this report was to compare two different methods for dose optimisation of antimicrobials. The probability of target attainment (PTA) was calculated using Monte Carlo simulation to predict the PK/PD target of fT>MIC or modelling and simulation of time-kill curve data. Ceftobiprole, the paradigm compound, activity against two MRSA strains was determined, ATCC 33591 (MIC=2mg/L) and a clinical isolate (MIC=1mg/L). A two-subpopulation model accounting for drug degradation during the experiment adequately fit the time-kill curve data (concentration range 0.25-16× MIC). The PTA was calculated for plasma, skeletal muscle and subcutaneous adipose tissue based on data from a microdialysis study in healthy volunteers. A two-compartment model with distribution factors to account for differences between free serum and tissue interstitial space fluid concentration appropriately fit the pharmacokinetic data. Pharmacodynamic endpoints of fT>MIC of 30% or 40% and 1- or 2-log kill were used. The PTA was >90% in all tissues based on the PK/PD endpoint of fT>MIC >40%. The PTAs based on a 1- or 2-log kill from the time-kill experiments were lower than those calculated based on fT>MIC. The PTA of a 1-log kill was >90% for both MRSA isolates for plasma and skeletal muscle but was slightly below 90% for subcutaneous adipose tissue (both isolates ca. 88%). The results support a dosing regimen of 500mg three times daily as a 2-h intravenous infusion. This dose should be confirmed as additional pharmacokinetic data from various patient populations become available.

  2. Pharmacokinetics and pharmacokinetic-dynamic modelling of rocuronium in infants and children

    NARCIS (Netherlands)

    Wierda, J.MKH; Meretoja, O.A; Taivainen, T; Proost, Hans


    We have determined the pharmacokinetics and pharmacokinetic-pharmacodynamic relationship of rocuronium in infants and children. We studied infants (n = 5, 0.1-0.8 yr) and children (n = 5, 2.3-8 yr), ASA II, in the ICU while undergoing artificial ventilation under i.v. anaesthesia with an arterial ca

  3. Review of pharmacokinetic models for target controlled infusions in anesthesia

    Directory of Open Access Journals (Sweden)

    Subash Kennedy Sivasubramaniam


    Full Text Available Intravenous injection of anesthetic drugs dates back to the 17th Century when opium and chloral hydrate have been injected intravenously. It was not until the 1930s intravenous anesthesia became popular with the invention of barbiturates.Early intravenous anesthetic agents such as barbiturates were ideal for induction of anesthesia, but not suitable for maintenance of anesthesia. Most of these drugs accumulated significantly with increasing durations of infusion and also resulted in cardiorespiratory depression. The invention of propofol and shorter acting opioid analgesics such as remifentanil and alfentanil have revolutionized intravenous anesthesia. The rapid onset and offset of these drugs lends itself to being suitable agents for maintenance of anesthesia over prolonged periods of time. Detailed understanding of the pharmacokinetics of propofol and remifentanil, combined with technological advances in intravenous pumps capable of accurate delivery of drugs have resulted in great development of the field of total intravenous anesthesia and target controlled infusions. I would like to discuss, in this article, the pharmacokinetics and pharmacokinetic models behind these intravenous infusion pumps. [Int J Basic Clin Pharmacol 2014; 3(3.000: 417-423

  4. Prediction of a potentially effective dose in humans for BAY 60–5521, a potent inhibitor of cholesteryl ester transfer protein (CETP) by allometric species scaling and combined pharmacodynamic and physiologically-based pharmacokinetic modelling (United States)

    Weber, Olaf; Willmann, Stefan; Bischoff, Hilmar; Li, Volkhart; Vakalopoulos, Alexandros; Lustig, Klemens; Hafner, Frank-Thorsten; Heinig, Roland; Schmeck, Carsten; Buehner, Klaus


    AIMS The purpose of this work was to support the prediction of a potentially effective dose for the CETP-inhibitor, BAY 60–5521, in humans. METHODS A combination of allometric scaling of the pharmacokinetics of the CETP-inhibitor BAY 60–5521 with pharmacodynamic studies in CETP-transgenic mice and in human plasma with physiologically-based pharmacokinetic (PBPK) modelling was used to support the selection of the first-in-man dose. RESULTS The PBPK approach predicts a greater extent of distribution for BAY 60–5521 in humans compared with the allometric scaling method as reflected by a larger predicted volume of distribution and longer elimination half-life. The combined approach led to an estimate of a potentially effective dose for BAY 60–5521 of 51 mg in humans. CONCLUSION The approach described in this paper supported the prediction of a potentially effective dose for the CETP-inhibitor BAY 60–5521 in humans. Confirmation of the dose estimate was obtained in a first-in-man study. PMID:21762205

  5. Evaluation of methods for estimating population pharmacokinetics parameters. I. Michaelis-Menten model: routine clinical pharmacokinetic data. (United States)

    Sheiner, L B; Beal, S L


    Individual pharmacokinetic par parameters quantify the pharmacokinetics of an individual, while population pharmacokinetic parameters quantify population mean kinetics, interindividual variability, and residual intraindividual variability plus measurement error. Individual pharmacokinetics are estimated by fitting individual data to a pharmacokinetic model. Population pharmacokinetic parameters are estimated either by fitting all individual's data together as though there was no individual kinetic differences (the naive pooled data approach), or by fitting each individual's data separately, and then combining the individual parameter estimates (the two-stage approach). A third approach, NONMEM, takes a middle course between these, and avoids shortcomings of each of them. A data set consisting of 124 steady-state phenytoin concentration-dosage pairs from 49 patients, obtained in the routine course of their therapy, was analyzed by each method. The resulting population parameter estimates differ considerably (population mean Km, for example, is estimated as 1.57, 5.36, and 4.44 micrograms/ml by the naive pooled data, two-stage, and NONMEN approaches, respectively). Simulations of the data were analyzed to investigate these differences. The simulations indicate that the pooled data approach fails to estimate variabilities and produces imprecise estimates of mean kinetics. The two-stage approach produces good estimates of mean kinetics, but biased and imprecise estimates of interindividual variability. NONMEN produces accurate and precise estimates of all parameters, and also reasonable confidence intervals for them. This performance is exactly what is expected from theoretical considerations and provides empirical support for the use of NONMEM when estimating population pharmacokinetics from routine type patient data.

  6. Pharmacokinetic-pharmacodynamic modeling of diclofenac in normal and Freund's complete adjuvant-induced arthritic rats


    Zhang, Jing; Li, Pei; Guo, Hai-fang; Liu, Li; Liu, Xiao-dong


    Aim: To characterize pharmacokinetic-pharmacodynamic modeling of diclofenac in Freund's complete adjuvant (FCA)-induced arthritic rats using prostaglandin E2 (PGE2) as a biomarker. Methods: The pharmacokinetics of diclofenac was investigated using 20-day-old arthritic rats. PGE2 level in the rats was measured using an enzyme immunoassay. A pharmacokinetic-pharmacodynamic (PK-PD) model was developed to illustrate the relationship between the plasma concentration of diclofenac and the inhibitio...

  7. Nonparametric Bayes approach for a semi-mechanistic pharmacokinetic and pharmacodynamic model (United States)

    Dong, Yan

    Both frequentist and Bayesian approaches have been used to characterize population pharmacokinetics and pharmacodynamics(PK/PD) models. These methods focus on estimating the population parameters and assessing the association between the characteristics of PK/PD and the subject covariates. In this work, we propose a Dirichlet process mixture model to classify the patients based on their individualized pharmacokinetic and pharmacodynamic profiles. Then we can predict the new patients' dose-response curves given their concentration-time profiles. Additionally, we implement a modern Markov Chain Monte Carlo algorithm for sampling inference of parameters. The detailed sampling procedures as well as the results are discussed in a simulation data and a real data example. We also evaluate an approximate solution of a system of nonlinear differential equations from Euler's method and compare the results with a general numerical solver, ode from R package, deSolve.

  8. Paediatric pharmacokinetics: key considerations (United States)

    Batchelor, Hannah Katharine; Marriott, John Francis


    A number of anatomical and physiological factors determine the pharmacokinetic profile of a drug. Differences in physiology in paediatric populations compared with adults can influence the concentration of drug within the plasma or tissue. Healthcare professionals need to be aware of anatomical and physiological changes that affect pharmacokinetic profiles of drugs to understand consequences of dose adjustments in infants and children. Pharmacokinetic clinical trials in children are complicated owing to the limitations on blood sample volumes and perception of pain in children resulting from blood sampling. There are alternative sampling techniques that can minimize the invasive nature of such trials. Population based models can also limit the sampling required from each individual by increasing the overall sample size to generate robust pharmacokinetic data. This review details key considerations in the design and development of paediatric pharmacokinetic clinical trials. PMID:25855821

  9. Drug-drug interactions between moxifloxacin and rifampicin based on pharmacokinetics in vivo in rats. (United States)

    Huang, Lifei; Liu, Jiajun; Yu, Xin; Shi, Lei; Liu, Jian; Xiao, Heping; Huang, Yi


    Moxifloxacin and rifampicin are all the first-line options for the treatment of active tuberculosis, which are often combined for the treatment of multidrug resistance pulmonary tuberculosis in clinic. However, the potential drug-drug interactions between moxifloxacin and rifampicin were unknown. The aim of this study was to investigate the drug-drug interactions between moxifloxacin and rifampicin based on their pharmacokinetics in vivo after oral administration of the single drug and both drugs, and reveal their mutual effects on their pharmacokinetics. Eighteen male Sprague-Dawley rats were randomly assigned to three groups: moxifloxacin group, rifampicin group and moxifloxacin + rifampicin group. Plasma concentrations of moxifloxacin and rifampicin were determined using LC-MS at the designated time points after drug administration, and the main pharmacokinetic parameters were calculated. In addition, effects of moxifloxacin and rifampicin on their metabolic rate and absorption were investigated using rat liver microsome incubation systems and Caco-2 cell transwell model. The main pharmacokinetic parameters of moxifloxacin including Tmax , Cmax , t1/2 and AUC(0-t) increased more in the moxifloxacin + rifampicin group than in the moxifloxacin group, but the difference was not significant (p > 0.05). However, the pharmacokinetic parameters of rifampicin, including peak concentration, area under the concentration-time curve, half-life and the area under the first moment plasma concentration-time curve, increased significantly (p 0.05). The rat liver microsome incubation experiment indicated that moxifloxacin could increase the metabolic rate of rifampicin from 23.7 to 38.7 min. However, the Caco-2 cell transwell experiment showed that moxifloxacin could not affect the absorption rate of rifampicin. These changes could enhance the drug efficacy, but they could also cause drug accumulation, which might induce adverse effect, so it was suggested that the drug dosage

  10. Application of Bayesian population physiologically based pharmacokinetic (PBPK) modeling and Markov chain Monte Carlo simulations to pesticide kinetics studies in protected marine mammals: DDT, DDE, and DDD in harbor porpoises. (United States)

    Weijs, Liesbeth; Yang, Raymond S H; Das, Krishna; Covaci, Adrian; Blust, Ronny


    Physiologically based pharmacokinetic (PBPK) modeling in marine mammals is a challenge because of the lack of parameter information and the ban on exposure experiments. To minimize uncertainty and variability, parameter estimation methods are required for the development of reliable PBPK models. The present study is the first to develop PBPK models for the lifetime bioaccumulation of p,p'-DDT, p,p'-DDE, and p,p'-DDD in harbor porpoises. In addition, this study is also the first to apply the Bayesian approach executed with Markov chain Monte Carlo simulations using two data sets of harbor porpoises from the Black and North Seas. Parameters from the literature were used as priors for the first "model update" using the Black Sea data set, the resulting posterior parameters were then used as priors for the second "model update" using the North Sea data set. As such, PBPK models with parameters specific for harbor porpoises could be strengthened with more robust probability distributions. As the science and biomonitoring effort progress in this area, more data sets will become available to further strengthen and update the parameters in the PBPK models for harbor porpoises as a species anywhere in the world. Further, such an approach could very well be extended to other protected marine mammals.

  11. Pharmacokinetic properties and in silico ADME modeling in drug discovery. (United States)

    Honório, Kathia M; Moda, Tiago L; Andricopulo, Adriano D


    The discovery and development of a new drug are time-consuming, difficult and expensive. This complex process has evolved from classical methods into an integration of modern technologies and innovative strategies addressed to the design of new chemical entities to treat a variety of diseases. The development of new drug candidates is often limited by initial compounds lacking reasonable chemical and biological properties for further lead optimization. Huge libraries of compounds are frequently selected for biological screening using a variety of techniques and standard models to assess potency, affinity and selectivity. In this context, it is very important to study the pharmacokinetic profile of the compounds under investigation. Recent advances have been made in the collection of data and the development of models to assess and predict pharmacokinetic properties (ADME--absorption, distribution, metabolism and excretion) of bioactive compounds in the early stages of drug discovery projects. This paper provides a brief perspective on the evolution of in silico ADME tools, addressing challenges, limitations, and opportunities in medicinal chemistry.

  12. Pharmacokinetic modeling of ascorbate diffusion through normal and tumor tissue. (United States)

    Kuiper, Caroline; Vissers, Margreet C M; Hicks, Kevin O


    Ascorbate is delivered to cells via the vasculature, but its ability to penetrate into tissues remote from blood vessels is unknown. This is particularly relevant to solid tumors, which often contain regions with dysfunctional vasculature, with impaired oxygen and nutrient delivery, resulting in upregulation of the hypoxic response and also the likely depletion of essential plasma-derived biomolecules, such as ascorbate. In this study, we have utilized a well-established multicell-layered, three-dimensional pharmacokinetic model to measure ascorbate diffusion and transport parameters through dense tissue in vitro. Ascorbate was found to penetrate the tissue at a slightly lower rate than mannitol and to travel via the paracellular route. Uptake parameters into the cells were also determined. These data were fitted to the diffusion model, and simulations of ascorbate pharmacokinetics in normal tissue and in hypoxic tumor tissue were performed with varying input concentrations, ranging from normal dietary plasma levels (10-100 μM) to pharmacological levels (>1 mM) as seen with intravenous infusion. The data and simulations demonstrate heterogeneous distribution of ascorbate in tumor tissue at physiological blood levels and provide insight into the range of plasma ascorbate concentrations and exposure times needed to saturate all regions of a tumor. The predictions suggest that supraphysiological plasma ascorbate concentrations (>100 μM) are required to achieve effective delivery of ascorbate to poorly vascularized tumor tissue.

  13. PKQuest_Java: free, interactive physiologically based pharmacokinetic software package and tutorial

    Directory of Open Access Journals (Sweden)

    Levitt David G


    Full Text Available Abstract Background Physiologically based pharmacokinetics (PBPK uses a realistic organ model to describe drug kinetics. The blood-tissue exchange of each organ is characterized by its volume, perfusion, metabolism, capillary permeability and blood/tissue partition coefficient. PBPK applications require both sophisticated mathematical modeling software and a reliable complete set of physiological parameters. Currently there are no software packages available that combine ease of use with the versatility that is required of a general PBPK program. Findings The program is written in Java and is available for free download at Included in the download is a detailed tutorial that discusses the pharmacokinetics of 6 solutes (D2O, amoxicillin, desflurane, propofol, ethanol and thiopental illustrated using experimental human pharmacokinetic data. The complete PBPK description for each solute is stored in Excel spreadsheets that are included in the download. The main features of the program are: 1 Intuitive and versatile interactive interface; 2 Absolute and semi-logarithmic graphical output; 3 Pre-programmed optimized human parameter data set (but, arbitrary values can be input; 4 Time dependent changes in the PBPK parameters; 5 Non-linear parameter optimization; 6 Unique approach to determine the oral "first pass metabolism" of non-linear solutes (e.g. ethanol; 7 Pulmonary perfusion/ventilation heterogeneity for volatile solutes; 8 Input and output of Excel spreadsheet data; 9 Antecubital vein sampling. Conclusion PKQuest_Java is a free, easy to use, interactive PBPK software routine. The user can either directly use the pre-programmed optimized human or rat data set, or enter an arbitrary data set. It is designed so that drugs that are classified as "extracellular" or "highly fat soluble" do not require information about tissue/blood partition coefficients and can be modeled by a minimum of user input parameters. PKQuest

  14. Predicting absorption and pharmacokinetic profile of carbamazepine from controlled-release tablet formulation in humans using rabbit model

    Directory of Open Access Journals (Sweden)

    Homšek Irena


    Full Text Available Controlled-release (CR pharmaceutical formulations offer several advantages over the conventional, immediate release dosage forms of the same drug, including reduced dosing frequency, decreased incidence and/or intensity of adverse effects, greater selectivity of pharmacological activity, reduced drug plasma fluctuation, and better compliance. After a drug product has been registered, and is already on market, minor changes in formulation might be needed. At the same time, the product has to remain effective and safe for patients that could be confirmed via plasma drug concentrations and pharmacokinetic characteristics. It is challenging to predict human absorption and pharmacokinetic characteristics of a drug based on the in vitro dissolution test and the animal pharmacokinetic data. Therefore, the objective of this study was to establish correlation of the pharmacokinetic parameters of carbamazepine (CBZ CR tablet formulation between the rabbit and the human model, and to establish in vitro in vivo correlation (IVIVC based on the predicted fractions of absorbed CBZ. Although differences in mean plasma concentration profiles were notified, the data concerning the predicted fraction of drug absorbed were almost superimposable. Accordingly, it can be concluded that rabbits may be representative as an in vivo model for predicting the pharmacokinetics of the CR formulation of CBZ in humans.

  15. A population pharmacokinetic model for perioperative dosing of factor VIII in hemophilia A patients

    NARCIS (Netherlands)

    Hazendonk, Hendrika; Fijnvandraat, Karin; Lock, Janske; Driessens, Mariette; van der Meer, Felix; Meijer, Karina; Kruip, Marieke; Laros-van Gorkom, Britta; Peters, Marjolein; de Wildt, Saskia; Leebeek, Frank; Cnossen, Marjon; Mathot, Ron


    The role of pharmacokinetic-guided dosing of factor concentrates in hemophilia is currently a subject of debate and focuses on long-term prophylactic treatment. Few data are available on its impact in the perioperative period. In this study, a population pharmacokinetic model for currently registere

  16. Mathematical modeling and simulation in animal health. Part I: Moving beyond pharmacokinetics. (United States)

    Riviere, J E; Gabrielsson, J; Fink, M; Mochel, J


    The application of mathematical modeling to problems in animal health has a rich history in the form of pharmacokinetic modeling applied to problems in veterinary medicine. Advances in modeling and simulation beyond pharmacokinetics have the potential to streamline and speed-up drug research and development programs. To foster these goals, a series of manuscripts will be published with the following goals: (i) expand the application of modeling and simulation to issues in veterinary pharmacology; (ii) bridge the gap between the level of modeling and simulation practiced in human and veterinary pharmacology; (iii) explore how modeling and simulation concepts can be used to improve our understanding of common issues not readily addressed in human pharmacology (e.g. breed differences, tissue residue depletion, vast weight ranges among adults within a single species, interspecies differences, small animal species research where data collection is limited to sparse sampling, availability of different sampling matrices); and (iv) describe how quantitative pharmacology approaches could help understanding key pharmacokinetic and pharmacodynamic characteristics of a drug candidate, with the goal of providing explicit, reproducible, and predictive evidence for optimizing drug development plans, enabling critical decision making, and eventually bringing safe and effective medicines to patients. This study introduces these concepts and introduces new approaches to modeling and simulation as well as clearly articulate basic assumptions and good practices. The driving force behind these activities is to create predictive models that are based on solid physiological and pharmacological principles as well as adhering to the limitations that are fundamental to applying mathematical and statistical models to biological systems.

  17. Physiologically based pharmacokinetic model for ethyl tertiary-butyl ether and tertiary-butyl alcohol in rats: Contribution of binding to α2u-globulin in male rats and high-exposure nonlinear kinetics to toxicity and cancer outcomes. (United States)

    Borghoff, Susan J; Ring, Caroline; Banton, Marcy I; Leavens, Teresa L


    In cancer bioassays, inhalation, but not drinking water exposure to ethyl tertiary-butyl ether (ETBE), caused liver tumors in male rats, while tertiary-butyl alcohol (TBA), an ETBE metabolite, caused kidney tumors in male rats following exposure via drinking water. To understand the contribution of ETBE and TBA kinetics under varying exposure scenarios to these tumor responses, a physiologically based pharmacokinetic model was developed based on a previously published model for methyl tertiary-butyl ether, a structurally similar chemical, and verified against the literature and study report data. The model included ETBE and TBA binding to the male rat-specific protein α2u-globulin, which plays a role in the ETBE and TBA kidney response observed in male rats. Metabolism of ETBE and TBA was described as a single, saturable pathway in the liver. The model predicted similar kidney AUC0-∞ for TBA for various exposure scenarios from ETBE and TBA cancer bioassays, supporting a male-rat-specific mode of action for TBA-induced kidney tumors. The model also predicted nonlinear kinetics at ETBE inhalation exposure concentrations above ~2000 ppm, based on blood AUC0-∞ for ETBE and TBA. The shift from linear to nonlinear kinetics at exposure concentrations below the concentration associated with liver tumors in rats (5000 ppm) suggests the mode of action for liver tumors operates under nonlinear kinetics following chronic exposure and is not relevant for assessing human risk. Copyright © 2016 The Authors Journal of Applied Toxicology Published by John Wiley & Sons Ltd.

  18. Differential pharmacokinetics and pharmacokinetic/pharmacodynamic modelling of robenacoxib and ketoprofen in a feline model of inflammation. (United States)

    Pelligand, L; King, J N; Hormazabal, V; Toutain, P L; Elliott, J; Lees, P


    Robenacoxib and ketoprofen are acidic nonsteroidal anti-inflammatory drugs (NSAIDs). Both are licensed for once daily administration in the cat, despite having short blood half-lives. This study reports the pharmacokinetic/pharmacodynamic (PK/PD) modelling of each drug in a feline model of inflammation. Eight cats were enrolled in a randomized, controlled, three-period cross-over study. In each period, sterile inflammation was induced by the injection of carrageenan into a subcutaneously implanted tissue cage, immediately before the subcutaneous injection of robenacoxib (2 mg/kg), ketoprofen (2 mg/kg) or placebo. Blood samples were taken for the determination of drug and serum thromboxane (Tx)B2 concentrations (measuring COX-1 activity). Tissue cage exudate samples were obtained for drug and prostaglandin (PG)E2 concentrations (measuring COX-2 activity). Individual animal pharmacokinetic and pharmacodynamic parameters for COX-1 and COX-2 inhibition were generated by PK/PD modelling. S(+) ketoprofen clearance scaled by bioavailability (CL/F) was 0.114 L/kg/h (elimination half-life = 1.62 h). For robenacoxib, blood CL/F was 0.684 L/kg/h (elimination half-life = 1.13 h). Exudate elimination half-lives were 25.9 and 41.5 h for S(+) ketoprofen and robenacoxib, respectively. Both drugs reduced exudate PGE2 concentration significantly between 6 and 36 h. Ketoprofen significantly suppressed (>97%) serum TxB2 between 4 min and 24 h, whereas suppression was mild and transient with robenacoxib. In vivo IC50 COX-1/IC50 COX-2 ratios were 66.9:1 for robenacoxib and 1:107 for S(+) ketoprofen. The carboxylic acid nature of both drugs may contribute to the prolonged COX-2 inhibition in exudate, despite short half-lives in blood.

  19. Population pharmacokinetic-pharmacodynamic modeling of biological agents: when modeling meets reality. (United States)

    Mould, Diane R; Frame, Bill


    The pharmacokinetics (PK) and pharmacodynamics (PD) of many biological agents (biologics) have inherent complexities requiring specialized approaches to develop reliable, unbiased models. Three cases are covered: preponderance of zero values, nonresponder subpopulations, and adaptive dosing. Engineered biologics exhibit high affinity for target receptors. Biologics can saturate receptors, abolishing free receptor levels for protracted periods. Consequently, the distribution of observations can be heavy at, and near, the boundary. A 2-part model (ie, a truncated δ log-normal distribution) may be appropriate. Mixture models identify subpopulations based on bimodal or multimodal distributions of η values. With biologics, PD may be compromised because of lack of receptors, or the PD may be affected because of other events resulting in erratic excursions. Nonresponders exhibit a random walk-around placebo trajectory, resulting in high residual variability. The distributions of etas are often badly skewed or polymodal. An indescribable mixture model separates subjects who are nonresponders, providing diagnostic pharmacologic information on the drug. Many biologics use PD-based adaptive dosing. During model development, data used for model development include adaptive dosing. For simulation, adaptive dosing must be implemented. Failure to account for dose adjustments results in biased or inflated prediction intervals because subjects in the simulated data undergo inappropriate dose adjustments.

  20. Development of a Human Physiologically Based Pharmacokinetic (PBPK Toolkit for Environmental Pollutants

    Directory of Open Access Journals (Sweden)

    Patricia Ruiz


    Full Text Available Physiologically Based Pharmacokinetic (PBPK models can be used to determine the internal dose and strengthen exposure assessment. Many PBPK models are available, but they are not easily accessible for field use. The Agency for Toxic Substances and Disease Registry (ATSDR has conducted translational research to develop a human PBPK model toolkit by recoding published PBPK models. This toolkit, when fully developed, will provide a platform that consists of a series of priority PBPK models of environmental pollutants. Presented here is work on recoded PBPK models for volatile organic compounds (VOCs and metals. Good agreement was generally obtained between the original and the recoded models. This toolkit will be available for ATSDR scientists and public health assessors to perform simulations of exposures from contaminated environmental media at sites of concern and to help interpret biomonitoring data. It can be used as screening tools that can provide useful information for the protection of the public.

  1. Comparative pharmacokinetic analysis based on nonlinear mixed effect model%基于非线性混合效应模型的比较药动学分析方法研究

    Institute of Scientific and Technical Information of China (English)

    李禄金; 李宪星; 许羚; 吕映华; 陈君超; 郑青山


    比较药动学研究贯穿药物研发的整个阶段,通过求算个体药动学参数,推测各处理因素间AUC、Cmax比值的90%置信区间,然后与事先设定的等效区间进行比较,最终判断各处理因素间是否等效,为用药剂量的合理调整提供依据.然而,很多比较药动学研究为稀疏采样设计,传统的统计矩法很难对个体药动学参数进行估计,此时需要借助群体药动学的计算方法,利用非线性混合效应模型进行计算.本研究在密集采样设计比较药动学研究实例基础之上,模拟稀疏采样过程,对稀疏数据采用非线性混合效应模型分析,原密集数据采用统计矩法分析,通过Bootstrap法1000次重复抽样,最终比较两种方法所得参数的90%置信区间.结果表明非线性混合效应模型对稀疏数据处理结果可靠,与统计矩法计算结果一致,为此类比较药动学研究提供了参考.%Comparative pharmacokinetic (PK) analysis is often carried out throughout the entire period of drug development the common approach for the assessment of pharmacokinetics between different treatments requires that the individual PK parameters, which employs estimation of 90% confidence intervals for the ratio of average parameters, such as AUC and Cmax, these 90% confidence intervals then need to be compared with the pre-specified equivalent interval, and last we determine whether the two treatments are equivalent. Unfortunately in many clinical circumstances. some or even all of the individuals can only be sparsely sampled, making the individual evaluation difficult by the conventional non-compartmental analysis. In such cases, nonlinear mixed effect model (NONMEM) could be applied to analyze the sparse data. In this article, we simulated a sparsety sampling design trial based on the dense sampling data from a truly comparative PK study. The sparse data were analyzed with NONMEM method, and the original dense data were analyzed with non

  2. Pharmacokinetic-pharmacodynamic modeling of dopamine D2 receptor occupancy in humans using Bayesian modeling tools

    NARCIS (Netherlands)

    Johnson, Martin; Mafirakureva, Nyashadzaishe; Kozielska, Magdalena; Pilla Reddy, Venkatesh; Vermeulen, An; Liu, Jing; de Greef, Rik; Groothuis, Genoveva; Danhof, Meindert; Proost, Johannes


    Objectives: Blockade of dopamine-2 receptors is the key pharmacological component to the antipsychotic efficacy of both the typical and atypical antipsychotics (1). A pharmacokinetic-pharmacodynamic (PK-PD) modeling approach was used to describe the relationship between the plasma concentration of a

  3. Semiphysiological versus Empirical Modelling of the Population Pharmacokinetics of Free and Total Cefazolin during Pregnancy

    Directory of Open Access Journals (Sweden)

    J. G. Coen van Hasselt


    Full Text Available This work describes a first population pharmacokinetic (PK model for free and total cefazolin during pregnancy, which can be used for dose regimen optimization. Secondly, analysis of PK studies in pregnant patients is challenging due to study design limitations. We therefore developed a semiphysiological modeling approach, which leveraged gestation-induced changes in creatinine clearance (CrCL into a population PK model. This model was then compared to the conventional empirical covariate model. First, a base two-compartmental PK model with a linear protein binding was developed. The empirical covariate model for gestational changes consisted of a linear relationship between CL and gestational age. The semiphysiological model was based on the base population PK model and a separately developed mixed-effect model for gestation-induced change in CrCL. Estimates for baseline clearance (CL were 0.119 L/min (RSE 58% and 0.142 L/min (RSE 44% for the empirical and semiphysiological models, respectively. Both models described the available PK data comparably well. However, as the semiphysiological model was based on prior knowledge of gestation-induced changes in renal function, this model may have improved predictive performance. This work demonstrates how a hybrid semiphysiological population PK approach may be of relevance in order to derive more informative inferences.

  4. Using physiologically based pharmacokinetic modeling to address nonlinear kinetics and changes in rodent physiology and metabolism due to aging and adaptation in deriving reference values for propylene glycol methyl ether and propylene glycol methyl ether acetate.

    Energy Technology Data Exchange (ETDEWEB)

    Kirman, C R.; Sweeney, Lisa M.; Corley, Rick A.; Gargas, M L.


    Reference values, including an oral reference dose (RfD) and an inhalation reference concentration (RfC), were derived for propylene glycol methyl ether (PGME), and an oral RfD was derived for its acetate (PGMEA). These values were based upon transient sedation observed in F344 rats and B6C3F1 mice during a two-year inhalation study. The dose-response relationship for sedation was characterized using internal dose measures as predicted by a physiologically based pharmacokinetic (PBPK) model for PGME and its acetate. PBPK modeling was used to account for changes in rodent physiology and metabolism due to aging and adaptation, based on data collected during weeks 1, 2, 26, 52, and 78 of a chronic inhalation study. The peak concentration of PGME in richly perfused tissues was selected as the most appropriate internal dose measure based upon a consideration of the mode of action for sedation and similarities in tissue partitioning between brain and other richly perfused tissues. Internal doses (peak tissue concentrations of PGME) were designated as either no-observed-adverse-effect levels (NOAELs) or lowest-observed-adverse-effect levels (LOAELs) based upon the presence or absence of sedation at each time-point, species, and sex in the two year study. Distributions of the NOAEL and LOAEL values expressed in terms of internal dose were characterized using an arithmetic mean and standard deviation, with the mean internal NOAEL serving as the basis for the reference values, which was then divided by appropriate uncertainty factors. Where data were permitting, chemical-specific adjustment factors were derived to replace default uncertainty factor values of ten. Nonlinear kinetics are were predicted by the model in all species at PGME concentrations exceeding 100 ppm, which complicates interspecies and low-dose extrapolations. To address this complication, reference values were derived using two approaches which differ with respect to the order in which these extrapolations

  5. Organophosphorus Insecticide Pharmacokinetics

    Energy Technology Data Exchange (ETDEWEB)

    Timchalk, Charles


    This chapter highlights a number of current and future applications of pharmacokinetics to assess organophosphate (OP) insecticide dosimetry, biological response and risk in humans exposed to these agents. Organophosphates represent a large family of pesticides where insecticidal as well as toxicological mode of action is associated with their ability to target and inhibit acetylcholinesterase (AChE). Pharmacokinetics entails the quantitative integration of physiological and metabolic processes associated with the absorption, distribution, metabolism and excretion (ADME) of drugs and xenobiotics. Pharmacokinetic studies provide important data on the amount of toxicant delivered to a target site as well as species-, age-, gender-specific and dose-dependent differences in biological response. These studies have been conducted with organophosphorus insecticides in multiple species, at various dose levels, and across different routes of exposure to understand their in vivo pharmacokinetics and how they contribute to the observed toxicological response. To access human exposure to organophosphorus insecticides, human pharmacokinetic studies have been conducted and used to develop biological monitoring strategies based on the quantitation of key metabolites in biological fluids. Pharmacokinetic studies with these insecticides are also useful to facilitate extrapolation of dosimetry and biological response from animals to humans and for the assessment of human health risk. In this regard, physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) models are being utilized to assess risk and understand the toxicological implications of known or suspected exposures to various insecticides. In this chapter a number of examples are presented that illustrate the utility and limitation of pharmacokinetic studies to address human health concerns associated with organophosphorus insecticides.


    Institute of Scientific and Technical Information of China (English)

    胥宁; 刘永涛; 杨秋红; 艾晓辉


    为了预测喹烯酮在草鱼体内药物残留, 建立其在草鱼体内生理药动学模型.通过搜集大量文献获得鱼的生理解剖参数, 采用已有的喹烯酮试验数据拟合得到药物特异性参数.基于 acslXtreme 生理药动学软件,进行模型假设、血流图设计、质量平衡方程的建立和模型拟合.喹烯酮为小分子药物, 其分布服从血流限速型, 在肝脏代谢, 从肾脏消除.喹烯酮通过口服进入肠道, 然后经肝脏代谢进入血液循环, 因此设定 5 个房室, 即肝、肾、肌肉、肠和其他组织.经过一系列的计算和调试, 最终建立喹烯酮在草体内5室生理药动模型, 成功拟合连续饲喂药物 60d之后的药物残留消除曲线, 其中肝脏中的预测结果比肾脏和肌肉高, 与实测数据一致.因此, 喹烯酮在鱼体内生理药动模型具有一定的应用价值, 将是药物残留检测的新亮点.%An effective physiological-based pharmacokinetic (PB-PK) model can be used to analogize and extrapolate the in vivo drug concentrations in different administrations and environments, as well as in different species of animals, hence it has become more and more popular in the drug residual prediction in aquatic animals. In order to predict drug residues of quinocetone in grass carp (Ctenopharyngodon idellus), we established the PB-PK model of quinocetone in this study. We obtained the physiological and anatomical parameters of fish from literatures, and estimated the drug-specific parameters of quinocetone by fitting the existing data. We used the physiological pharmacokinetic soft-ware, asclXtreme, to make the model assumptions, to design the blood flow chart, to generate the mass balance equa-tions and to complete the model fitting. Quinocetone was a small molecule drug, and itsin vivo disposition was blood flow-limited. It was metabolized by the liver and excreted by the kidney. Quinocetone entered the intestine through oral administration and

  7. A population pharmacokinetic model for perioperative dosing of factor VIII in hemophilia A patients (United States)

    Hazendonk, Hendrika; Fijnvandraat, Karin; Lock, Janske; Driessens, Mariëtte; van der Meer, Felix; Meijer, Karina; Kruip, Marieke; Gorkom, Britta Laros-van; Peters, Marjolein; de Wildt, Saskia; Leebeek, Frank; Cnossen, Marjon; Mathôt, Ron


    The role of pharmacokinetic-guided dosing of factor concentrates in hemophilia is currently a subject of debate and focuses on long-term prophylactic treatment. Few data are available on its impact in the perioperative period. In this study, a population pharmacokinetic model for currently registered factor VIII concentrates was developed for severe and moderate adult and pediatric hemophilia A patients (FVIII levels hemophilia A patients by Bayesian adaptive dosing. PMID:27390359

  8. Population pharmacokinetic modelling of morphine, gabapentin and their combination in the rat

    DEFF Research Database (Denmark)

    Papathanasiou, Theodoros; Juul, Rasmus Vestergaard; Gabel-Jensen, Charlotte;


    -administration of the two drugs leads to modifications of their pharmacokinetic profiles. Methods The pharmacokinetics of morphine, morphine-3-glucuronide and gabapentin were characterised in rats following subcutaneous injections of morphine, gabapentin or their combination. Non-linear mixed effects modelling was applied...... The finding of a lack of pharmacokinetic interaction strengthens the notion that the combination of the two drugs leads to better efficacy in pain treatment due to interaction at the pharmacodynamic level. The interaction found between gabapentin and morphine-3-glucuronide, the latter being inactive, might......Purpose The combination of morphine and gabapentin seems promising for the treatment of postoperative and neuropathic pain. Despite the well characterised pharmacodynamic interaction, little is known about possible pharmacokinetic interactions. The aim of this study was to evaluate whether co...

  9. Comparison of cerebral pharmacokinetics of buprenorphine and norbuprenorphine in an in vivo sheep model. (United States)

    Jensen, M L; Foster, D; Upton, R; Grant, C; Martinez, A; Somogyi, A


    The pharmacokinetics and time course of blood-brain equilibration of buprenorphine (BUP) and norbuprenorphine (norBUP) in sheep were characterized. Sheep were administered 0.04 mg kg(-1) BUP or 0.6 mg kg(-1) norBUP as 4-min i.v. infusions. The cerebral kinetics were inferred from arterio-sagittal sinus concentration gradients and changes in cerebral blood flow. These data were fitted to physiologically based pharmacokinetic models. BUP cerebral kinetics were best described by a membrane-limited model with a large equilibration delay (half-life of 20 min) between brain and blood due to intermediate permeability (47 ml min(-1)) and a large cerebral distribution volume (595 ml). Significant limitation in permeability (6 ml min(-1)) characterized the cerebral kinetics of norBUP with a cerebral distribution volume (157 ml) giving a blood-brain equilibration half-life (21 min) similar to that for BUP. The logD of BUP and norBUP were 3.93 +/- 0.08 and 1.18 +/- 0.04 (mean +/- SD), respectively. Both compounds revealed slow cerebral equilibration with variations in degree of permeability and distribution volume reflecting the difference in lipophilicity. It is possible that norBUP contributes to the central effects seen after chronic BUP administration as this study demonstrated its entry into the brain.

  10. Pharmacokinetic and pharmacodynamic integration and modeling of enrofloxacin in swine for Escherichia coli

    Directory of Open Access Journals (Sweden)

    Jianyi eWang


    Full Text Available The aim of this study was tooptimize the dose regimens of enrofloxacin to reduce the development of fluoroquinolone resistance in Escherichia coli (E.coli using pharmacokinetic/pharmacodynamic (PK/PD modeling approach. The single dose (2.5 mg/kg body weight of enrofloxacin was administered intramuscularly (IM to the healthy pigs. Using cannulation, the pharmacokinetic properties, including peak concentration (Cmax, time to reach Cmax (Tmax and area under the curve (AUC, were determined in plasma and ileum content. The Cmax, Tmax, and AUC in the plasma were 1.09 ± 0.11 μg/mL, 1.27 ± 0.35 h and 12.70 ± 2.72 µg•h/mL, respectively. While in ileum content, the Cmax, Tmax and AUC were 7.07 ± 0.26 μg/mL, 5.54 ± 0.42 h and 136.18 ± 12.50 µg•h/mL, respectively. Based on the minimum inhibitory concentration (MIC data of 918 E.coli isolates, an E.coli O101/K99 strain (enrofloxacin MIC = 0.25 μg/mL was selected for pharmacodynamic studies. The in vitro minimum bactericidal concentration (MBC, mutant prevention concentration (MPC and ex vivo time-killing curves for enrofloxacin in ileum content were established against the selected E.coli O101/K99 strain. Integrating the in vivo pharmacokinetic data and ex vivo pharmacodynamic data, a sigmoid Emax (Hill equation was established to provide values for ileum content of AUC24h/MIC producing, bactericidal activity (52.65 h and virtual eradication of bacteria (78.06 h. A dosage regimen of 1.96 mg/kg every 12 h for 3 days should be sufficient in the treatment of E.coli.

  11. Pharmacokinetic and Pharmacodynamic Integration and Modeling of Enrofloxacin in Swine for Escherichia coli. (United States)

    Wang, Jianyi; Hao, Haihong; Huang, Lingli; Liu, Zhenli; Chen, Dongmei; Yuan, Zonghui


    The aim of this study was to optimize the dose regimens of enrofloxacin to reduce the development of fluoroquinolone resistance in Escherichia coli (E.coli) using pharmacokinetic/pharmacodynamic (PK/PD) modeling approach. The single dose (2.5 mg/kg body weight) of enrofloxacin was administered intramuscularly (IM) to the healthy pigs. Using cannulation, the pharmacokinetic properties, including peak concentration (C max), time to reach C max (T max), and area under the curve (AUC), were determined in plasma and ileum content. The C max, T max, and AUC in the plasma were 1.09 ± 0.11 μg/mL, 1.27 ± 0.35 h, and 12.70 ± 2.72 μg·h/mL, respectively. While in ileum content, the C max, T max, and AUC were 7.07 ± 0.26 μg/mL, 5.54 ± 0.42 h, and 136.18 ± 12.50 μg·h/mL, respectively. Based on the minimum inhibitory concentration (MIC) data of 918 E. coli isolates, an E. coli O101/K99 strain (enrofloxacin MIC = 0.25 μg/mL) was selected for pharmacodynamic studies. The in vitro minimum bactericidal concentration (MBC), mutant prevention concentration (MPC), and ex vivo time-killing curves for enrofloxacin in ileum content were established against the selected E. coli O101/K99 strain. Integrating the in vivo pharmacokinetic data and ex vivo pharmacodynamic data, a sigmoid E max (Hill) equation was established to provide values for ileum content of AUC24h/MIC producing, bactericidal activity (52.65 h), and virtual eradication of bacteria (78.06 h). A dosage regimen of 1.96 mg/kg every 12 h for 3 days should be sufficient in the treatment of E. coli.

  12. Utility of population pharmacokinetic modeling in the assessment of therapeutic protein-drug interactions. (United States)

    Chow, Andrew T; Earp, Justin C; Gupta, Manish; Hanley, William; Hu, Chuanpu; Wang, Diane D; Zajic, Stefan; Zhu, Min


    Assessment of pharmacokinetic (PK) based drug-drug interactions (DDI) is essential for ensuring patient safety and drug efficacy. With the substantial increase in therapeutic proteins (TP) entering the market and drug development, evaluation of TP-drug interaction (TPDI) has become increasingly important. Unlike for small molecule (e.g., chemical-based) drugs, conducting TPDI studies often presents logistical challenges, while the population PK (PPK) modeling may be a viable approach dealing with the issues. A working group was formed with members from the pharmaceutical industry and the FDA to assess the utility of PPK-based TPDI assessment including study designs, data analysis methods, and implementation strategy. This paper summarizes key issues for consideration as well as a proposed strategy with focuses on (1) PPK approach for exploratory assessment; (2) PPK approach for confirmatory assessment; (3) importance of data quality; (4) implementation strategy; and (5) potential regulatory implications. Advantages and limitations of the approach are also discussed.

  13. Application of Physiologically-Based Pharmacokinetic Modeling to Explore the Role of Kidney Transporters in Renal Reabsorption of Perfluorooctanoic Acid in the Rat (United States)

    Worley, Rachel Rogers; Fisher, Jeffrey


    Renal elimination and the resulting clearance of perfluorooctanoic acid (PFOA) from the serum exhibit pronounced sex differences in the adult rat. The literature suggests that this is largely due to hormonally regulated expression of organic anion transporters (OATs) on the apical and basolateral membranes of the proximal tubule cells that facilitate excretion and reabsorption of PFOA from the filtrate into the blood. Previously developed PBPK models of PFOA exposure in the rat have not been parameterized to specifically account for transporter-mediated renal elimination. We developed a PBPK model for PFOA in the male and female rat to explore the role of Oat1, Oat3, and Oatp1a1 in sex-specific renal reabsorption and excretion of PFOA. Descriptions of the kinetic behavior of these transporters were extrapolated from in vitro studies and the model was used to simulate time-course serum, liver, and urine data for intravenous (IV) and oral exposures in both sexes. Model predicted concentrations of PFOA in the liver, serum, and urine showed good agreement with experimental data for both the male and female rat indicating that in vitro derived physiological descriptions of transporter-mediated renal reabsorption can successfully predict sex-dependent excretion of PFOA in the rat. This study supports the hypothesis that sex-specific serum half-lives for PFOA are largely driven by expression of transporters in the kidney and contributes to the development of PBPK modeling as a tool for evaluating the role of transporters in renal clearance. PMID:26522833

  14. A Multi-Route Model of Nicotine-Cotinine Pharmacokinetics, Pharmacodynamics and Brain Nicotinic Acetylcholine Receptor Binding in Humans

    Energy Technology Data Exchange (ETDEWEB)

    Teeguarden, Justin G.; Housand, Conrad; Smith, Jordan N.; Hinderliter, Paul M.; Gunawan, Rudy; Timchalk, Charles


    The pharmacokinetics of nicotine, the pharmacologically active alkaloid in tobacco responsible for addiction, are well characterized in humans. We developed a physiologically based pharmacokinetic/pharmacodynamic model of nicotine pharmacokinetics, brain dosimetry and brain nicotinic acetylcholine receptor (nAChRs) occupancy. A Bayesian framework was applied to optimize model parameters against multiple human data sets. The resulting model was consistent with both calibration and test data sets, but in general underestimated variability. A pharmacodynamic model relating nicotine levels to increases in heart rate as a proxy for the pharmacological effects of nicotine accurately described the nicotine related changes in heart rate and the development and decay of tolerance to nicotine. The PBPK model was utilized to quantitatively capture the combined impact of variation in physiological and metabolic parameters, nicotine availability and smoking compensation on the change in number of cigarettes smoked and toxicant exposure in a population of 10,000 people presented with a reduced toxicant (50%), reduced nicotine (50%) cigarette Across the population, toxicant exposure is reduced in some but not all smokers. Reductions are not in proportion to reductions in toxicant yields, largely due to partial compensation in response to reduced nicotine yields. This framework can be used as a key element of a dosimetry-driven risk assessment strategy for cigarette smoke constituents.

  15. Pharmacokinetic/Pharmacodynamic Relationship of Gabapentin in a CFA-induced Inflammatory Hyperalgesia Rat Model

    DEFF Research Database (Denmark)

    Larsen, Malte Selch; Keizer, Ron; Munro, Gordon;


    PURPOSE: Gabapentin displays non-linear drug disposition, which complicates dosing for optimal therapeutic effect. Thus, the current study was performed to elucidate the pharmacokinetic/pharmacodynamic (PKPD) relationship of gabapentin's effect on mechanical hypersensitivity in a rat model of CFA...... provides further knowledge into the understanding of gabapentin's non-linear pharmacokinetics and the link between plasma/brain disposition and anti-hyperalgesic effects. The model suggests that intestinal absorption is the primary source of non-linearity and that the investigated rat model provides...

  16. Mixed-effects modelling of the interspecies pharmacokinetic scaling of pegylated human erythropoietin. (United States)

    Jolling, Koen; Perez Ruixo, Juan Jose; Hemeryck, Alex; Vermeulen, An; Greway, Tony


    The aim of this study was to develop a population pharmacokinetic model for interspecies allometric scaling of pegylated r-HuEPO (PEG-EPO) pharmacokinetics to man. A total of 927 serum concentrations from 193 rats, 6 rabbits, 34 monkeys, and 9 dogs obtained after a single dose of PEG-EPO, administered by the i.v. (dose range: 12.5-550 microg/kg) and s.c. (dose range: 12.5-500 microg/kg) routes, were pooled in this analysis. An open two-compartment model with first-order absorption and lag time (Tlag) and linear elimination from the central compartment was fitted to the data using the NONMEM V software. Body weight (WT) was used as a scaling factor and the effect of brain weight (BW), sex, and pregnancy status on the pharmacokinetic parameters was investigated. The final model was evaluated by means of a non-parametric bootstrap analysis and used to predict the PEG-EPO pharmacokinetic parameters in healthy male subjects. The systemic clearance (CL) in males was estimated to be 4.08WT1.030xBW-0.345 ml/h. In females, the CL was 90.7% of the CL in males. The volumes of the central (Vc) and the peripheral (Vp) compartment were characterized as 57.8WT0.959 ml, and 48.1WT1.150 ml, respectively. Intercompartmental flow was estimated at 2.32WT0.930 ml/h. Absorption rate constant (Ka) was estimated at 0.0538WT-0.149. The absolute s.c. bioavailability F was calculated at 52.5, 80.2, and 49.4% in rat, monkey, and dog, respectively. The interindividual variability in the population pharmacokinetic parameters was fairly low (parametric bootstrap confirmed the accuracy of the NONMEM estimates. The mean model predicted pharmacokinetic parameters in healthy male subjects of 70 kg were estimated at: CL: 26.2 ml/h; Vc: 3.6l; Q: 286 l/h; Vp: 6.9l, and Ka: 0.031 h-1. The population pharmacokinetic model developed was appropriate to describe the time course of PEG-EPO serum concentrations and their variability in different species. The model predicted pharmacokinetics of PEG-EPO in

  17. Triprotic acid-base microequilibria and pharmacokinetic sequelae of cetirizine. (United States)

    Marosi, Attila; Kovács, Zsuzsanna; Béni, Szabolcs; Kökösi, József; Noszál, Béla


    (1)H NMR-pH titrations of cetirizine, the widely used antihistamine and four related compounds were carried out and the related 11 macroscopic protonation constants were determined. The interactivity parameter between the two piperazine amine groups was obtained from two symmetric piperazine derivatives. Combining these two types of datasets, all the 12 microconstants and derived tautomeric constants of cetirizine were calculated. Upon this basis, the conflicting literature data of cetirizine microspeciation were clarified, and the pharmacokinetic absorption-distribution properties could be interpreted. The pH-dependent distribution of the microspecies is provided.

  18. Systemic and direct nose-to-brain transport pharmacokinetic model for remoxipride after intravenous and intranasal administration. (United States)

    Stevens, Jasper; Ploeger, Bart A; van der Graaf, Piet H; Danhof, Meindert; de Lange, Elizabeth C M


    Intranasal (IN) administration could be an attractive mode of delivery for drugs targeting the central nervous system, potentially providing a high bioavailability because of avoidance of a hepatic first-pass effect and rapid onset of action. However, controversy remains whether a direct transport route from the nasal cavity into the brain exists. Pharmacokinetic modeling is proposed to identify the existence of direct nose-to-brain transport in a quantitative manner. The selective dopamine-D2 receptor antagonist remoxipride was administered at different dosages, in freely moving rats, by the IN and intravenous (IV) route. Plasma and brain extracellular fluid (ECF) concentration-time profiles were obtained and simultaneously analyzed using nonlinear mixed-effects modeling. Brain ECF/plasma area under the curve ratios were 0.28 and 0.19 after IN and IV administration, respectively. A multicompartment pharmacokinetic model with two absorption compartments (nose-to-systemic and nose-to-brain) was found to best describe the observed pharmacokinetic data. Absorption was described in terms of bioavailability and rate. Total bioavailability after IN administration was 89%, of which 75% was attributed to direct nose-to brain transport. Direct nose-to-brain absorption rate was slow, explaining prolonged brain ECF exposure after IN compared with IV administration. These studies explicitly provide separation and quantitation of systemic and direct nose-to-brain transport after IN administration of remoxipride in the rat. Describing remoxipride pharmacokinetics at the target site (brain ECF) in a semiphysiology-based manner would allow for better prediction of pharmacodynamic effects.

  19. Predictive Performance of a Busulfan Pharmacokinetic Model in Children and Young Adults

    NARCIS (Netherlands)

    Bartelink, Imke H.; van Kesteren, Charlotte; Boelens, Jaap J.; Egberts, Toine C. G.; Bierings, Marc B.; Cuvelier, Geoff D. E.; Wynn, Robert F.; Slatter, Mary A.; Chiesa, Robert; Danhof, Meindert; Knibbe, Catherijne A. J.


    Background: Recently a pediatric pharmacokinetic (PK) model was developed for busulfan to explain the wide variability in PK of busulfan in children, as this variability is known to influence the outcome of hematopoietic stem cell transplantation in terms of toxicity and event free survival. This st

  20. Modeling the Pharmacokinetics of Perfluorooctanoic Acid (PFOA) During Gestation and Lactation in Mice (United States)

    To address the pharmacokinetics of PFOA during gestation and lactation, a biologically supported dynamic model was developed. A two compartment system linked via placental blood flow described gestation, while milk production linked the dam to a pup litter compartment during lact...

  1. Semiphysiological versus empirical modelling of the population pharmacokinetics of free and total cefazolin during pregnancy

    NARCIS (Netherlands)

    van Hasselt, J G Coen; Allegaert, Karel; van Calsteren, Kristel; Beijnen, Jos H; Schellens, Jan H M; Huitema, Alwin D R


    This work describes a first population pharmacokinetic (PK) model for free and total cefazolin during pregnancy, which can be used for dose regimen optimization. Secondly, analysis of PK studies in pregnant patients is challenging due to study design limitations. We therefore developed a semiphysiol

  2. Performance of Propofol Target-Controlled Infusion Models in the Obese : Pharmacokinetic and Pharmacodynamic Analysis

    NARCIS (Netherlands)

    Cortinez, Luis I.; De la Fuente, Natalia; Eleveld, Douglas J.; Oliveros, Ana; Crovari, Fernando; Sepulveda, Pablo; Ibacache, Mauricio; Solari, Sandra


    BACKGROUND: Obesity is associated with important physiologic changes that can potentially affect the pharmacokinetic (PK) and pharmacodynamic (PD) profile of anesthetic drugs. We designed this study to assess the predictive performance of 5 currently available propofol PK models in morbidly obese pa

  3. Interspecies Mixed-Effect Pharmacokinetic Modeling of Penicillin G in Cattle and Swine (United States)

    Li, Mengjie; Gehring, Ronette; Tell, Lisa; Baynes, Ronald; Huang, Qingbiao


    Extralabel drug use of penicillin G in food-producing animals may cause an excess of residues in tissue which will have the potential to damage human health. Of all the antibiotics, penicillin G may have the greatest potential for producing allergic responses to the consumer of food animal products. There are, however, no population pharmacokinetic studies of penicillin G for food animals. The objective of this study was to develop a population pharmacokinetic model to describe the time-concentration data profile of penicillin G across two species. Data were collected from previously published pharmacokinetic studies in which several formulations of penicillin G were administered to diverse populations of cattle and swine. Liver, kidney, and muscle residue data were also used in this study. Compartmental models with first-order absorption and elimination were fit to plasma and tissue concentrations using a nonlinear mixed-effect modeling approach. A 3-compartment model with extra tissue compartments was selected to describe the pharmacokinetics of penicillin G. Typical population parameter estimates (interindividual variability) were central volumes of distribution of 3.45 liters (12%) and 3.05 liters (8.8%) and central clearance of 105 liters/h (32%) and 16.9 liters/h (14%) for cattle and swine, respectively, with peripheral clearance of 24.8 liters/h (13%) and 9.65 liters/h (23%) for cattle and 13.7 liters/h (85%) and 0.52 liters/h (40%) for swine. Body weight and age were the covariates in the final pharmacokinetic models. This study established a robust model of penicillin for a large and diverse population of food-producing animals which could be applied to other antibiotics and species in future analyses. PMID:24867969

  4. A pharmacokinetic-pharmacodynamic model for intrathecal baclofen in patients with severe spasticity

    NARCIS (Netherlands)

    Heetla, H. W.; Proost, J. H.; Molmans, B. H.; Staal, M. J.; van Laar, T.


    AimsIntrathecal baclofen (ITB) has proven to be an effective and safe treatment for severe spasticity. However, although ITB is used extensively, clinical decisions are based on very scarce pharmacokinetic-pharmacodynamic (PKPD) data. The aim of this study was to measure baclofen CSF concentrations

  5. Busulfan in infants to adult hematopoietic cell transplant recipients: A population pharmacokinetic model for initial and Bayesian dose personalization (United States)

    McCune, Jeannine S.; Bemer, Meagan J.; Barrett, Jeffrey S.; Baker, K. Scott; Gamis, Alan S.; Holford, Nicholas H.G.


    Purpose Personalizing intravenous (IV) busulfan doses to a target plasma concentration at steady state (Css) is an essential component of hematopoietic cell transplantation (HCT). We sought to develop a population pharmacokinetic model to predict IV busulfan doses over a wide age spectrum (0.1 – 66 years) that accounts for differences in age and body size. Experimental design A population pharmacokinetic model based on normal fat mass and maturation based on post-menstrual age was built from 12,380 busulfan concentration-time points obtained after IV busulfan administration in 1,610 HCT recipients. Subsequently, simulation results of the initial dose necessary to achieve a target Css with this model were compared with pediatric-only models. Results A two-compartment model with first-order elimination best fit the data. The population busulfan clearance was 12.4 L/h for an adult male with 62kg normal fat mass (equivalent to 70kg total body weight). Busulfan clearance, scaled to body size – specifically normal fat mass, is predicted to be 95% of the adult clearance at 2.5 years post-natal age. With a target Css of 770 ng/mL, a higher proportion of initial doses achieved the therapeutic window with this age- and size-dependent model (72%) compared to dosing recommended by the Food and Drug Administration (57%) or the European Medicines Agency (70%). Conclusion This is the first population pharmacokinetic model developed to predict initial IV busulfan doses and personalize to a target Css over a wide age spectrum, ranging from infants to adults. PMID:24218510

  6. Computational Analysis of Pharmacokinetic Behavior of Ampicillin

    Directory of Open Access Journals (Sweden)

    Mária Ďurišová


    Full Text Available orrespondence: Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, 841 04 Bratislava, Slovak Republic. Phone + 42-1254775928; Fax +421254775928; E-mail: 84 RESEARCH ARTICLE The objective of this study was to perform a computational analysis of the pharmacokinetic behavior of ampicillin, using data from the literature. A method based on the theory of dynamic systems was used for modeling purposes. The method used has been introduced to pharmacokinetics with the aim to contribute to the knowledge base in pharmacokinetics by including the modeling method which enables researchers to develop mathematical models of various pharmacokinetic processes in an identical way, using identical model structures. A few examples of a successful use of the modeling method considered here in pharmacokinetics can be found in full texts articles available free of charge at the website of the author, and in the example given in the this study. The modeling method employed in this study can be used to develop a mathematical model of the pharmacokinetic behavior of any drug, under the condition that the pharmacokinetic behavior of the drug under study can be at least partially approximated using linear models.

  7. Pharmacokinetic-pharmacodynamic modeling of diclofenac in normal and Freund's complete adjuvant-induced arthritic rats

    Institute of Scientific and Technical Information of China (English)

    Jing ZHANG; Pei LI; Hai-fang GUO; Li LIU; Xiao-dong LIU


    Aim:To characterize pharmacokinetic-pharmacodynamic modeling of diclofenac in Freund's complete adjuvant (FCA)-induced arthritic rats using prostaglandin E2 (PGE2) as a biomarker.Methods:The pharmacokinetics of diclofenac was investigated using 20-day-old arthritic rats.PGE2 level in the rats was measured using an enzyme immunoassay.A pharmacokinetic-pharmacodynamic (PK-PD) model was developed to illustrate the relationship between the plasma concentration of diclofenac and the inhibition of PGE2 production.The inhibition of diclofenac on lipopolysaccharide (LPS)-induced PGE2 production in blood cells was investigated in vitro.Results:Similar pharmacokinetic behavior of diclofenac was found both in normal and FCA-induced arthritic rats.Diclofenac significantly decreased the plasma levels of PGE2 in both normal and arthritic rats.The inhibitory effect on PGE2 levels in the plasma was in proportion to the plasma concentration of diclofenac.No delay in the onset of inhibition was observed,suggesting that the effect compartment was located in the central compartment.An inhibitory effect sigmoid/max model was selected to characterize the relationship between the plasma concentration of diclofenac and the inhibition of PGE2 production in vivo.The /max model was also used to illustrate the inhibition of diclofenac on LPS-induced PGE2 production in blood cells in vitro.Conclusion:Arthritis induced by FCA does not alter the pharmacokinetic behaviors of diclofenac in rats,but the pharmacodynamics of diclofenac is slightly affected.A PK-PD model characterizing an inhibitory effect sigmoid /max can be used to fit the relationship between the plasma PGE2 and diclofenac levels in both normal rats and FCA-induced arthritic rats.

  8. Pharmacokinetics, Pharmacodynamics and Population Pharmacokinetic/Pharmacodynamic Modelling of Bilastine, a Second-Generation Antihistamine, in Healthy Japanese Subjects


    Togawa, Michinori; Yamaya, Hidetoshi; Rodríguez, Mónica; Nagashima, Hirotaka


    Background and objectives Bilastine is a novel second-generation antihistamine for the symptomatic treatment of allergic rhinitis and urticaria. The objective of this study was to evaluate the pharmacokinetics, pharmacodynamics, and tolerability of bilastine following single and multiple oral doses in healthy Japanese subjects. The pharmacokinetic and pharmacodynamic profiles were compared with those reported in Caucasian subjects. Methods In a single-blind, randomized, placebo-controlled, pa...

  9. An overview of the pharmacokinetics of polymer-based nanoassemblies and nanoparticles. (United States)

    Zhao, Qing-He; Qiu, Li-Yan


    Advancements in the design and synthesis of polymer-based nanoassemblies and nanoparticles, combined with achievements in nanotechnology and medicine, have resulted in remarkable applications of polymer nanosystems in the areas of nanomedicine and pharmaceutical sciences. However, a complete understanding of the absorption, distribution, metabolism, and elimination (ADME) processes of such polymer nanosystems in living systems has not been achieved. The influences of the pharmacokinetic parameters of polymer nanomaterials on the ADME processes are reviewed in this article, with discussions of the absorption and transportation of polymer nanoparticles across biological barriers, the factors affecting the bodily distribution of polymer nanocarriers, the transformation of polymer nanomaterials in vivo, the elimination pathway of polymer nanoparticles from biological systems, and perspectives of future pharmacokinetics and safety investigations of polymer-based nanoassemblies. A full and better understanding of the pharmacokinetic parameters of polymer-based nanomaterials is of vital importance in developing polymer nanosystems with optimal pharmacokinetics and biological safety for applications in nanomedicine and the pharmaceutical industry.

  10. A pharmacokinetic approach to model-guided design of infliximab schedules in ulcerative colitis patients

    Directory of Open Access Journals (Sweden)

    Alejandro Pérez-Pitarch


    Full Text Available Background: Infliximab, an anti-tumour necrosis factor approved for treatment of Crohn's disease and ulcerative colitis, is administered at predefined interdose-intervals. On insufficient response or loss of response, treatment can be intensified. The lack or loss of response is likely related to complex pharmacokinetics of infliximab. Aims: To explore optimal dosing strategies of infliximab in treatment-naïve patients with ulcerative colitis through predictive Monte Carlo simulations based on a validated population PK model. Methods: A population of 2,000 treatment-naïve patients was generated by Montecarlo simulation. Six dosing strategies for maintenance therapy were simulated on this population. Strategies 1 and 2 consisted on 5 mg/kg and 6 mg/kg doses, respectively, and 8 weeks inter-dose interval. Strategies 3 and 4 used Individualized doses, adjusted to albumin level, sex and body weight, and a fix inter-dose interval of 8 weeks to achieve a target trough concentration of 5 mg/L or 6 mg/L, respectively. Strategies 5 and 6 used a fix dose of 5 mg/kg and individualized inter-dose intervals, adjusted to the same covariates, to achieve a target concentration, of 5 mg/L or 6 mg/L, respectively. Results: Strategies 2-6 reached trough levels statistically higher than strategy 1 (p < 0.05. Strategy 5 proved to be the best dosing strategy. It was associated with a higher proportion of responder patients than strategy 1 (62 % vs. 40 % without reaching higher peak concentrations. Conclusions: Optimization of maintenance treatment of colitis with infliximab by a pharmacokinetic approach could benefit infliximab-naive patients with ulcerative colitis.

  11. Target-mediated pharmacokinetic/pharmacodynamic model based meta-analysis and dosing regimen optimization of a long-acting release formulation of exenatide in patients with type 2 diabetes mellitus. (United States)

    Li, Hanqing; Xu, Jiayin; Fan, Xiaohong


    A hybrid pharmacokinetic/pharmacodynamic (PK/PD) model with extended-release (ER) process and target mediated drug disposition (TMDD) was developed for exenatide ER to account for its complex absorption process and glucagon-like peptide 1 receptor (GLP-1R)-mediated non-linear PK behaviors along with its influences to fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c). Using hybrid PK/PD model, simulations were done to explore the potential dosing regimens which could achieve likelihood of more pharmacodynamic exposure with respect to FPG and HbA1c over a much shorter period compared with the currently used treatment protocol. The mean PK/PD data about exenatide ER for type 2 diabetes mellitus (T2DM) were digitized from the publications, and the hybrid PK/PD model was performed using the Monolix 4.3 program. The plasma concentration-time and FPG/HbA1c-time profiles for exenatide ER subcutaneously administrated to patients with T2DM were well described by this hybrid model. Monte Carlo simulation was applied to mimic the PK profiles when higher loading dose 7.5 and 5.0 mg exenatide ER were subcutaneously administrated with different dosing intervals at the first 3 weeks of 30-week treatment. Two potentially optimizing schedules could improve the likelihood of achieving much more FPG and HbA1c exposures than currently used clinical treatment protocol.

  12. Pharmacokinetic studies of neuromuscular blocking agents: good clinical research practice (GCRP). (United States)

    Viby-Mogensen, J; Ostergaard, D; Donati, F; Fisher, D; Hunter, J; Kampmann, J P; Kopman, A; Proost, J H; Rasmussen, S N; Skovgaard, L T; Varin, F; Wright, P M


    In September 1997, an international consensus conference on standardization of studies of neuromuscular blocking agents was held in Copenhagen, Denmark. Based on the conference, a set of guidelines for good clinical research practice (GCRP) in pharmacokinetic studies of neuromuscular blocking agents is presented. Guidelines include: design of the study; relevant patient groups to investigate; test drug administration, sampling and analysis; pharmacokinetic analysis; pharmacokinetic/pharmacodynamic modeling; population pharmacokinetics; statistics; and presentation of pharmacokinetic data. The guidelines are intended to aid those working in this research area; it is hoped that they will assist researchers, editors of scientific papers, and pharmaceutical companies in improving the quality of pharmacokinetic studies.

  13. Population pharmacokinetic modeling of a subcutaneous depot for GnRH antagonist degarelix

    DEFF Research Database (Denmark)

    Tornøe, Christoffer Wenzel; Agersø, Henrik; Nielsen, Henrik Aalborg;

    Purpose. The objective of this study is to develop a population pharmacokinetic (PK) model that describes the subcutaneous (SC) depot formation of gonadotropin-releasing hormone (GnRH) antagonist degarelix, which is being developed for treatment of prostate cancer, exhibiting dose-volume and dose...... depot model describes the PK profile of GnRH antagonist degarelix. This modeling approach might also be applicable for other depot-formulated drugs exhibiting complex PK profiles....

  14. Population Pharmacokinetic Modeling of a Subcutaneous Depot for GnRH Antagonist Degarelix

    DEFF Research Database (Denmark)

    Tornøe, Christoffer Wenzel; Agersø, Henrik; Nielsen, Henrik Aalborg;


    Purpose. The objective of this study is to develop a population pharmacokinetic (PK) model that describes the subcutaneous (SC) depot formation of gonadotropin-releasing hormone ( GnRH) antagonist degarelix, which is being developed for treatment of prostate cancer, exhibiting dose-volume and dose...... depot model describes the PK profile of GnRH antagonist degarelix. This modeling approach might also be applicable for other depot-formulated drugs exhibiting complex PK profiles....

  15. Design evaluation and optimisation in crossover pharmacokinetic studies analysed by nonlinear mixed effects models


    Nguyen, Thu Thuy; Bazzoli, Caroline; Mentré, France


    International audience; Bioequivalence or interaction trials are commonly studied in crossover design and can be analysed by nonlinear mixed effects models as an alternative to noncompartmental approach. We propose an extension of the population Fisher information matrix in nonlinear mixed effects models to design crossover pharmacokinetic trials, using a linearisation of the model around the random effect expectation, including within-subject variability and discrete covariates fixed or chan...

  16. Assessment of pharmacokinetic interaction of spirulina with glitazone in a type 2 diabetes rat model. (United States)

    Gupta, Annu; Nair, Anroop; Kumria, Rachna; Al-Dhubiab, Bandar-E; Chattopadhyaya, Ipshita; Gupta, Sumeet


    The objective of the current study was to assess the possible pharmacokinetic interactions of spirulina with glitazones in an insulin resistance rat model. Wistar male albino rats were equally divided into five groups: insulin resistant rats+spirulina (500 mg/kg)+pioglitazone (10 mg/kg), insulin resistant rats+pioglitazone (10 mg/kg), insulin resistant rats+spirulina (500 mg/kg)+rosiglitazone (10 mg/kg), insulin resistant rats+rosiglitazone (10 mg/kg), and insulin resistant rats+spirulina (500 mg/kg). Described doses of pioglitazone, rosiglitazone, or spirulina were per orally administered and the plasma drug concentrations were determined. The pharmacokinetic parameters such as Tmax, Cmax, AUC(0-α), t1/2, and Kel were determined by plotting the drug concentration as a function of time. The data observed in this acute study indicated that there was no statistically significant difference in any of the pharmacokinetic parameters (Tmax, Cmax, AUC(0-α), t1/2, and Kel) of glitazones (pioglitazone, rosiglitazone) or spirulina, when they were coadministered. Given the promising results, this study concludes that the coadministration of spirulina does not influence the pharmacokinetics of glitazones in a type 2 diabetes rat model. Further chronic in vivo studies are recommended to assess the real time effect.

  17. First principles pharmacokinetic modeling: A quantitative study on Cyclosporin

    DEFF Research Database (Denmark)

    Mošat', Andrej; Lueshen, Eric; Heitzig, Martina


    renal and hepatic clearances, elimination half-life, and mass transfer coefficients, to establish drug biodistribution dynamics in all organs and tissues. This multi-scale model satisfies first principles and conservation of mass, species and momentum.Prediction of organ drug bioaccumulation...... as a function of cardiac output, physiology, pathology or administration route may be possible with the proposed PBPK framework. Successful application of our model-based drug development method may lead to more efficient preclinical trials, accelerated knowledge gain from animal experiments, and shortened time-to-market...

  18. Population pharmacokinetic/pharmacodynamic modelling of the hypothalamic-pituitary-gonadal axis



    The present thesis deals with different aspects of population pharmacokinetic/ pharmacodynamic (PK/PD) modelling of the male hypothalamic-pituitary-go-nadal (HPG) axis. The thesis consists of a summary report and five scientific research papers. An overview of the main topics covered in the thesis is provided in the summary report including PK/PD modelling in drug development, the pathological, physiological, and pharmacological aspects of the male HPG axis, and a detailed description of the ...

  19. Relevance of pharmacokinetic and pharmacodynamic modeling to clinical care of critically ill patients. (United States)

    Bulitta, Jurgen B; Landersdorfer, Cornelia B; Forrest, Alan; Brown, Silvia V; Neely, Michael N; Tsuji, Brian T; Louie, Arnold


    Efficacious therapy is of utmost importance to save lives and prevent bacterial resistance in critically ill patients. This review summarizes pharmacokinetic (PK) and pharmacodynamic (PD) modeling methods to optimize clinical care of critically ill patients in empiric and individualized therapy. While these methods apply to all therapeutic areas, we focus on antibiotics to highlight important applications, as emergence of resistance is a significant problem. Nonparametric and parametric population PK modeling, multiple-model dosage design, Monte Carlo simulations, and Bayesian adaptive feedback control are the methods of choice to optimize therapy. Population PK can estimate between patient variability and account for potentially increased clearances and large volumes of distribution in critically ill patients. Once patient- specific PK data become available, target concentration intervention and adaptive feedback control algorithms can most precisely achieve target goals such as clinical cure of an infection or resistance prevention in stable and unstable patients with rapidly changing PK parameters. Many bacterial resistance mechanisms cause PK/PD targets for resistance prevention to be usually several-fold higher than targets for near-maximal killing. In vitro infection models such as the hollow fiber and one-compartment infection models allow one to study antibiotic-induced bacterial killing and emergence of resistance of mono- and combination therapies over clinically relevant treatment durations. Mechanism-based (and empirical) PK/PD modeling can incorporate effects of the immune system and allow one to design innovative dosage regimens and prospective validation studies. Mechanism-based modeling holds great promise to optimize mono- and combination therapy of anti-infectives and drugs from other therapeutic areas for critically ill patients.

  20. Enhancing population pharmacokinetic modeling efficiency and quality using an integrated workflow. (United States)

    Schmidt, Henning; Radivojevic, Andrijana


    Population pharmacokinetic (popPK) analyses are at the core of Pharmacometrics and need to be performed regularly. Although these analyses are relatively standard, a large variability can be observed in both the time (efficiency) and the way they are performed (quality). Main reasons for this variability include the level of experience of a modeler, personal preferences and tools. This paper aims to examine how the process of popPK model building can be supported in order to increase its efficiency and quality. The presented approach to the conduct of popPK analyses is centered around three key components: (1) identification of most common and important popPK model features, (2) required information content and formatting of the data for modeling, and (3) methodology, workflow and workflow supporting tools. This approach has been used in several popPK modeling projects and a documented example is provided in the supplementary material. Efficiency of model building is improved by avoiding repetitive coding and other labor-intensive tasks and by putting the emphasis on a fit-for-purpose model. Quality is improved by ensuring that the workflow and tools are in alignment with a popPK modeling guidance which is established within an organization. The main conclusion of this paper is that workflow based approaches to popPK modeling are feasible and have significant potential to ameliorate its various aspects. However, the implementation of such an approach in a pharmacometric organization requires openness towards innovation and change-the key ingredient for evolution of integrative and quantitative drug development in the pharmaceutical industry.

  1. Pharmacokinetic/pharmacodynamic modeling of biomarker response to sunitinib in healthy volunteers. (United States)

    Lindauer, A; Di Gion, P; Kanefendt, F; Tomalik-Scharte, D; Kinzig, M; Rodamer, M; Dodos, F; Sörgel, F; Fuhr, U; Jaehde, U


    A pharmacokinetic/pharmacodynamic (PK/PD) study of the tyrosine kinase inhibitor sunitinib was conducted in 12 healthy volunteers using blood pressure and circulating biomarker levels as PD markers. Blood pressure was measured, and plasma concentration-time courses of sunitinib, its major metabolite SU12662, vascular endothelial growth factors VEGF-A and VEGF-C, and soluble VEGF receptor-2 (sVEGFR-2) were studied in healthy subjects receiving 50 mg of sunitinib orally for 3-5 consecutive days. Using NONMEM, PK/PD models were established that predicted changes (expressed as multiples relative to baseline values) in systolic blood pressure, diastolic blood pressure, VEGF-A level, and sVEGFR-2 level, of 1.10, 1.18, 2.24, and 0.76, respectively, for a typical subject after 4 weeks of treatment with 50 mg/day. Simulated blood pressure-time courses compare excellently with published data in patients, whereas changes in circulating biomarkers were greater in patients than simulations suggest for healthy subjects. In conclusion, the tumor-independent pharmacological response to sunitinib could be described by PK/PD models, thereby facilitating model-based investigations with antiangiogenic drugs, using blood pressure and circulating proteins as biomarkers.

  2. Bioenergetic and pharmacokinetic model for exposure of common loon (Gavia immer) chicks to methylmercury (United States)

    Karasov, W.H.; Kenow, K.P.; Meyer, M.W.; Fournier, F.


    A bioenergetics model was used to predict food intake of common loon (Gavia immer) chicks as a function of body mass during development, and a pharmacokinetics model, based on first-order kinetics in a single compartment, was used to predict blood Hg level as a function of food intake rate, food Hg content, body mass, and Hg absorption and elimination. Predictions were tested in captive growing chicks fed trout (Salmo gairdneri) with average MeHg concentrations of 0.02 (control), 0.4, and 1.2 ??g/g wet mass (delivered as CH3HgCl). Predicted food intake matched observed intake through 50 d of age but then exceeded observed intake by an amount that grew progressively larger with age, reaching a significant overestimate of 28% by the end of the trial. Respiration in older, nongrowing birds probably was overestimated by using rates measured in younger, growing birds. Close agreement was found between simulations and measured blood Hg, which varied significantly with dietary Hg and age. Although chicks may hatch with different blood Hg levels, their blood level is determined mainly by dietary Hg level beyond approximately two weeks of age. The model also may be useful for predicting Hg levels in adults and in the eggs that they lay, but its accuracy in both chicks and adults needs to be tested in free-living birds. ?? 2007 SETAC.

  3. A Cell-Based Pharmacokinetics Assay for Evaluating Tubulin-Binding Drugs (United States)

    Wang, Yuwei; Liu, Jihua; Zhang, Jun; Wang, Liping; Chan, Jonathon; Wang, Hai; Jin, Yi; Yu, Lei; Grainger, David W.; Ying, Wenbin


    Increasing evidence reveals that traditional pharmacokinetics parameters based on plasma drug concentrations are insufficient to reliably demonstrate accurate pharmacological effects of drugs in target organs or cells in vivo. This underscores the increasing need to improve the types and qualities of cellular pharmacokinetic information for drug preclinical screening and clinical efficacy assessments. Here we report a whole cell-based method to assess drugs that disturb microtubule dynamics to better understand different formulation-mediated intracellular drug release profiles. As proof of concept for this approach, we compared the well-known taxane class of anti-microtubule drugs based on paclitaxel (PTX), including clinically familiar albumin nanoparticle-based Abraxane™, and a polymer nanoparticle-based degradable paclitaxel carrier, poly(L-glutamic acid)-paclitaxel conjugate (PGA-PTX, also known as CT-2103) versus control PTX. This in vitro cell-based evaluation of PTX efficacy includes determining the cellular kinetics of tubulin polymerization, relative populations of cells under G2 mitotic arrest, cell proliferation and total cell viability. For these taxane tubulin-binding compounds, the kinetics of cell microtubule stabilization directly correlate with G2 arrest and cell proliferation, reflecting the kinetics and amounts of intracellular PTX release. Each individual cell-based dose-response experiment correlates with published, key therapeutic parameters and taken together, provide a comprehensive understanding of drug intracellular pharmacokinetics at both cellular and molecular levels. This whole cell-based evaluating method is convenient, quantitative and cost-effective for evaluating new formulations designed to optimize cellular pharmacokinetics for drugs perturbing tubulin polymerization as well as assisting in explaining drug mechanisms of action at cellular levels. PMID:24688312

  4. A cell-based pharmacokinetics assay for evaluating tubulin-binding drugs. (United States)

    Wang, Yuwei; Liu, Jihua; Zhang, Jun; Wang, Liping; Chan, Jonathon; Wang, Hai; Jin, Yi; Yu, Lei; Grainger, David W; Ying, Wenbin


    Increasing evidence reveals that traditional pharmacokinetics parameters based on plasma drug concentrations are insufficient to reliably demonstrate accurate pharmacological effects of drugs in target organs or cells in vivo. This underscores the increasing need to improve the types and qualities of cellular pharmacokinetic information for drug preclinical screening and clinical efficacy assessments. Here we report a whole cell-based method to assess drugs that disturb microtubule dynamics to better understand different formulation-mediated intracellular drug release profiles. As proof of concept for this approach, we compared the well-known taxane class of anti-microtubule drugs based on paclitaxel (PTX), including clinically familiar albumin nanoparticle-based Abraxane™, and a polymer nanoparticle-based degradable paclitaxel carrier, poly(L-glutamic acid)-paclitaxel conjugate (PGA-PTX, also known as CT-2103) versus control PTX. This in vitro cell-based evaluation of PTX efficacy includes determining the cellular kinetics of tubulin polymerization, relative populations of cells under G2 mitotic arrest, cell proliferation and total cell viability. For these taxane tubulin-binding compounds, the kinetics of cell microtubule stabilization directly correlate with G2 arrest and cell proliferation, reflecting the kinetics and amounts of intracellular PTX release. Each individual cell-based dose-response experiment correlates with published, key therapeutic parameters and taken together, provide a comprehensive understanding of drug intracellular pharmacokinetics at both cellular and molecular levels. This whole cell-based evaluating method is convenient, quantitative and cost-effective for evaluating new formulations designed to optimize cellular pharmacokinetics for drugs perturbing tubulin polymerization as well as assisting in explaining drug mechanisms of action at cellular levels.

  5. Design evaluation and optimisation in crossover pharmacokinetic studies analysed by nonlinear mixed effects models. (United States)

    Nguyen, Thu Thuy; Bazzoli, Caroline; Mentré, France


    Bioequivalence or interaction trials are commonly studied in crossover design and can be analysed by nonlinear mixed effects models as an alternative to noncompartmental approach. We propose an extension of the population Fisher information matrix in nonlinear mixed effects models to design crossover pharmacokinetic trials, using a linearisation of the model around the random effect expectation, including within-subject variability and discrete covariates fixed or changing between periods. We use the expected standard errors of treatment effect to compute the power for the Wald test of comparison or equivalence and the number of subjects needed for a given power. We perform various simulations mimicking crossover two-period trials to show the relevance of these developments. We then apply these developments to design a crossover pharmacokinetic study of amoxicillin in piglets and implement them in the new version 3.2 of the r function PFIM.

  6. ADMET evaluation in drug discovery. 11. PharmacoKinetics Knowledge Base (PKKB): a comprehensive database of pharmacokinetic and toxic properties for drugs. (United States)

    Cao, Dongyue; Wang, Junmei; Zhou, Rui; Li, Youyong; Yu, Huidong; Hou, Tingjun


    Good and extensive experimental ADMET (absorption, distribution, metabolism, excretion, and toxicity) data is critical for developing reliable in silico ADMET models. Here we develop a PharmacoKinetics Knowledge Base (PKKB) to compile comprehensive information about ADMET properties into a single electronic repository. We incorporate more than 10 000 experimental ADMET measurements of 1685 drugs into the PKKB. The ADMET properties in the PKKB include octanol/water partition coefficient, solubility, dissociation constant, intestinal absorption, Caco-2 permeability, human bioavailability, plasma protein binding, blood-plasma partitioning ratio, volume of distribution, metabolism, half-life, excretion, urinary excretion, clearance, toxicity, half lethal dose in rat or mouse, etc. The PKKB provides the most extensive collection of freely available data for ADMET properties up to date. All these ADMET properties, as well as the pharmacological information and the calculated physiochemical properties are integrated into a web-based information system. Eleven separated data sets for octanol/water partition coefficient, solubility, blood-brain partitioning, intestinal absorption, Caco-2 permeability, human oral bioavailability, and P-glycoprotein inhibitors have been provided for free download and can be used directly for ADMET modeling. The PKKB is available online at

  7. Elucidation of arctigenin pharmacokinetics after intravenous and oral administrations in rats: integration of in vitro and in vivo findings via semi-mechanistic pharmacokinetic modeling. (United States)

    Gao, Qiong; Zhang, Yufeng; Wo, Siukwan; Zuo, Zhong


    Although arctigenin (AR) has attracted substantial research interests due to its promising and diverse therapeutic effects, studies regarding its biotransformation were limited. The current study aims to provide information regarding the pharmacokinetic properties of AR via various in vitro and in vivo experiments as well as semi-mechanistic pharmacokinetic modeling. Our in vitro rat microsome incubation studies revealed that glucuronidation was the main intestinal and liver metabolic pathway of AR, which occurred with V max, K m, and Clint of 47.5 ± 3.4 nmol/min/mg, 204 ± 22 μM, and 233 ± 9 μl/min/mg with intestinal microsomes and 2.92 ± 0.07 nmol/min/mg, 22.7 ± 1.2 μM, and 129 ± 4 μl/min/mg with liver microsomes, respectively. In addition, demethylation and hydrolysis of AR occurred with liver microsomes but not with intestinal microsomes. In vitro incubation of AR and its metabolites in intestinal content demonstrated that glucuronides of AR excreted in bile could be further hydrolyzed back to the parent compound, suggesting its potential enterohepatic circulation. Furthermore, rapid formation followed by fast elimination of arctigenic acid (AA) and arctigenin-4'-O-glucuronide (AG) was observed after both intravenous (IV) and oral administrations of AR in rats. Linear pharmacokinetics was observed at three different doses for AR, AA, and AG after IV administration of AR (0.48-2.4 mg/kg, r (2) > 0.99). Finally, an integrated semi-mechanistic pharmacokinetic model using in vitro enzyme kinetic and in vivo pharmacokinetic parameters was successfully developed to describe plasma concentrations of AR, AA, and AG after both IV and oral administration of AR at all tested doses.

  8. Lack of meaningful effect of ridaforolimus on the pharmacokinetics of midazolam in cancer patients: model prediction and clinical confirmation. (United States)

    Stroh, Mark; Talaty, Jennifer; Sandhu, Punam; McCrea, Jacqueline; Patnaik, Amita; Tolcher, Anthony; Palcza, John; Orford, Keith; Breidinger, Sheila; Narasimhan, Narayana; Panebianco, Deborah; Lush, Richard; Papadopoulos, Kyriakos P; Wagner, John A; Trucksis, Michele; Agrawal, Nancy


    Ridaforolimus, a unique non-prodrug analog of rapamycin, is a potent inhibitor of mTOR under development for cancer treatment. In vitro data suggest ridaforolimus is a reversible and time-dependent inhibitor of CYP3A. A model-based evaluation suggested an increase in midazolam area under the curve (AUC(0- ∞)) of between 1.13- and 1.25-fold in the presence of therapeutic concentrations of ridaforolimus. The pharmacokinetic interaction between multiple oral doses of ridaforolimus and a single oral dose of midazolam was evaluated in an open-label, fixed-sequence study, in which cancer patients received a single oral dose of 2 mg midazolam followed by 5 consecutive daily single oral doses of 40 mg ridaforolimus with a single dose of 2 mg midazolam with the fifth ridaforolimus dose. Changes in midazolam exposure were minimal [geometric mean ratios and 90% confidence intervals: 1.23 (1.07, 1.40) for AUC(0-∞) and 0.92 (0.82, 1.03) for maximum concentrations (C(max)), respectively]. Consistent with model predictions, ridaforolimus had no clinically important effect on midazolam pharmacokinetics and is not anticipated to be a perpetrator of drug-drug interactions (DDIs) when coadministered with CYP3A substrates. Model-based approaches can provide reasonable estimates of DDI liability, potentially obviating the need to conduct dedicated DDI studies especially in challenging populations like cancer patients.

  9. A pharmacokinetic model to document the actual disposition of topical ivermectin in cattle


    Laffont, Céline M.; Bousquet-Mélou, Alain; Bralet, David; Alvinerie, Roger; Fink-Gremmels, Johanna; Toutain, Pierre-Louis


    International audience; Ivermectin is a worldwide-used antiparasitic drug largely administered to cattle as a topical formulation (pour-on). The actual plasma and faecal disposition of pour-on ivermectin in cattle was documented using an original pharmacokinetic model, and taking into account the oral ingestion of the topical drug following physiological licking as a secondary route of exposure. Six pairs of monozygotic twin cattle received successively one i.v. and two pour-on administration...

  10. Design of optimized hypoxia-activated prodrugs using pharmacokinetic/pharmacodynamic modeling

    Directory of Open Access Journals (Sweden)

    Annika Bettina Foehrenbacher


    Full Text Available Hypoxia contributes to resistance of tumors to some cytotoxic drugs and to radiotherapy, but can in principle be exploited with hypoxia-activated prodrugs (HAP. HAP in clinical development fall into two broad groups. Class I HAP (like the benzotriazine N-oxides tirapazamine and SN30000, are activated under relatively mild hypoxia. In contrast, Class II HAP (such as the nitro compounds PR-104A or TH-302 are maximally activated only under extreme hypoxia, but their active metabolites (effectors diffuse to cells at intermediate O2 and thus also eliminate moderately hypoxic cells. Here, we use a spatially resolved pharmacokinetic/pharmacodynamic (SR-PK/PD model to compare these two strategies and to identify the features required in an optimal Class II HAP. The model uses a Green’s function approach to calculate spatial and longitudinal gradients of O2, prodrug and effector concentrations, and resulting killing in a digitized 3D tumor microregion to estimate activity as monotherapy and in combination with radiotherapy. An analogous model for a normal tissue with mild hypoxia and short intervesssel distances (based on a cremaster muscle microvessel network was used to estimate tumor selectivity of cell killing. This showed that Class II HAP offer advantages over Class I including higher tumor selectivity and greater freedom to vary prodrug diffusibility and rate of metabolic activation. The model suggests that the largest gains in class II HAP antitumor activity could be realized by optimizing effector stability and prodrug activation rates. We also use the model to show that diffusion of effector into blood vessels is unlikely to materially increase systemic exposure for realistic tumor burdens and effector clearances. However, we show that the tumor selectivity achievable by hypoxia-dependent prodrug activation alone is limited if dose-limiting normal tissues are even mildly hypoxic

  11. Pharmacokinetic and pharmacodynamic integration and modelling of marbofloxacin in calves for Mannheimia haemolytica and Pasteurella multocida. (United States)

    Potter, T; Illambas, J; Pelligand, L; Rycroft, A; Lees, P


    The pharmacokinetics (PK) and pharmacodynamics (PD) of marbofloxacin were established in calves for six strains of each of the pneumonia pathogens Mannheimia haemolytica and Pasteurella multocida. The distribution of marbofloxacin into inflamed (exudate) and non-inflamed (transudate) tissue cage fluids allowed comparison with the serum concentration-time profile. To establish the PD profile, minimum inhibitory concentration (MIC) was determined in Mueller-Hinton broth (MHB) and calf serum. Moderately higher MICs were obtained for serum compared to MHB. An initial integration of PK-PD data established C(max)/MIC ratios of 45.0 and AUC(24h)/MIC values of 174.7 h, based on serum MICs, for both bacterial species. Using bacterial time-kill curves, generated ex vivo for serum marbofloxacin concentrations, PK-PD modelling established three levels of growth inhibition: AUC(24 h)/MIC ratios for no reduction, 3 log(10) and 4 log(10) reductions in bacterial count from the initial inoculum count were 41.9, 59.5 and 68.0 h for M. haemolytica and 48.6, 64.9 and 74.8 h for P. multocida, on average respectively. Inter-strain variability for 3 log(10) and 4 log(10) reductions in bacterial count was smaller for P. multocida than for M. haemolytica. In conjunction with literature data on MIC(90) values, the present results allowed prediction of dosages for efficacy for each organism for the three levels of growth inhibition.

  12. Pharmacokinetic modeling: Prediction and evaluation of route dependent dosimetry of bisphenol A in monkeys with extrapolation to humans

    Energy Technology Data Exchange (ETDEWEB)

    Fisher, Jeffrey W., E-mail:; Twaddle, Nathan C.; Vanlandingham, Michelle; Doerge, Daniel R.


    A physiologically based pharmacokinetic (PBPK) model was developed for bisphenol A (BPA) in adult rhesus monkeys using intravenous (iv) and oral bolus doses of 100 {mu}g d6-BPA/kg (). This calibrated PBPK adult monkey model for BPA was then evaluated against published monkey kinetic studies with BPA. Using two versions of the adult monkey model based on monkey BPA kinetic data from and , the aglycone BPA pharmacokinetics were simulated for human oral ingestion of 5 mg d16-BPA per person (Voelkel et al., 2002). Voelkel et al. were unable to detect the aglycone BPA in plasma, but were able to detect BPA metabolites. These human model predictions of the aglycone BPA in plasma were then compared to previously published PBPK model predictions obtained by simulating the Voelkel et al. kinetic study. Our BPA human model, using two parameter sets reflecting two adult monkey studies, both predicted lower aglycone levels in human serum than the previous human BPA PBPK model predictions. BPA was metabolized at all ages of monkey (PND 5 to adult) by the gut wall and liver. However, the hepatic metabolism of BPA and systemic clearance of its phase II metabolites appear to be slower in younger monkeys than adults. The use of the current non-human primate BPA model parameters provides more confidence in predicting the aglycone BPA in serum levels in humans after oral ingestion of BPA. -- Highlights: Black-Right-Pointing-Pointer A bisphenol A (BPA) PBPK model for the infant and adult monkey was constructed. Black-Right-Pointing-Pointer The hepatic metabolic rate of BPA increased with age of the monkey. Black-Right-Pointing-Pointer The systemic clearance rate of metabolites increased with age of the monkey. Black-Right-Pointing-Pointer Gut wall metabolism of orally administered BPA was substantial across all ages of monkeys. Black-Right-Pointing-Pointer Aglycone BPA plasma concentrations were predicted in humans orally given oral doses of deuterated BPA.

  13. Pharmacokinetics-Based Approaches for Bioequivalence Evaluation of Topical Dermatological Drug Products. (United States)

    Raney, Sam G; Franz, Thomas J; Lehman, Paul A; Lionberger, Robert; Chen, Mei-Ling


    The pharmacokinetic approach has accelerated the development of high-quality generic medicines with extraordinary cost savings, transforming the pharmaceutical industry and healthcare system in the USA. While this is true for systemically absorbed drug products, the availability of generic versions of topical dermatological products remains constrained due to the limited methods accepted for bioequivalence evaluation of these products. The current review explores the possibility of developing appropriate bioequivalence approaches based on pharmacokinetic principles for topical dermatological products. This review focuses on the strengths and limitations of the three most promising pharmacokinetics-based methods to evaluate the performance and bioequivalence of topical dermatological products, which include in vivo skin stripping, in vivo microdialysis, and in vitro permeation testing (IVPT) with excised human skin. It is hoped that recent advances in pharmaceutical and regulatory science will facilitate the development of robust bioequivalence approaches for these dosage forms, enable more efficient methodologies to compare the performance of new drug products in certain pre-approval or post-approval change situations, and promote the availability of high-quality generic versions of topical dermatological products.

  14. Validation of a Best-Fit Pharmacokinetic Model for Scopolamine Disposition after Intranasal Administration (United States)

    Wu, L.; Chow, D. S-L.; Tam, V.; Putcha, L.


    An intranasal gel formulation of scopolamine (INSCOP) was developed for the treatment of Motion Sickness. Bioavailability and pharmacokinetics (PK) were determined per Investigative New Drug (IND) evaluation guidance by the Food and Drug Administration. Earlier, we reported the development of a PK model that can predict the relationship between plasma, saliva and urinary scopolamine (SCOP) concentrations using data collected from an IND clinical trial with INSCOP. This data analysis project is designed to validate the reported best fit PK model for SCOP by comparing observed and model predicted SCOP concentration-time profiles after administration of INSCOP.

  15. Novel endogenous glycan therapy for retinal diseases: safety, in vitro stability, ocular pharmacokinetic modeling, and biodistribution. (United States)

    Swaminathan, Shankar; Li, Huiling; Palamoor, Mallika; de Obarrio, Walter T Luchsinger; Madhura, Dorababu; Meibohm, Bernd; Jablonski, Monica M


    Asialo, tri-antennary oligosaccharide (NA3 glycan) is an endogenous compound, which supports proper folding of outer segment membranes, promotes normal ultrastructure, and maintains protein expression patterns of photoreceptors and Müller cells in the absence of retinal pigment epithelium support. It is a potential new therapeutic for atrophic age-related macular degeneration (AMD) and other retinal degenerative disorders. Herein, we evaluate the safety, in vitro stability, ocular pharmacokinetics and biodistribution of NA3. NA3 was injected into the vitreous of New Zealand white rabbits at two concentrations viz. 1 nM (minimum effective concentration (MEC)) and 100 nM (100XMEC) at three time points. Safety was evaluated using routine clinical and laboratory tests. Ocular pharmacokinetics and biodistribution of [(3)H]NA3 were estimated using scintillation counting in various parts of the eye, multiple peripheral organs, and plasma. Pharmacokinetic parameters were estimated by non-compartmental modeling. A 2-aminobenzamide labeling and hydrophilic interaction liquid interaction chromatography were used to assess plasma and vitreous stability. NA3 was well tolerated by the eye. The concentration of NA3 in eye tissues was in the order: vitreous > retina > sclera/choroid > aqueous humor > cornea > lens. Area under the curve (0 to infinity) (AUC∞) was the highest in the vitreous thereby providing a positive concentration gradient for NA3 to reach the retina. Half-lives in critical eye tissues ranged between 40 and 60 h. NA3 concentrations were negligible in peripheral organs. Radioactivity from [(3)H]NA3 was excreted via urine and feces. NA3 was stable at 37°C in vitreous over a minimum of 6 days, while it degraded rapidly in plasma. Collectively, these results document that NA3 shows a good safety profile and favorable ocular pharmacokinetics.

  16. Pharmacokinetic aspects and in vitro–in vivo correlation potential for lipid-based formulations

    Directory of Open Access Journals (Sweden)

    Sivacharan Kollipara


    Full Text Available Lipid-based formulations have been an attractive choice among novel drug delivery systems for enhancing the solubility and bioavailability of poorly soluble drugs due to their ability to keep the drug in solubilized state in the gastrointestinal tract. These formulations offer multiple advantages such as reduction in food effect and inter-individual variability, ease of preparation, and the possibility of manufacturing using common excipients available in the market. Despite these advantages, very few products are available in the present market, perhaps due to limited knowledge in the in vitro tests (for prediction of in vivo fate and lack of understanding of the mechanisms behind pharmacokinetic and biopharmaceutical aspects of lipid formulations after oral administration. The current review aims to provide a detailed understanding of the in vivo processing steps involved after oral administration of lipid formulations, their pharmacokinetic aspects and in vitro in vivo correlation (IVIVC perspectives. Various pharmacokinetic and biopharmaceutical aspects such as formulation dispersion and lipid digestion, bioavailability enhancement mechanisms, impact of excipients on efflux transporters, and lymphatic transport are discussed with examples. In addition, various IVIVC approaches towards predicting in vivo data from in vitro dispersion/precipitation, in vitro lipolysis and ex vivo permeation studies are also discussed in detail with help of case studies.

  17. Pharmacokinetic aspects and in vitro-in vivo correlation potential for lipid-based formulations. (United States)

    Kollipara, Sivacharan; Gandhi, Rajesh Kumar


    Lipid-based formulations have been an attractive choice among novel drug delivery systems for enhancing the solubility and bioavailability of poorly soluble drugs due to their ability to keep the drug in solubilized state in the gastrointestinal tract. These formulations offer multiple advantages such as reduction in food effect and inter-individual variability, ease of preparation, and the possibility of manufacturing using common excipients available in the market. Despite these advantages, very few products are available in the present market, perhaps due to limited knowledge in the in vitro tests (for prediction of in vivo fate) and lack of understanding of the mechanisms behind pharmacokinetic and biopharmaceutical aspects of lipid formulations after oral administration. The current review aims to provide a detailed understanding of the in vivo processing steps involved after oral administration of lipid formulations, their pharmacokinetic aspects and in vitro in vivo correlation (IVIVC) perspectives. Various pharmacokinetic and biopharmaceutical aspects such as formulation dispersion and lipid digestion, bioavailability enhancement mechanisms, impact of excipients on efflux transporters, and lymphatic transport are discussed with examples. In addition, various IVIVC approaches towards predicting in vivo data from in vitro dispersion/precipitation, in vitro lipolysis and ex vivo permeation studies are also discussed in detail with help of case studies.

  18. Population pharmacokinetic modeling of oxcarbazepine active metabolite in Chinese patients with epilepsy. (United States)

    Yu, Yunli; Zhang, Quanying; Xu, Wenjun; Lv, Chengzhe; Hao, Gang


    The aim of the study was to develop a population pharmacokinetic (PPK) model of oxcarbazepine and optimize the treatment of oxcarbazepine in Chinese patients with epilepsy. A total of 108 oxcarbazepine therapeutic drug monitoring samples from 78 patients with epilepsy were collected in this study. The pharmacologically active metabolite 10,11-dihydro-10-hydrocarbamazepine (MHD) was used as the analytical target for monitoring therapy of oxcarbazepine. Patients' clinical data were retrospectively collected. The PPK model for MHD was developed using Phoenix NLME 1.2 with a non-linear mixed-effect model. MHD pharmacokinetics obeys a one-compartment model with first-order absorption and elimination. The effect of age, gender, red blood cell count, red blood cell specific volume, hemoglobin (HGB), alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), and serum creatine were analyzed. Bootstrap and data splitting were used simultaneously to validate the final PPK models. The mean values of volume of distribution and clearance of MHD in the patients were 14.2 L and 2.38 L h(-1), respectively. BUN and HGB influenced the MHD volume of distribution according to the following equation: V = tvV × (BUN/4.76)(-0.007) × (HGB/140)(-0.001) × e (ηV) . The MHD clearance was dependent on ALT and gender as follows: CL = tvCL × (ALT/30)(0.181) × (gender) × 1.083 × e (ηCL). The final PPK model was demonstrated to be suitable and effective and it can be used to evaluate the pharmacokinetic parameters of MHD in Chinese patients with epilepsy and to choose an optimal dosage regimen of oxcarbazepine on the basis of these parameters.

  19. Pharmacokinetic-pharmacodynamic modelling of opioids in healthy human volunteers. A minireview



    Pain is characterized by its multi-dimensional nature, explaining in part why the pharmacokinetic/pharmacodynamic (PK/PD) relationships are not straightforward for analgesics. The first part of this MiniReview gives an overview of PK, PD and PK/PD models, as well as of population approach used in analgesic studies. The second part updates the state-of-the-art in the PK/PD relationship of opioids, focusing on data obtained on experimental human pain models, a useful tool to characterize the PD...

  20. A Population Pharmacokinetic Model for Disposition in Plasma, Saliva and Urine of Scopolamine after Intranasal Administration to Healthy Human Subjects (United States)

    Wu, L.; Tam, V. H.; Chow, D. S. L.; Putcha, L.


    An intranasal gel formulation of scopolamine (INSCOP) was developed for the treatment of Space Motion Sickness. The bioavailability and pharmacokinetics (PK) were evaluated under the Food and Drug Administration guidelines for clinical trials with an Investigative New Drug (IND) protocol. The aim of this project was to develop a PK model that can predict the relationship between plasma, saliva and urinary scopolamine concentrations using data collected from the IND clinical trials with INSCOP. Methods: Twelve healthy human subjects were administered three dose levels (0.1, 0.2 and 0.4 mg) of INSCOP. Serial blood, saliva and urine samples were collected between 5 min and 24 h after dosing and scopolamine concentrations were measured by using a validated LC-MS-MS assay. Pharmacokinetic Compartmental models, using actual dosing and sampling times, were built using Phoenix (version 1.2). Model selection was based on the likelihood ratio test on the difference of criteria (-2LL) and comparison of the quality of fit plots. Results: The best structural model for INSCOP (minimal -2LL= 502.8) was established. It consisted of one compartment each for plasma, saliva and urine, respectively, which were connected with linear transport processes except the nonlinear PK process from plasma to saliva compartment. The best-fit estimates of PK parameters from individual PK compartmental analysis and Population PK model analysis were shown in Tables 1 and 2, respectively. Conclusion: A population PK model that could predict population and individual PK of scopolamine in plasma, saliva and urine after dosing was developed and validated. Incorporating a non-linear transfer from plasma to saliva compartments resulted in a significantly improved model fitting. The model could be used to predict scopolamine plasma concentrations from salivary and urinary drug levels, allowing non-invasive therapeutic monitoring of scopolamine in space and other remote environments.

  1. Signal-to-noise ratio, contrast-to-noise ratio and pharmacokinetic modeling considerations in dynamic contrast-enhanced magnetic resonance imaging. (United States)

    Li, Xin; Huang, Wei; Rooney, William D


    With advances in magnetic resonance imaging (MRI) technology, dynamic contrast-enhanced (DCE)-MRI is approaching the capability to simultaneously deliver both high spatial and high temporal resolutions for clinical applications. However, signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) considerations and their impacts regarding pharmacokinetic modeling of the time-course data continue to represent challenges in the design of DCE-MRI acquisitions. Given that many acquisition parameters can affect the nature of DCE-MRI data, minimizing tissue-specific data acquisition discrepancy (among sites and scanner models) is as important as synchronizing pharmacokinetic modeling approaches. For cancer-related DCE-MRI studies where rapid contrast reagent (CR) extravasation is expected, current DCE-MRI protocols often adopt a three-dimensional fast low-angle shot (FLASH) sequence to achieve spatial-temporal resolution requirements. Based on breast and prostate DCE-MRI data acquired with different FLASH sequence parameters, this paper elucidates a number of SNR and CNR considerations for acquisition optimization and pharmacokinetic modeling implications therein. Simulations based on region of interest data further indicate that the effects of intercompartmental water exchange often play an important role in DCE time-course data modeling, especially for protocols optimized for post-CR SNR.

  2. Pharmacokinetic and pharmacodynamic modelling of marbofloxacin administered alone and in combination with tolfenamic acid in goats. (United States)

    Sidhu, P K; Landoni, M F; Aliabadi, F S; Lees, P


    In a four-period cross-over study, the fluoroquinolone antibacterial drug marbofloxacin (MB) was administered to goats intramuscularly (IM) at a dose rate of 2 mg/kg, both alone and in combination with the non-steroidal anti-inflammatory drug tolfenamic acid (TA), also administered IM at a dose rate of 2 mg/kg. Using a tissue cage model of inflammation, based on the irritant actions of carrageenan, the pharmacokinetics (PK) of MB and MB in combination with TA were determined. MB mean values of area under concentration-time curve (AUC) were similar for serum (5.60 microg h/mL), inflamed tissue cage fluid (exudate; 5.32 microg h/mL) and non-inflamed tissue cage fluid (transudate; 4.82 microg h/mL). Values of mean residence time (MRT) of MB in exudate (15.5 h) and transudate (15.8 h) differed significantly from serum MRT (4.23 h). Co-administration of TA did not affect the PK profile of MB. The pharmacodynamics of MB were investigated using a caprine strain of Mannheimia haemolytica. Integration of PK data with ex vivo bacterial time-kill curve data for serum, exudate and transudate provided AUC(24h)/minimum inhibitory concentration (MIC) ratios of 160, 133 and 121 h, respectively, for the strain of organism used. Modelling of the ex vivo time-kill data to the sigmoid E(max) equation provided AUC(24h)/MIC values required for bacteriostatic and bactericidal actions of MB and for virtual eradication of the organism of 27.6, 96.2 and 147.3 h, respectively. Corresponding values for MB+TA were 20.5, 66.5 and 103.0 h. These data were used to predict once daily dosage schedules of MB for subsequent clinical evaluation.

  3. Population Pharmacokinetic Modeling of Tribendimidine Metabolites in Opisthorchis viverrini-Infected Adults (United States)

    Penny, Melissa A.; Duthaler, Urs; Odermatt, Peter; Sayasone, Somphou; Keiser, Jennifer


    There is a pressing need for alternative treatments against the liver fluke Opisthorchis viverrini. Oral tribendimidine is a promising candidate, but its population pharmacokinetic properties are unknown. Two phase IIa trials were conducted in Laos in O. viverrini-infected adults receiving single oral doses of 25 to 600 mg tribendimidine administered as different formulations in each study (study 1 used 200-mg tablets, and study 2 used 50-mg tablets). Venous whole blood, plasma, and capillary dried blood spots were sampled frequently from 68 adults, and concentrations of the tribendimidine metabolites dADT (deacetylated amidantel) and adADT (acetylated dADT) were measured. Population pharmacokinetics were assessed by using nonlinear mixed-effects modeling. The relationship between drug exposure and cure (assessed at 21 days posttreatment) was evaluated by using univariable logistic regression. A six-transit compartment absorption model with a one-disposition compartment for each metabolite described the data well. Compared to the 50-mg formulation (study 2), the 200-mg formulation (study 1) had a 40.1% higher mean transit absorption time, a 113% higher dADT volume of distribution, and a 364% higher adADT volume of distribution. Each 10-year increase in age was associated with a 12.7% lower dADT clearance and a 21.2% lower adADT clearance. The highest cure rates (≥55%) were observed with doses of ≥100 mg. Higher dADT, but not adADT, peak concentrations and exposures were associated with cure (P = 0.004 and 0.003, respectively). For the first time, population pharmacokinetics of tribendimidine have been described. Known differences in the 200-mg versus 50-mg formulations were captured by covariate modeling. Further studies are needed to validate the structural model and confirm covariate relationships. (This study has been registered with the ISRCTN Registry under no. ISRCTN96948551.) PMID:27431233

  4. PNIPAM nanoparticles for targeted and enhanced nose-to-brain delivery of curcuminoids: UPLC/ESI-Q-ToF-MS/MS-based pharmacokinetics and pharmacodynamic evaluation in cerebral ischemia model. (United States)

    Ahmad, Niyaz; Ahmad, Iqbal; Umar, Sadiq; Iqbal, Zeenat; Samim, Mohd; Ahmad, Farhan Jalees


    Stroke is a one of the leading causes of disease and deaths worldwide, which causes irreversible deterioration of the central nervous system. Curcuminoids are reported to have a potential role in the amelioration of cerebral ischemia but they exhibit low serum and tissue levels due to low solubility and poor absorption. Curcumin (CUR), demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC)-loaded PNIPAM nanoparticles (NPs) were prepared by free radical polymerization and characterized for particles size, entrapment efficiency, zeta potential, in vitro release and ex vivo permeation study. Optimized CUR, DMC and BDMC-loaded NPs had the mean size of 92.46 ± 2.8, 91.23 ± 4.2 and 94.28 ± 1.91 nm; zeta potential of -16.2 ± 1.42, -15.6 ± 1.33 and -16.6 ± 1.21 mV; loading capacity of 39.31 ± 3.7, 38.91 ± 3.6 and 40.61 ± 3.6% and entrapment efficiency of 84.63 ± 4.2, 84.71 ± 3.99 and 85.73 ± 4.31%, respectively. Ultra-performance liquid chromatography/electrospray ionization quadrupole time-of-flight mass spectroscopy based bioanalytical method was developed and validated for pharmacokinetics, biodistribution, brain-targeting efficiency and brain drug-targeting potential studies post-intranasal (i.n.) administration which showed enhanced bioavailability of curcuminoids in brain as compared to intravenous administration. Improved neurobehavioural activity (locomotor and grip strength) and reduced cytokines levels (TNF-α and IL-1β) was observed in middle cerebral artery occlusion induced cerebral ischemic rats after i.n. administration of curcuminoids NPs. Finally, the toxicity study was performed which revealed safe nature of developed NPs.

  5. An Engineering Approach to Biomedical Sciences: Advanced Testing Methods and Pharmacokinetic Modeling (United States)

    Lamberti, Gaetano; Cascone, Sara; Titomanlio, Giuseppe


    In this paper, the philosophy of a research in pharmacology field, driven by an engineering approach, was described along with some case histories and examples. The improvement in the testing methods for pharmaceutical systems (in-vitro techniques), as well as the proposal and the testing of mathematical models to describe the pharmacokinetics (in-silico techniques) are reported with the aim of pointing out methodologies and tools able to reduce the need of expensive and ethical problematic in-vivo measurements. PMID:23905061

  6. Application of a single-objective, hybrid genetic algorithm approach to pharmacokinetic model building. (United States)

    Sherer, Eric A; Sale, Mark E; Pollock, Bruce G; Belani, Chandra P; Egorin, Merrill J; Ivy, Percy S; Lieberman, Jeffrey A; Manuck, Stephen B; Marder, Stephen R; Muldoon, Matthew F; Scher, Howard I; Solit, David B; Bies, Robert R


    A limitation in traditional stepwise population pharmacokinetic model building is the difficulty in handling interactions between model components. To address this issue, a method was previously introduced which couples NONMEM parameter estimation and model fitness evaluation to a single-objective, hybrid genetic algorithm for global optimization of the model structure. In this study, the generalizability of this approach for pharmacokinetic model building is evaluated by comparing (1) correct and spurious covariate relationships in a simulated dataset resulting from automated stepwise covariate modeling, Lasso methods, and single-objective hybrid genetic algorithm approaches to covariate identification and (2) information criteria values, model structures, convergence, and model parameter values resulting from manual stepwise versus single-objective, hybrid genetic algorithm approaches to model building for seven compounds. Both manual stepwise and single-objective, hybrid genetic algorithm approaches to model building were applied, blinded to the results of the other approach, for selection of the compartment structure as well as inclusion and model form of inter-individual and inter-occasion variability, residual error, and covariates from a common set of model options. For the simulated dataset, stepwise covariate modeling identified three of four true covariates and two spurious covariates; Lasso identified two of four true and 0 spurious covariates; and the single-objective, hybrid genetic algorithm identified three of four true covariates and one spurious covariate. For the clinical datasets, the Akaike information criterion was a median of 22.3 points lower (range of 470.5 point decrease to 0.1 point decrease) for the best single-objective hybrid genetic-algorithm candidate model versus the final manual stepwise model: the Akaike information criterion was lower by greater than 10 points for four compounds and differed by less than 10 points for three

  7. Limitations of Single Slice Dynamic Contrast Enhanced MR in Pharmacokinetic Modeling of Bone Sarcomas

    Energy Technology Data Exchange (ETDEWEB)

    Toms, Andoni P. (Dept. of Radiology, The Norfolk and Norwich Univ. Hospital, Norwich, Norfolk (United Kingdom)); White, Lawrence M.; Bleakney, Robert R. (Dept. of Medical Imaging, Mount Sinai Hospital, Toronto, ON (Canada)); Kandel, Rita (Dept. of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON (Canada)); Noseworthy, Michael (Health Sciences Centre, Faculty of Health Sciences, McMaster Univ., Hamilton, ON (Canada)); Lee, Shepstone (Institute of Health, Univ. of East Anglia, Norwich, Norfolk (United Kingdom)); Blackstein, Martin E. (Dept. of Oncology, Mount Sinai Hospital, Toronto, ON (Canada)); Wunder, Jay (Musculoskeletal Oncology Unit, Mount Sinai Hospital, Toronto, ON (Canada))


    Background: Single slice dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) appears to provide perfusion data about sarcomas in vivo that correlate with tumor necrosis on equivalent pathological sections. However, sarcomas are heterogeneous and therefore single slice DCE-MRI may not correlate with total tumor necrosis. Purpose: To determine whether changes in pharmacokinetic modeling of DCE-MRI, during chemotherapy for primary bone sarcomas correlated with histological measures of total tumor necrosis. Material and Methods: Twelve patients with appendicular primary bone sarcomas were included in the study. Each patient had DCE-MRI before, and after completion, of pre-operative chemotherapy. The mean arterial slope (A), endothelial permeability coefficient (Ktrans), and extravascular extracellular volume (Ve) were derived from each data set using a modified two compartment pharmacokinetic model. Total tumor necrosis rates were compared with changes in A, Ktrans, and Ve. Results: Six patients had total tumor necrosis of =90% and six had a measure of <90%. The median percentage changes in A, Ktrans, and Ve for the =90% necrosis group were -52.5% (-83 to 6), -66% (-82 to 26), and 23.5% (-26 to 40), respectively. For the <90% necrosis group, A = - 35% (-75 to 132), Ktrans= - 53 (-66 to 149) and Ve= - 14.5% (-42 to 40). One patient with >90% necrosis had increases in all three measures. Comparison of the two groups generated P-values of 0.699 for A, 0.18 for Ktrans, and 0.31 for Ve. Conclusion: There was no statistically significant correlation between changes in pharmacokinetic perfusion parameters and total tumor necrosis. When using single slice DCE-MRI heterogeneous histology of primary bone sarcomas and repair mediated angiogenesis might both be confounding factors

  8. Dynamic 99mTc-MAG3 renography: images for quality control obtained by combining pharmacokinetic modelling, an anthropomorphic computer phantom and Monte Carlo simulated scintillation camera imaging (United States)

    Brolin, Gustav; Sjögreen Gleisner, Katarina; Ljungberg, Michael


    In dynamic renal scintigraphy, the main interest is the radiopharmaceutical redistribution as a function of time. Quality control (QC) of renal procedures often relies on phantom experiments to compare image-based results with the measurement setup. A phantom with a realistic anatomy and time-varying activity distribution is therefore desirable. This work describes a pharmacokinetic (PK) compartment model for 99mTc-MAG3, used for defining a dynamic whole-body activity distribution within a digital phantom (XCAT) for accurate Monte Carlo (MC)-based images for QC. Each phantom structure is assigned a time-activity curve provided by the PK model, employing parameter values consistent with MAG3 pharmacokinetics. This approach ensures that the total amount of tracer in the phantom is preserved between time points, and it allows for modifications of the pharmacokinetics in a controlled fashion. By adjusting parameter values in the PK model, different clinically realistic scenarios can be mimicked, regarding, e.g., the relative renal uptake and renal transit time. Using the MC code SIMIND, a complete set of renography images including effects of photon attenuation, scattering, limited spatial resolution and noise, are simulated. The obtained image data can be used to evaluate quantitative techniques and computer software in clinical renography.

  9. Pharmacokinetic/pharmacodynamic evaluation of sulbactam against Acinetobacter baumannii in in vitro and murine thigh and lung infection models. (United States)

    Yokoyama, Yuta; Matsumoto, Kazuaki; Ikawa, Kazuro; Watanabe, Erika; Shigemi, Akari; Umezaki, Yasuhiro; Nakamura, Koyo; Ueno, Keiichiro; Morikawa, Norifumi; Takeda, Yasuo


    Acinetobacter baumannii is a pathogen that has become globally associated with nosocomial infections. Sulbactam, a potent inhibitor of β-lactamases, was previously shown to be active against A. baumannii strains in vitro and effective against A. baumannii infections. However, a pharmacokinetic/pharmacodynamic (PK/PD) analysis of sulbactam against A. baumannii infections has not yet been performed. This is necessary because optimisation of dosing regimens should be based on PK/PD analysis. Therefore, in vitro and in vivo PK/PD analyses of sulbactam were performed using murine thigh and lung infection models of A. baumannii to evaluate the pharmacokinetics and pharmacodynamics of sulbactam. Sulbactam showed time-dependent bactericidal activity in vitro against A. baumannii. The PK/PD index that best correlated with its in vivo effects was the time that the free drug concentration remained above the minimum inhibitory concentration (fT>MIC) both in the thigh (R(2)=0.95) and lung (R(2)=0.96) infection models. Values of fT>MIC for a static effect and 1, 2 and 3log10 kill, respectively, were 21.0%, 32.9%, 43.6% and 57.3% in the thigh infection model and 20.4%, 24.5%, 29.3% and 37.3% in the lung infection model. Here we report the in vitro and in vivo time-dependent activities of sulbactam against A. baumannii infection and demonstrate that sulbactam was sufficiently bactericidal when an fT>MIC of >60% against A. baumannii thigh infection and >40% against A. baumannii lung infection was achieved.

  10. Correlation between macrolide lung pharmacokinetics and therapeutic efficacy in a mouse model of pneumococcal pneumonia. (United States)

    Veber, B; Vallée, E; Desmonts, J M; Pocidalo, J J; Azoulay-Dupuis, E


    The correlation between the pharmacokinetics of erythromycin, roxithromycin, clarithromycin, spiramycin and azithromycin and their efficacy was investigated in two pneumococcal pneumonia models. Female Swiss and C57B1/6 mice were infected with Streptococcus pneumoniae strain P4241 by the intratracheal per oral route. This virulent strain produces acute pneumonia with death within 3-4 days (Swiss mice), or subacute pneumonia with death within 10 days (C57B1/6 mice) in untreated mice and the outcome of the disease is closely related to progressive weight loss. Swiss mice received three doses of each macrolide 50 mg/kg bd beginning 18 h post-infection. C57B1/6 mice received three doses of each macrolide 25 mg/kg, bd (except azithromycin was 12.5 mg/kg bd) beginning 48 h post-infection. Cure rates were evaluated on the basis of body weight variations recorded daily after the end of treatment. Pharmacokinetic parameters were determined in infected and non-infected mice after a single dose of each macrolide 50 mg/kg sc. The pharmacokinetics of azithromycin was also determined in leucopenic Swiss mice. We observed a hierarchy of in-vivo efficacy as follows: azithromycin > spiramycin = clarithromycin > roxithromycin = erythromycin which did not correlate with in-vitro MIC or MBC. The same hierarchy was found in terms of the lung T1/2. Lung T1/2s of macrolides could thus be predictive of their efficacy in respiratory tract infections. A reduced tissue AUC of azithromycin was seen in leucopenic mice suggesting leucocytes may help transport macrolides to sites of infection.

  11. A pharmacokinetic-pharmacodynamic model of morphine exposure and subsequent morphine consumption in postoperative pain

    DEFF Research Database (Denmark)

    Juul, Rasmus Vestergaard; Nyberg, Joakim; Lund, Trine Meldgaard


    Purpose To characterize the pharmacokinetic-pharmacodynamic (PK-PD) relationship between exposure of morphine and subsequent morphine consumption and to develop simulation tools for model validation. Methods Dose, formulation and time of morphine administration was available from a published study...... in 63 patients receiving intravenous, oral immediate release or oral controlled release morphine on request after hip surgery. The PK-PD relationship between predicted exposure of morphine and morphine consumption was modeled using repeated time to event (RTTE) modeling in NONMEM. To validate the RTTE...... model, a visual predictive check method was developed with simulated morphine consumption given the exposure of preceding morphine administration. Results The probability of requesting morphine was found to be significantly related to the exposure of morphine as well as night/day. Oral controlled...

  12. Assessing pharmacokinetics of different doses of fosfomycin in laboratory rats enables adequate exposure for pharmacodynamic models. (United States)

    Poeppl, Wolfgang; Lingscheid, Tilman; Bernitzky, Dominik; Donath, Oliver; Reznicek, Gottfried; Zeitlinger, Markus; Burgmann, Heinz


    Fosfomycin has been the subject of numerous pharmacodynamic in vivo models in recent years. The present study set out to determine fosfomycin pharmacokinetics in laboratory rats to enable adequate dosing regimens in future rodent models. Fosfomycin was given intraperitoneally as single doses of 75, 200 and 500 mg/kg bodyweight to 4 Sprague-Dawley rats per dose group. Blood samples were collected over 8 h and fosfomycin concentrations were determined by HPLC-mass spectrometry. Fosfomycin showed a dose-proportional pharmacokinetic profile indicated by a correlation of 0.99 for maximum concentration and area under the concentration-time curve (AUC). The mean AUC0-8 after intraperitoneal administration of 75, 200 or 500 mg/kg bodyweight fosfomycin were 109.4, 387.0 and 829.1 µg·h/ml, respectively. In conclusion, a dosing regimen of 200-500 mg/kg 3 times daily is appropriate to obtain serum concentrations in laboratory rats, closely mimicking human serum concentrations over time.

  13. Population pharmacokinetic-pharmacodynamic-disease progression model for effects of anakinra in Lewis rats with collagen-induced arthritis. (United States)

    Liu, Dongyang; Lon, Hoi-Kei; Dubois, Debra C; Almon, Richard R; Jusko, William J


    A population pharmacokinetic-pharmacodynamic-disease progression (PK/PD/DIS) model was developed to characterize the effects of anakinra in collagen-induced arthritic (CIA) rats and explore the role of interleukin-1β (IL-1β) in rheumatoid arthritis. The CIA rats received either vehicle, or anakinra at 100 mg/kg for about 33 h, 100 mg/kg for about 188 h, or 10 mg/kg for about 188 h by subcutaneous infusion. Plasma concentrations of anakinra were assayed by enzyme-linked immunosorbent assay. Swelling of rat hind paws was measured. Population PK/PD/DIS parameters were computed for the various groups using non-linear mixed-effects modeling software (NONMEM® Version VI). The final model was assessed using visual predictive checks and nonparameter stratified bootstrapping. A two-compartment PK model with two sequential absorption processes and linear elimination was used to capture PK profiles of anakinra. A transduction-based feedback model incorporating logistic growth rate captured disease progression and indirect response model I captured drug effects. The PK and paw swelling versus time profiles in CIA rats were fitted well. Anakinra has modest effects (I ( max ) = 0.28) on paw edema in CIA rats. The profiles are well-described by our PK/PD/DIS model which provides a basis for future mechanism-based assessment of anakinra dynamics in rheumatoid arthritis.

  14. Model-based meta-analysis for development of a population-pharmacokinetic (PPK) model for Vitamin D3 and its 25OHD3 metabolite using both individual and arm-level data. (United States)

    Ocampo-Pelland, Alanna S; Gastonguay, Marc R; French, Jonathan F; Riggs, Matthew M


    Clinical studies investigating relationships between D3 and 25OHD3 vary in dosing regimen, assays, demographics, and control of exogenous D3. This leads to uncertain and conflicting exposure-related associations with D3 and 25OHD3. To elucidate this parent-metabolite system, a PPK model was developed to predict mean D3 and 25OHD3 exposure from varied doses and administration routes. Sources of exposure variability related to metabolite baseline, weight, and assay type were explored. Specific search criteria were used in PUBMED to identify public source PK data pertaining to D3 and 25OHD3 in healthy or osteoporotic populations. Overall 57 studies representing 5395 individuals were selected, including 25 individual-level profiles and treatment-arm data. IV, oral, single and multiple dose data were used, with D3 and 25OHD3 dosing. A nonlinear mixed effects model was developed to simultaneously model PK dispositions of D3 and 25OHD3 (NONMEM v7.2), which were described by 2-compartment models with nonlinear and linear clearances, respectively. Proportional and additive assay variances were included on the 25OHD3 prediction. Unit-level random effects were weighted by treatment-arm size. D3 model estimates, relative to bioavailability were: maximum rate of metabolism ([Formula: see text], 1.62 nmol/h), Michaelis-Menten constant ([Formula: see text], 6.39 nmol/L), central volume of distribution ([Formula: see text], 15.5 L), intercompartmental clearance ([Formula: see text], 0.185 L/h), peripheral volume of distribution ([Formula: see text], 2333 L/h), and baseline concentration ([Formula: see text], 3.75 nmol/L). For 25OHD3 ([Formula: see text] = metabolite): [Formula: see text] = 0.0153 L/h, [Formula: see text] = 4.35 L, [Formula: see text] = 6.87 L, [Formula: see text] = 0.0507 L/h. Simulations of 25OHD3 concentration indicated an inverse relationship between 25OHD3 baseline and response, as well as a less than proportional 25OHD3 response. Estimation of assay bias

  15. Dosage assessment of valnemulin in pigs based on population pharmacokinetic and Monte Carlo simulation. (United States)

    Yuan, L G; Tang, Y Z; Zhang, Y X; Sun, J; Luo, X Y; Zhu, L X; Zhang, Z; Wang, R; Liu, Y H


    To estimate the valnemulin pharmacokinetic profile in a swine population and to assess a dosage regimen for increasing the likelihood of optimization. This study was, respectively, performed in 22 sows culled by p.o. administration and in 80 growing-finishing pigs by i.v. administration at a single dose of 10 mg/kg to develop a population pharmacokinetic model and Monte Carlo simulation. The relationships among the plasma concentration, dose, and time of valnemulin in pigs were illustrated as C(i,v) = X(0 )(8.4191 × 10(-4) × e(-0.2371t) + 1.2788 × 10(-5) × e(-0.0069t)) after i.v. and C(p.o) = X(0) (-8.4964 × 10(-4) × e(-0.5840t) + 8.4195 × e(-0.2371t) + 7.6869 × 10(-6) × e(-0.0069t)) after p.o. Monte Carlo simulation showed that T(>MIC) was more than 24 h when a single daily dosage at 13.5 mg/kg BW in pigs was administrated by p.o., and MIC was 0.031 mg/L. It was concluded that the current dosage regimen at 10-12 mg/kg BW led to valnemulin underexposure if the MIC was more than 0.031 mg/L and could increase the risk of treatment failure and/or drug resistance.

  16. Computational approaches and metrics required for formulating biologically realistic nanomaterial pharmacokinetic models (United States)

    Riviere, Jim E.; Scoglio, Caterina; Sahneh, Faryad D.; Monteiro-Riviere, Nancy A.


    The field of nanomaterial pharmacokinetics is in its infancy, with major advances largely restricted by a lack of biologically relevant metrics, fundamental differences between particles and small molecules of organic chemicals and drugs relative to biological processes involved in disposition, a scarcity of sufficiently rich and characterized in vivo data and a lack of computational approaches to integrating nanomaterial properties to biological endpoints. A central concept that links nanomaterial properties to biological disposition, in addition to their colloidal properties, is the tendency to form a biocorona which modulates biological interactions including cellular uptake and biodistribution. Pharmacokinetic models must take this crucial process into consideration to accurately predict in vivo disposition, especially when extrapolating from laboratory animals to humans since allometric principles may not be applicable. The dynamics of corona formation, which modulates biological interactions including cellular uptake and biodistribution, is thereby a crucial process involved in the rate and extent of biodisposition. The challenge will be to develop a quantitative metric that characterizes a nanoparticle's surface adsorption forces that are important for predicting biocorona dynamics. These types of integrative quantitative approaches discussed in this paper for the dynamics of corona formation must be developed before realistic engineered nanomaterial risk assessment can be accomplished.

  17. Rational design of CPP-based drug delivery systems: considerations from pharmacokinetics. (United States)

    Mickan, Arite; Sarko, Dikran; Haberkorn, Uwe; Mier, Walter


    Therapeutics are restricted from cellular internalization due to the biological barrier formed by the cell membrane. Especially for therapeutics with high molecular weight, strategies are required to enable delivery to intracellular targets. Cell-penetrating peptides (CPPs) represent a powerful tool to mediate the entry of large cargos such as proteins, siRNA and nanoparticles. The high diversity of CPPs is the prerequisite to use this class of carriers for various applications. However, therapies based on CPPs are hampered by their unfavorable pharmacokinetics, mainly dominated by their rapid renal clearance and their lack of specificity. Rational design is required to overcome these disadvantages and thereby exploits the actual potential of CPPs. We summarize and highlight the current state of knowledge with special emphasis on pharmacokinetics. The unclear internalization pathways of CPPs remain one of the main obstacles and therefore have been in the focus of research. In this review, several promising strategies such as the combination with targeting sequences, activatable CPPs and adjustment of the molecular weight are described. In addition, new absorption pathways such as nasal, pulmonary or transdermal uptake expand the applicability of CPPs and may be a promising prospect for clinical application.

  18. Population modeling and simulation study of the pharmacokinetics and antituberculosis pharmacodynamics of isoniazid in lungs. (United States)

    Lalande, L; Bourguignon, L; Bihari, S; Maire, P; Neely, M; Jelliffe, R; Goutelle, S


    Among first-line antituberculosis drugs, isoniazid (INH) displays the greatest early bactericidal activity (EBA) and is key to reducing contagiousness in treated patients. The pulmonary pharmacokinetics and pharmacodynamics of INH have not been fully characterized with modeling and simulation approaches. INH concentrations measured in plasma, epithelial lining fluid, and alveolar cells for 89 patients, including fast acetylators (FAs) and slow acetylators (SAs), were modeled by use of population pharmacokinetic modeling. Then the model was used to simulate the EBA of INH in lungs and to investigate the influences of INH dose, acetylator status, and M. tuberculosis MIC on this effect. A three-compartment model adequately described INH concentrations in plasma and lungs. With an MIC of 0.0625 mg/liter, simulations showed that the mean bactericidal effect of a standard 300-mg daily dose of INH was only 11% lower for FA subjects than for SA subjects and that dose increases had little influence on the effects in either FA or SA subjects. With an MIC value of 1 mg/liter, the mean bactericidal effect associated with a 300-mg daily dose of INH in SA subjects was 41% greater than that in FA subjects. With the same MIC, increasing the daily INH dose from 300 mg to 450 mg resulted in a 22% increase in FA subjects. These results suggest that patients infected with M. tuberculosis with low-level resistance, especially FA patients, may benefit from higher INH doses, while dose adjustment for acetylator status has no significant impact on the EBA in patients with low-MIC strains.

  19. Pharmacokinetic and pharmacodynamic modelling of marbofloxacin administered alone and in combination with tolfenamic acid in calves. (United States)

    Sidhu, P K; Landoni, M F; Aliabadi, M H S; Toutain, P L; Lees, P


    In a four-period, cross-over study, the fluoroquinolone antibacterial drug marbofloxacin (MB) was administered to calves, alone and in combination with the nonsteroidal anti-inflammatory drug tolfenamic acid (TA). Both drugs were administered intramuscularly (IM) at doses of 2 mg/kg. A tissue cage model of inflammation, based on the actions of the mild irritant carrageenan, was used to evaluate the pharmacokinetics (PK) of MB and MB in combination with TA. MB mean values of area under concentration-time curve (AUC) were 15.1 μg·h/mL for serum, 12.1 μg·h/mL for inflamed tissue cage fluid (exudate) and 9.6 μg·h/mL for noninflamed tissue cage fluid (transudate). Values of C(max) were 1.84, 0.35 and 0.31 μg/mL, respectively, for serum, exudate and transudate. Mean residence time (MRT) of 23.6 h (exudate) and 22.6 h (transudate) also differed significantly from serum MRT (8.6 h). Co-administration of TA did not affect the PK profile of MB. The pharmacodynamics of MB was investigated using a bovine strain of Mannheimia haemolytica. Time-kill curves were established ex vivo on serum, exudate and transudate samples. Modelling the ex vivo serum time-kill data to the sigmoid E(max) equation provided AUC(24 h) /MIC values required for bacteriostatic (18.3 h) and bactericidal actions (92 h) of MB and for virtual eradication of the organism was 139 h. Corresponding values for MB + TA were 20.1, 69 and 106 h. These data were used to predict once daily dosage schedules for a bactericidal action, assuming a MIC(90) value of 0.24 μg/mL, a dose of 2.6 mg/kg for MB and 2.19 mg/kg for MB + TA were determined, which are similar to the currently recommended dose of 2.0 mg/kg.

  20. Population Pharmacokinetics of Intranasal Scopolamine (United States)

    Wu, L.; Chow, D. S. L.; Putcha, L.


    Introduction: An intranasal gel dosage formulation of scopolamine (INSCOP) was developed for the treatment of Space Motion Sickness (SMS).The bioavailability and pharmacokinetics (PK) was evaluated using data collected in Phase II IND protocols. We reported earlier statistically significant gender differences in PK parameters of INSCOP at a dose level of 0.4 mg. To identify covariates that influence PK parameters of INSCOP, we examined population covariates of INSCOP PK model for 0.4 mg dose. Methods: Plasma scopolamine concentrations versus time data were collected from 20 normal healthy human subjects (11 male/9 female) after a 0.4 mg dose. Phoenix NLME was employed for PK analysis of these data using gender, body weight and age as covariates for model selection. Model selection was based on a likelihood ratio test on the difference of criteria (-2LL). Statistical significance for base model building and individual covariate analysis was set at P less than 0.05{delta(-2LL)=3.84}. Results: A one-compartment pharmacokinetic model with first-order elimination best described INSCOP concentration ]time profiles. Inclusion of gender, body weight and age as covariates individually significantly reduced -2LL by the cut-off value of 3.84(P less than 0.05) when tested against the base model. After the forward stepwise selection and backward elimination steps, gender was selected to add to the final model which had significant influence on absorption rate constant (ka) and the volume of distribution (V) of INSCOP. Conclusion: A population pharmacokinetic model for INSCOP has been identified and gender was a significant contributing covariate for the final model. The volume of distribution and Ka were significantly higher in males than in females which confirm gender-dependent pharmacokinetics of scopolamine after administration of a 0.4 mg dose.

  1. Pharmacokinetic and pharmacodynamic evaluation of AZD5847 in a mouse model of tuberculosis. (United States)

    Balasubramanian, V; Solapure, Suresh; Shandil, Radha; Gaonkar, Sheshagiri; Mahesh, K N; Reddy, Jitender; Deshpande, Abhijeet; Bharath, Sowmya; Kumar, Naveen; Wright, Lindsay; Melnick, David; Butler, Scott L


    AZD5847, a novel oxazolidinone with an MIC of 1 μg/ml, exhibits exposure-dependent killing kinetics against extracellular and intracellular Mycobacterium tuberculosis. Oral administration of AZD5847 to mice infected with M. tuberculosis H37Rv in a chronic-infection model resulted in a 1.0-log10 reduction in the lung CFU count after 4 weeks of treatment at a daily area under the concentration-time curve (AUC) of 105 to 158 μg · h/ml. The pharmacokinetic-pharmacodynamic parameter that best predicted success in an acute-infection model was an AUC for the free, unbound fraction of the drug/MIC ratio of ≥ 20. The percentage of time above the MIC in all of the efficacious regimens was 25% or greater.

  2. QbD-based carbopol transgel formulation: characterization, pharmacokinetic assessment and therapeutic efficacy in diabetes. (United States)

    Prasad, Prem Sundar; Imam, Syed Sarim; Aqil, Mohammed; Sultana, Yasmin; Ali, Asgar


    In order to develop transdermal drug delivery system that facilitates the skin permeation of Pioglitazone (PZ) encapsulated in carbopol-based transgel system (proniosomes/niosome). The developed formulations were optimized using quality by design (QbD) approach and particle size, percentage entrapment and transdermal flux were determined. It was found to be more efficient delivery carriers with high encapsulation and enhanced flux value demonstrated that the permeation of PZ through skin was significantly increased with developed formulation. The transdermal enhancement from proniosome was 3.16 times higher than that of PZ from control formulation (ethanol buffer formulation, 3:7), which was further confirmed by confocal laser scanning microscopy. In vivo pharmacokinetic study of carbopol transgel showed a significant increase in bioavailability (2.26 times) compared with tablet formulation. It also showed better antidiabetic activity in comparison to marketed tablet, so our results suggest that carbopol-based transgel are an efficient carrier for delivery of pioglitazone through skin.

  3. Pharmacokinetics/pharmacodynamics of antofloxacin hydrochloride in a neutropenic murine thigh model of Staphylococcus aureus infection

    Institute of Scientific and Technical Information of China (English)

    Xiu-mei XIAO; Yong-hong XIAO


    Aim:Antofloxacin hydrochloride is a new fluoroquinolone antibiotic with broad-spectrum in vitro activity.Using the neutropenic murine thigh infection model,we defined the pharmacodynamic profile and property of antofloxacin hydroehloride against Staphylococcus aureus.Methods:Single-dose pharmacokinetic studies of antofloxacin hydrochloride were carried out in thigh infected mice.Therapy was initiated at 2 h postinoculation with 5-640 mg/kg per d fractionated for different dosing regimens.The thighs were removed for bacterial measurement after 24 h of therapy,the best pharmacokinetic/ pharmacodynamic (PK/PD) index correlated with the efficacy was determined by nonlinear regression analysis.A sigmoid Emax dose-response model was used to estimate the daily dose and AUC24 h/MIC (minimal inhibitory concentration) required to achieve a static effect.Results:The PK was linear with similar elimination half-life over the dose range studied.The AUC24 h/MIC ratio was the PK/PD parameter that best correlated with efficacy (R2=92.3%,90.8% for the two organisms,compared with Cmax/MIC and T>MIC [%],respectively).The 24 h static dose ranged from 34.3 to 153.7 mg/kg per d for all S aureus strains,the total AUC24h/MIC ratio to achieve bacteriostatic effect varied from 31.7 to 122.5 (mean,65.7±30.6).Conclusion:Antofloxacin hydrochloride showed powerful antibacterial activity against the S aureus isolates used in our neutropenic infected mice model.Our data suggested that the AUC/MIC ratio appeared to be most closely linked to the bacterial outcome (R290%),and a total AUC24/MIC ratio of 65.7 appears to be the target value to achieve a net bactericidal activity against S aureus,similar to the results of other fluoroquinolones.

  4. Amikacin Pharmacokinetics/Pharmacodynamics in a Novel Hollow-Fiber Mycobacterium abscessus Disease Model. (United States)

    Ferro, Beatriz E; Srivastava, Shashikant; Deshpande, Devyani; Sherman, Carleton M; Pasipanodya, Jotam G; van Soolingen, Dick; Mouton, Johan W; van Ingen, Jakko; Gumbo, Tawanda


    The treatment of pulmonary Mycobacterium abscessus disease is associated with very high failure rates and easily acquired drug resistance. Amikacin is the key drug in treatment regimens, but the optimal doses are unknown. No good preclinical model exists to perform formal pharmacokinetics/pharmacodynamics experiments to determine these optimal doses. We developed a hollow-fiber system model of M. abscessus disease and studied amikacin exposure effects and dose scheduling. We mimicked amikacin human pulmonary pharmacokinetics. Both amikacin microbial kill and acquired drug resistance were linked to the peak concentration-to-MIC ratios; the peak/MIC ratio associated with 80% of maximal kill (EC80) was 3.20. However, on the day of the most extensive microbial kill, the bacillary burden did not fall below the starting inoculum. We performed Monte Carlo simulations of 10,000 patients with pulmonary M. abscessus infection and examined the probability that patients treated with one of 6 doses from 750 mg to 4,000 mg would achieve or exceed the EC80. We also examined these doses for the ability to achieve a cumulative area under the concentration-time curve of 82,232 mg · h/liter × days, which is associated with ototoxicity. The standard amikacin doses of 750 to 1,500 mg a day achieved the EC80 in ≤ 21% of the patients, while a dose of 4 g/day achieved this in 70% of the patients but at the cost of high rates of ototoxicity within a month or two. The susceptibility breakpoint was an MIC of 8 to 16 mg/liter. Thus, amikacin, as currently dosed, has limited efficacy against M. abscessus. It is urgent that different antibiotics be tested using our preclinical model and new regimens developed.

  5. Investigating the pharmacokinetics and biological distribution of silver-loaded polyphosphoester-based nanoparticles using (111) Ag as a radiotracer. (United States)

    Aweda, Tolulope A; Zhang, Shiyi; Mupanomunda, Chiedza; Burkemper, Jennifer; Heo, Gyu Seong; Bandara, Nilantha; Lin, Mai; Cutler, Cathy S; Cannon, Carolyn L; Youngs, Wiley J; Wooley, Karen L; Lapi, Suzanne E


    Purified (111) Ag was used as a radiotracer to investigate silver loading and release, pharmacokinetics, and biodistribution of polyphosphoester-based degradable shell crosslinked knedel-like (SCK) nanoparticles as a comparison to the previously reported small molecule, N-heterocyclic silver carbene complex analog (SCC1) for the delivery of therapeutic silver ions in mouse models. Biodistribution studies were conducted by aerosol administration of (111) Ag acetate, [(111) Ag]SCC1, and [(111) Ag]SCK doses directly into the lungs of C57BL/6 mice. Nebulization of the (111) Ag antimicrobials resulted in an average uptake of 1.07 ± 0.12% of the total aerosolized dose given per mouse. The average dose taken into the lungs of mice was estimated to be 2.6 ± 0.3% of the dose inhaled per mouse for [(111) Ag]SCC1 and twice as much dose was observed for the [(111) Ag]SCKs (5.0 ± 0.3% and 5.9 ± 0.8% for [(111) Ag]aSCK and [(111) Ag]zSCK, respectively) at 1 h post administration (p.a.). [(111) Ag]SCKs also exhibited higher dose retention in the lungs; 62-68% for [(111) Ag]SCKs and 43% for [(111) Ag]SCC1 of the initial 1 h dose were observed in the lungs at 24 h p.a.. This study demonstrates the utility of (111) Ag as a useful tool for monitoring the pharmacokinetics of silver-loaded antimicrobials in vivo.

  6. A framework for meta-analysis of veterinary drug pharmacokinetic data using mixed effect modeling. (United States)

    Li, Mengjie; Gehring, Ronette; Lin, Zhoumeng; Riviere, Jim


    Combining data from available studies is a useful approach to interpret the overwhelming amount of data generated in medical research from multiple studies. Paradoxically, in veterinary medicine, lack of data requires integrating available data to make meaningful population inferences. Nonlinear mixed-effects modeling is a useful tool to apply meta-analysis to diverse pharmacokinetic (PK) studies of veterinary drugs. This review provides a summary of the characteristics of PK data of veterinary drugs and how integration of these data may differ from human PK studies. The limits of meta-analysis include the sophistication of data mining, and generation of misleading results caused by biased or poor quality data. The overriding strength of meta-analysis applied to this field is that robust statistical analysis of the diverse sparse data sets inherent to veterinary medicine applications can be accomplished, thereby allowing population inferences to be made.

  7. Integrated exposure and dose modeling and analysis system. 1. Formulation and testing of microenvironmental and pharmacokinetic components

    Energy Technology Data Exchange (ETDEWEB)

    Georgopoulos, P.G.; Walia, A.; Roy, A.; Lioy, P.J. [Rutgers Univ. and Univ. of Medicine & Dentistry of New Jersey, Piscataway, NJ (United States)


    The conceptual and theoretical framework for a modular integrated Exposure and Dose Modeling and Analysis System (EDMAS) has been formulated, and its stepwise implementation and testing is currently in progress. This system aims to provide state-of-the art tools for performing integrated assessments of exposure and dose for individuals and populations. The integration of modeling components with each other as well as with available environmental, exposure, and toxicological databases in being accomplished with the use of computational tools that include interactive simulation environments, Geographical information Systems, and various data retrieval, management, statistical analysis, and visualization methods. This paper overviews the structure and modular nature of this integrated modeling system and focuses specifically on two of its components: (a) a hierarchy of physiologically based pharmacokinetic models (PBPKM), representing various levels of detail and sophistication, and (b) a family of microenvironmental models, that incorporate complex physical and chemical transformations. The deterministic implementation of these components is also presented here in two test applications: (i) a case study of benzene exposure indoors resulting from the volatilization of contaminated tap water and (ii) a case study of photochemical pollution infiltration indoors, in an office building environment. 77 refs., 6 figs., 2 tabs.

  8. Pharmacokinetics of Anti-VEGF Agent Aflibercept in Cancer Predicted by Data-Driven, Molecular-Detailed Model. (United States)

    Finley, S D; Angelikopoulos, P; Koumoutsakos, P; Popel, A S


    Mathematical models can support the drug development process by predicting the pharmacokinetic (PK) properties of the drug and optimal dosing regimens. We have developed a pharmacokinetic model that includes a biochemical molecular interaction network linked to a whole-body compartment model. We applied the model to study the PK of the anti-vascular endothelial growth factor (VEGF) cancer therapeutic agent, aflibercept. Clinical data is used to infer model parameters using a Bayesian approach, enabling a quantitative estimation of the contributions of specific transport processes and molecular interactions of the drug that cannot be examined in other PK modeling, and insight into the mechanisms of aflibercept's antiangiogenic action. Additionally, we predict the plasma and tissue concentrations of unbound and VEGF-bound aflibercept. Thus, we present a computational framework that can serve as a valuable tool for drug development efforts.

  9. A new model for the population pharmacokinetics of didanosine in healthy subjects

    Directory of Open Access Journals (Sweden)

    L.S. Velasque


    Full Text Available Didanosine (ddI is a component of highly active antiretroviral therapy drug combinations, used especially in resource-limited settings and in zidovudine-resistant patients. The population pharmacokinetics of ddI was evaluated in 48 healthy volunteers enrolled in two bioequivalence studies. These data, along with a set of co-variates, were the subject of a nonlinear mixed-effect modeling analysis using the NONMEM program. A two-compartment model with first order absorption (ADVAN3 TRANS3 was fitted to the serum ddI concentration data. Final pharmacokinetic parameters, expressed as functions of the co-variates gender and creatinine clearance (CL CR, were: oral clearance (CL = 55.1 + 240 x CL CR + 16.6 L/h for males and CL = 55.1 + 240 x CL CR for females, central volume (V2 = 9.8 L, intercompartmental clearance (Q = 40.9 L/h, peripheral volume (V3 = 62.7 + 22.9 L for males and V3 = 62.7 L for females, absorption rate constant (Ka = 1.51/h, and dissolution time of the tablet (D = 0.43 h. The intraindividual (residual variability expressed as coefficient of variation was 13.0%, whereas the interindividual variability of CL, Q, V3, Ka, and D was 20.1, 75.8, 20.6, 18.9, and 38.2%, respectively. The relatively high (>30% interindividual variability for some of these parameters, observed under the controlled experimental settings of bioequivalence trials in healthy volunteers, may result from genetic variability of the processes involved in ddI absorption and disposition.

  10. Pharmacokinetics of Exosomes-an Important Factor for Elucidating the Biological Roles of Exosomes and for the Development of Exosome-Based Therapeutics. (United States)

    Morishita, Masaki; Takahashi, Yuki; Nishikawa, Makiya; Takakura, Yoshinobu


    Exosomes are small membrane vesicles containing lipids, proteins, and nucleic acids. Recently, researchers have uncovered that exosomes are involved in various biological events, such as tumor growth, metastasis, and the immune response, by delivering their cargos to exosome-receiving cells. Moreover, exosomes are expected to be employed in therapeutic treatments, such as tissue regeneration therapy and antitumor immunotherapy, since exosomes are effective delivery vehicles for proteins, nucleic acids, and other bioactive compounds. To elucidate the biological functions of exosomes, and for the development of exosome-based therapeutics, the pharmacokinetics of exosomes is important. In this review, we aim to summarize current knowledge about the pharmacokinetics and biodistribution of exosomes. The pharmacokinetics of exogenously administered exosomes is discussed based on the tissue distribution, types of cells taking up exosomes, and key molecules in the pharmacokinetics of exosomes. In addition, recent progress in the methods to control the pharmacokinetics of exosomes is reviewed.

  11. Implications of mechanism-based inhibition of CYP2D6 for the pharmacokinetics and toxicity of MDMA. (United States)

    Yang, Jiansong; Jamei, Masoud; Heydari, Amir; Yeo, Karen R; de la Torre, Rafael; Farré, Magí; Tucker, Geoffrey T; Rostami-Hodjegan, Amin


    The aim of this study was to model the in vivo kinetic consequences of mechanism-based inhibition (MBI) of CYP2D6 by 3,4 methylenedioxymethamphetamine (MDMA, ecstasy). A model with physiologically-based components of drug metabolism was developed, taking account of change in the hepatic content of active CYP2D6 due to MBI by MDMA. Based on the in vitro information, plasma concentration time profiles of MDMA after various doses were computed and compared with reported observations. The analysis suggested that a typical recreational MDMA dose could inactivate most hepatic CYP2D6 within an hour, and the return to a basal level of CYP2D6 could take at least 10 days. Thus, the genetic polymorphism of CYP2D6 and coadministration of CYP2D6 inhibitors may have less impact on MDMA pharmacokinetics and the risk of acute toxicity than previously thought. This is consistent with clinical observations that indicate no obvious link between inherited CYP2D6 deficiency and acute MDMA intoxication.

  12. Development of a Web-Accessible Population Pharmacokinetic Service—Hemophilia (WAPPS-Hemo): Study Protocol (United States)

    Foster, Gary; Navarro-Ruan, Tamara; McEneny-King, Alanna; Edginton, Andrea N; Thabane, Lehana


    Background Individual pharmacokinetic assessment is a critical component of tailored prophylaxis for hemophilia patients. Population pharmacokinetics allows using individual sparse data, thus simplifying individual pharmacokinetic studies. Implementing population pharmacokinetics capacity for the hemophilia community is beyond individual reach and requires a system effort. Objective The Web-Accessible Population Pharmacokinetic Service—Hemophilia (WAPPS-Hemo) project aims to assemble a database of patient pharmacokinetic data for all existing factor concentrates, develop and validate population pharmacokinetics models, and integrate these models within a Web-based calculator for individualized pharmacokinetic estimation in patients at participating treatment centers. Methods Individual pharmacokinetic studies on factor VIII and IX concentrates will be sourced from pharmaceutical companies and independent investigators. All factor concentrate manufacturers, hemophilia treatment centers (HTCs), and independent investigators (identified via a systematic review of the literature) having on file pharmacokinetic data and willing to contribute full or sparse pharmacokinetic data will be eligible for participation. Multicompartmental modeling will be performed using a mixed-model approach for derivation and Bayesian forecasting for estimation of individual sparse data. NONMEM (ICON Development Solutions) will be used as modeling software. Results The WAPPS-Hemo research network has been launched and is currently joined by 30 HTCs from across the world. We have gathered dense individual pharmacokinetic data on 878 subjects, including several replicates, on 21 different molecules from 17 different sources. We have collected sparse individual pharmacokinetic data on 289 subjects from the participating centers through the testing phase of the WAPPS-Hemo Web interface. We have developed prototypal population pharmacokinetics models for 11 molecules. The WAPPS-Hemo website

  13. Population pharmacokinetic and pharmacodynamic modeling of different formulations of ONO-5334, cathepsin K inhibitor, in Caucasian and Japanese postmenopausal females. (United States)

    Hasegawa, Chihiro; Ohno, Tomoya; Umemura, Takeo; Honda, Naoki; Ohyama, Michiyo; Nagase, Shinichi; Small, Maria; Deacon, Steve; Ogawa, Mikio; Ieiri, Ichiro


    ONO-5334, a selective inhibitor of cathepsin K, is a potential new treatment for osteoporosis. The objectives of this study were to (1) develop population pharmacokinetic-pharmacodynamic (PK-PD) models for ONO-5334 using dose-ascending data from healthy postmenopausal females, (2) examine comparability of PK and/or PD profile between Caucasian and Japanese, and (3) compare PK-PD profile between immediate release tablet (IRT) and sustained release tablet (SRT). The population PK-PD models were developed for each formulation for post-dose levels of bone resorption markers (serum CTX and NTX). The data were provided from 4 phase 1 studies with total of 201 Caucasian and 94 Japanese subjects. Plasma concentrations of ONO-5334 and bone resorption markers were thoroughly evaluated in those studies. An indirect response model described relationships between bone resorption markers and plasma concentrations of ONO-5334. There was no significant difference in PK and pharmacodynamic potency (IC50 ) between Caucasian and Japanese. Based on the developed model, serum CTX and NTX after administration of ONO-5334 IRT or SRT were simulated, and the results showed that ONO-5334 SRT would provide comparable PD effect on bone resorption markers with lower dose relative to IRT.

  14. Development of ionic-complex-based nanostructured lipid carriers to improve the pharmacokinetic profiles of breviscapine

    Institute of Scientific and Technical Information of China (English)

    Mei LI; Yong ZHENG; Feng-ying SHAN; Jing ZHOU; Tao GONG; Zhi-rong ZHANG


    Aim:Breviscapine isolated from the Chinese herb Erigeron breviscapus (Vant) Hand-Mazz is widely used to treat cardiovascular and cerebrovascular diseases.The aim of this study was to improve the pharmacokinetic profiles of breviscapine using nanostructured lipid carrier based on an ionic complex formation.Methods:Breviscapine nanostructured lipid carrier (Bre-NLC) was prepared using the thin film homogenization method.The morphology of Bre-NLCs was determined using transmission electron microscopy.The mean particle size,polydispersity index,zeta-potential analysis and entrapment efficiency were analized.In vitro release was studied using the dialysis method.In vitro stability was studied in fresh plasma and liver slurry of rats.In vivo pharmacokinetics was analyzed in rats after intravenous injection of a dose equivalent to breviscapine (10 mg/kg).Results:The Bre-NLCs were spherical with a mean particle size of ~170 nm,a zeta potential of ~20 mV and a high entrapment efficiency of ~89%.Compared with a commercially available solution,a substantial decrease in the cumulative release of breviscapine was found for the Bre-NLCs.The NLC has a significantly protective effect against the liver enzyme degradation of breviscapine.After intravenous administration in rats,the Bre-NLCs exhibited a 32 times increase in the AUC0-t and a 12 times increase in T1/2 as compared to the commercially available breviscapine solution.Conclusion:The results demonstrate that the NLC has great potential to use as a novel sustained release system for breviscapine.

  15. Use of pharmacokinetic modelling to individualize FFP dosing in factor V deficiency. (United States)

    Shakhnovich, V; Daniel, J; Wicklund, B; Kearns, G; Neville, K


    Therapy with fresh frozen plasma (FFP) confers serious risks, such as contraction of blood-borne viruses, allergic reaction, volume overload and development of alloantibodies. The aim of this study was to apply principles of pharmacokinetic (PK) modelling to individual factor content of FFP to optimize individualized dosing, while minimizing potential risks of therapy. We used PK modelling to successfully target individual factor replacement in an 8-month-old patient receiving FFP for treatment of a severe congenital factor V (FV) deficiency. The model fit for the FV activity vs. time data was excellent (r = 0.98) and the model accurately predicted FV activity during the intraoperative and postoperative period. Accurate PK modelling of individual factor activity in FFP has the potential to provide better targeted therapy, enabling clinicians to more precisely dose patients requiring coagulation products, while avoiding wasteful and expensive product overtreatment, minimizing potentially life-threatening complications due to undertreatment and limiting harmful product-associated risks.

  16. Population Pharmacokinetic Modeling of the Enterohepatic Recirculation of Fimasartan in Rats, Dogs, and Humans. (United States)

    Kim, Tae Hwan; Shin, Soyoung; Landersdorfer, Cornelia B; Chi, Yong Ha; Paik, Soo Heui; Myung, Jayhyuk; Yadav, Rajbharan; Horkovics-Kovats, Stefan; Bulitta, Jürgen B; Shin, Beom Soo


    Enterohepatic recirculation (EHC) can greatly enhance plasma drug exposures and therapeutic effects. This study aimed to develop a population pharmacokinetic model that can simultaneously characterize the extent and time-course of EHC in three species using fimasartan, a novel angiotensin II receptor blocker, as a model drug. All fimasartan plasma concentration profiles in 32 rats (intravenous doses, 0.3-3 mg/kg; oral doses, 1-10 mg/kg), 34 dogs (intravenous doses, 0.3-1 mg/kg; oral doses, 1-10 mg/kg), and 42 healthy volunteers (single or multiple oral doses, 20-480 mg) were determined via liquid chromatography-tandem mass spectrometry (LC-MS/MS) and simultaneously modeled in S-ADAPT. The proposed model quantitatively characterized EHC in three species after oral and intravenous dosing. The median (range) fraction of drug undergoing recirculation was 76.3% (64.9-88.7%) in rats, 33.3% (24.0-45.9%) in dogs, and 65.6% (56.5-72.0%) in humans. In the presence compared with the absence of EHC, the area under the curve in plasma was predicted to be 4.22-fold (2.85-8.85) as high in rats, 1.50-fold (1.32-1.85) in dogs, and 2.91-fold (2.30-3.57) in humans. The modeled oral bioavailability in rats (median (range), 38.7% (20.0-59.8%)) and dogs (median, 7.13% to 15.4%, depending on the formulation) matched the non-compartmental estimates well. In humans, the predicted oral bioavailability was 25.1% (15.1-43.9%) under fasting and 18.2% (12.2-31.0%) under fed conditions. The allometrically scaled area under the curve predicted from rats was 420 ng·h/mL for 60 mg fimasartan compared with 424 ± 63 ng·h/mL observed in humans. The developed population pharmacokinetic model can be utilized to characterize the impact of EHC on plasma drug exposure in animals and humans.

  17. Pharmacokinetic-Pharmacodynamic modeling of enrofloxacin against Escherichia coli in broilers

    Directory of Open Access Journals (Sweden)

    Sang eKana


    Full Text Available The purpose of the present study was to establish a pharmacokinetic/pharmacodynamic (PK/PD modeling approach for the dosage schedule design and decreasing the emergence of drug-resistant bacteria. The minimal inhibitory concentration (MIC of 929 E. coli isolates from broilers to enrofloxacin and ciprofloxacin were determined following CLSI guidance. The MIC50 was calculated as the populational PD parameter for enrofloxacin against E. coli in broilers. The 101 E. coli strains with MIC closest to the MIC50 (0.05µg/mL were submitted for serotype identification. The 13 E. coli strains with O and K serotype were further utilitzed for determining pathogencity in mice. Of all the strains tested, the E. coli designated strain Anhui 112 was selected for establishing the disease model and PK/PD study. The pharmacokinetics (PKs of enrofloxacin after oral administration at the dose of 10mg/kg body weights (BW in healthy and infected broilers was evaluated with high-performance liquid chromatography (HPLC method. For intestinal contents after oral administration, the peak concentration (Cmax, the time when the maximum concentration reached (Tmax, and the area under the concentration-time curve (AUC were 21.69~31.69μg/mL, 1.13~1.23h, and 228.97~444.86μ, respectively. The MIC and minimal bactericidal concentration (MBC of enrofloxacin against E. coli (Anhui 112 in Mueller-Hinton (MH broth and intestinal contents were determined to be similar, 0.25μg/mL and 0.5μg/mL respectively. In this study, the sum of concentrations of enrofloxacin and its metabolite (ciprofloxacin was used for the PK/PD integration and modeling. The ex vivo growth inhibition data were fitted to the sigmoid Emax (Hill equation to provide values for intestinal contents of 24h area under concentration–time curve/MIC ratios (AUC0~24h/MIC producing, bacteriostasis (624.94h, bactericidal activity (1065.93h and bacterial eradication (1343.81h. PK/PD modeling was established to

  18. uSIMPK. An Excel for Windows-based simulation program for instruction of basic pharmacokinetics principles to pharmacy students. (United States)

    Brocks, Dion R


    Pharmacokinetics can be a challenging topic to teach due to the complex relationships inherent between physiological parameters, mathematical descriptors and equations, and their combined impact on shaping the blood fluid concentration vs. time curves of drugs. A computer program was developed within Microsoft Excel for Windows, designed to assist in the instruction of basic pharmacokinetics within an entry-to-practice pharmacy class environment. The program is composed of a series of spreadsheets (modules) linked by Visual Basic for Applications, intended to illustrate the relationships between pharmacokinetic and in some cases physiological parameters, doses and dose rates and the drug blood fluid concentration vs. time curves. Each module is accompanied by a simulation user's guide, prompting the user to change specific independent parameters and then observe the impact of the change(s) on the drug concentration vs. time curve and on other dependent parameters. "Slider" (or "scroll") bars can be selected to readily see the effects of repeated changes on the dependencies. Topics covered include one compartment single dose administration (iv bolus, oral, short infusion), intravenous infusion, repeated doses, renal and hepatic clearance, nonlinear elimination, two compartment model, plasma protein binding and the relationship between pharmacokinetics and drug effect. The program has been used in various forms in the classroom over a number of years, with positive ratings generally being received from students for its use in the classroom.

  19. Data Analysis Protocol for the Development and Evaluation of Population Pharmacokinetic Models for Incorporation Into the Web-Accessible Population Pharmacokinetic Service - Hemophilia (WAPPS-Hemo) (United States)

    McEneny-King, Alanna; Foster, Gary; Edginton, Andrea N


    Background Hemophilia is an inherited bleeding disorder caused by a deficiency in a specific clotting factor. This results in spontaneous bleeding episodes and eventual arthropathy. The mainstay of hemophilia treatment is prophylactic replacement of the missing factor, but an optimal regimen remains to be determined. Rather, individualized prophylaxis has been suggested to improve both patient safety and resource utilization. However, uptake of this approach has been hampered by the demanding sampling schedules and complex calculations required to obtain individual estimates of pharmacokinetic (PK) parameters. The use of population pharmacokinetics (PopPK) can alleviate this burden by reducing the number of plasma samples required for accurate estimation, but few tools incorporating this approach are readily available to clinicians. Objective The Web-accessible Population Pharmacokinetic Service - Hemophilia (WAPPS-Hemo) project aims to bridge this gap by providing a Web-accessible service for the reliable estimation of individual PK parameters from only a few patient samples. This service is predicated on the development of validated brand-specific PopPK models. Methods We describe the data analysis plan for the development and evaluation of each PopPK model to be incorporated into the WAPPS-Hemo platform. The data sources and structure of the dataset are discussed first, followed by the procedures for handling both data below limit of quantification (BLQ) and absence of such BLQ data. Next, we outline the strategies for building the appropriate structural and covariate models, including the possible need for a process algorithm when PK behavior varies between subjects or significant covariates are not provided. Prior to use in a prospective manner, the models will undergo extensive evaluation using a variety of techniques such as diagnostic plots, bootstrap analysis and cross-validation. Finally, we describe the incorporation of a validated PopPK model into the


    Directory of Open Access Journals (Sweden)

    Ruban E. A.


    , activation of insulin receptors and glucose uptake in the insulin-sensitive tissues. On the other hand, most polyphenols are characterized by low bioavailability mostly due to intensive metabolism. Thus absorption of such polyphenols as anthocyanins, phenolcarboxylic acids and some others appears low, but it is supposed that it could have been underestimated because not all metabolites might have been considered. Besides the absorption rate of these compounds is very rapid and may take place already in stomach. In contrary, rutin and other quercetin glycosides are absorbed only after release of the aglycones by the intestinal microflora. The elimination half-lives of most polyphenols tend to be short, especially in the case of anthocyanins. However, some polyphenolic compounds such as quercetin glycosides may have longer half-lives, and even accumulate in plasma with repeated ingestion. Conclusions. Polyphenols have unique therapeutic potential in the treatment of diabetes mellitus. Nevertheless, the possibility to use polyphenols as hypoglycemic agents in clinical practice is limited by their low bioavailability. Taking into account information reported in the literature on the hypoglycemic mechanisms and pharmacokinetics of polyphenols, promising method of increasing their bioavailability is the development of prolonged-release dosage forms based on polyphenol substances. This approach would extend residence time of polyphenols in the small intestine – the main site of hypoglycemic action in their intact, non-metabolized form, and will help maintain a constant concentration of active substances in the blood plasma, the target organs and tissues

  1. Characteristics and Research Progress of Physiologically Based Pharmacokinetic Model%生理药代动力学模型的特征及其国内外研究进展

    Institute of Scientific and Technical Information of China (English)

    董宇; 赵兰英; 吴萍; 王阶


    Introduce the characteristic and research status for physiologically based phannacokinetic model ( PBPK) . This article systemized and analysed the construction, features and application status of the PBPK model by reference 21 literatures from Pubmed. Currently, PBPK model has been widely used in the safety evaluation of toxic compounds, drug metabolism research, the influence of the drug by the enzymes and transport proteins, drug-drug interaction, and the research and development of new drugs. Although PBPK model has many advantages, and won the most encouraged evaluate results, but it need support of mathematics and computers, and cooperate of a multidisciplinary professionals, which including systems biology, medicine chemistry, pharmacology and statistic, etc, to further exploration and perfect.%介绍生理药代动力学(PBPK)模型的特征及其研究现状.通过Pubmed检索工具,查询国内外相关文献21篇,对PBPK模型的构建、模型特征和应用现状进行了文献整理和分析.目前PBPK模型已经广泛应用于有毒化合物的安全性评价、药物代谢过程研究、代谢酶和转运蛋白对药物代谢的影响、药物-药物相互作用以及新药的研发过程等研究之中.尽管PBPK模型有很多优势,获得了令人鼓舞的评价结果,但其构建需要数学和计算机的支持以及系统生物学、药物化学、药理学和数学、统计学等多学科专业人员合作,做进一步的探索和完善.

  2. Pharmacokinetic-pharmacodynamic relationship of anesthetic drugs: from modeling to clinical use [version 1; referees: 4 approved

    Directory of Open Access Journals (Sweden)

    Valerie Billard


    Full Text Available Anesthesia is a combination of unconsciousness, amnesia, and analgesia, expressed in sleeping patients by limited reaction to noxious stimulations. It is achieved by several classes of drugs, acting mainly on central nervous system. Compared to other therapeutic families, the anesthetic drugs, administered by intravenous or pulmonary route, are quickly distributed in the blood and induce in a few minutes effects that are fully reversible within minutes or hours. These effects change in parallel with the concentration of the drug, and the concentration time course of the drug follows with a reasonable precision mathematical models based on the Fick principle. Therefore, understanding concentration time course allows adjusting the dosing delivery scheme in order to control the effects.   The purpose of this short review is to describe the basis of pharmacokinetics and modeling, the concentration-effects relationship, and drug interactions modeling to offer to anesthesiologists and non-anesthesiologists an overview of the rules to follow to optimize anesthetic drug delivery.

  3. Revisiting Dosing Regimen Using Pharmacokinetic/Pharmacodynamic Mathematical Modeling: Densification and Intensification of Combination Cancer Therapy. (United States)

    Meille, Christophe; Barbolosi, Dominique; Ciccolini, Joseph; Freyer, Gilles; Iliadis, Athanassios


    Controlling effects of drugs administered in combination is particularly challenging with a densified regimen because of life-threatening hematological toxicities. We have developed a mathematical model to optimize drug dosing regimens and to redesign the dose intensification-dose escalation process, using densified cycles of combined anticancer drugs. A generic mathematical model was developed to describe the main components of the real process, including pharmacokinetics, safety and efficacy pharmacodynamics, and non-hematological toxicity risk. This model allowed for computing the distribution of the total drug amount of each drug in combination, for each escalation dose level, in order to minimize the average tumor mass for each cycle. This was achieved while complying with absolute neutrophil count clinical constraints and without exceeding a fixed risk of non-hematological dose-limiting toxicity. The innovative part of this work was the development of densifying and intensifying designs in a unified procedure. This model enabled us to determine the appropriate regimen in a pilot phase I/II study in metastatic breast patients for a 2-week-cycle treatment of docetaxel plus epirubicin doublet, and to propose a new dose-ranging process. In addition to the present application, this method can be further used to achieve optimization of any combination therapy, thus improving the efficacy versus toxicity balance of such a regimen.

  4. Optimizing hollow-fiber-based pharmacokinetic assay via chemical stability study to account for inaccurate simulated drug clearance of rifampicin. (United States)

    New, Lee Sun; Lim, Tze Peng; Oh, Jing Wen; Cheah, Gavin Jia Sheng; Kwa, Andrea L; Chan, Eric Chun Yong


    With increasing multidrug resistance coupled to a poor development pipeline, clinicians are exploring antimicrobial combinations to improve treatment outcomes. In vitro hollow-fiber infection model (HFIM) is employed to simulate human in vivo drug clearance and investigate pharmacodynamic synergism of antibiotics. Our overarching aim was to optimize the HFIM-based pharmacokinetic (PK) assay by using rifampicin and polymyxin B as probe drugs. An ultrapressure liquid chromatography tandem mass spectrometry method was validated for the quantification of rifampicin and polymyxin B components. In vitro profiling studies demonstrated that the experimental PK profiles of polymyxin B monotherapy were well correlated with the human population PK data while monotherapy with rifampicin failed to achieve the expected maximum plasma concentration. Chemical stability studies confirmed polymyxin B was stable in broth at 37 °C up to 12 h while rifampicin was unstable under the same conditions over 12 and 80 h. The calculated mean clearance of rifampicin due to chemical degradation was 0.098 ml/min accounting for 12.2 % of its clinical total clearance (CL = 0.8 ml/min) based on population PK data. Our novel finding reinforces the importance to optimize HFIM-based PK assay by performing chemical stability study so as to account for potential discrepancy between experimental and population PK profiles of antimicrobial agents.

  5. PANSYM: a symbolic equation generator for mathematical modelling, analysis and control of metabolic and pharmacokinetic systems. (United States)

    Thomaseth, K


    Software is presented for automatic generation of first-order ordinary differential equations (ODE) that arise from lumped parameter representations of metabolic and pharmacokinetic systems. The definition of system structures is accomplished by fractional transfer rates between state variables, together with input/output equations and initial conditions of state variables. General non-linear mathematical expressions can be assigned to all structure definition items. The software parses and interprets the system definitions and generates symbolically the mathematical expression of the model's set of ODE. In addition, symbolic derivatives of state equations are determined with respect to model parameters, state variables and external inputs. These derivatives represent the constituents of systems of sensitivity-differential and adjoint-differential equations that arise in identification and optimal control problems. Finally, output routines generate source code that, once compiled and linked to simulation programs, allows efficient numerical integration of the system of ODE. This software has been developed in PROLOG on Macintosh computers and has been extensively used with the programming environment MATLAB. Possible applications of this software include model building, sensitivity analysis, identification, optimal experiment design and numerical solution of optimal control problems.

  6. Population pharmacokinetic and pharmacodynamic modeling for assessing risk of bisphosphonate-related osteonecrosis of the jaw (United States)

    Sedghizadeh, Parish P.; Jones, Allan C.; LaVallee, Chris; Jelliffe, Roger W.; Le, Anh D.; Lee, Peter; Kiss, Andrew; Neely, Michael


    Objective We hypothesized that patients with bisphosphonate (BP)-related osteonecrosis of the jaw (BRONJ) accumulate higher levels of BP in bone than those without BRONJ. Study Design Using the Pmetrics® package and published data, we designed a population pharmacokinetic model of pamidronate concentration in plasma and bone and derived a toxic bone BP threshold of 0.2 mM. With the model, and using patient individual BP duration and bone mineral content estimated from lean body weight, we calculated bone BP levels in 153 subjects. Results Mean bone BP in 69 BRONJ cases was higher than in 84 controls (0.20 vs. 0.10 mM, P<0.001) consistent with the toxic bone threshold of 0.2 mM. BRONJ was also associated with longer duration BP therapy (5.3 vs. 2.7 years, P<0.001), older age (76 vs. 70 years, P<0.001), and Asian race (49% vs. 14%, P<0.001). Conclusions Our model accurately discriminated BRONJ cases from controls, among patients on BP therapy. PMID:23246224

  7. Integrating Dynamic Positron Emission Tomography and Conventional Pharmacokinetic Studies to Delineate Plasma and Tumor Pharmacokinetics of FAU, a Prodrug Bioactivated by Thymidylate Synthase. (United States)

    Li, Jing; Kim, Seongho; Shields, Anthony F; Douglas, Kirk A; McHugh, Christopher I; Lawhorn-Crews, Jawana M; Wu, Jianmei; Mangner, Thomas J; LoRusso, Patricia M


    FAU, a pyrimidine nucleotide analogue, is a prodrug bioactivated by intracellular thymidylate synthase to form FMAU, which is incorporated into DNA, causing cell death. This study presents a model-based approach to integrating dynamic positron emission tomography (PET) and conventional plasma pharmacokinetic studies to characterize the plasma and tissue pharmacokinetics of FAU and FMAU. Twelve cancer patients were enrolled into a phase 1 study, where conventional plasma pharmacokinetic evaluation of therapeutic FAU (50-1600 mg/m(2) ) and dynamic PET assessment of (18) F-FAU were performed. A parent-metabolite population pharmacokinetic model was developed to simultaneously fit PET-derived tissue data and conventional plasma pharmacokinetic data. The developed model enabled separation of PET-derived total tissue concentrations into the parent drug and metabolite components. The model provides quantitative, mechanistic insights into the bioactivation of FAU and retention of FMAU in normal and tumor tissues and has potential utility to predict tumor responsiveness to FAU treatment.

  8. [Amikacin pharmacokinetics in adults: a variability that question the dose calculation based on weight]. (United States)

    Bourguignon, Laurent; Goutelle, Sylvain; Gérard, Cécile; Guillermet, Anne; Burdin de Saint Martin, Julie; Maire, Pascal; Ducher, Michel


    The use of amikacin is difficult because of its toxicity and its pharmacokinetic variability. This variability is almost ignored in adult standard dosage regimens since only the weight is used in the dose calculation. Our objective is to test if the pharmacokinetic of amikacin can be regarded as homogenous, and if the method for calculating the dose according to patients' weight is appropriate. From a cohort of 580 patients, five groups of patients were created by statistical data partitioning. A population pharmacokinetic analysis was performed in each group. The adult population is not homogeneous in term of pharmacokinetics. The doses required to achieve a maximum concentration of 60 mg/L are strongly different (585 to 1507 mg) between groups. The exclusive use of the weight to calculate the dose of amikacine appears inappropriate for 80% of the patients, showing the limits of the formulae for calculating doses of aminoglycosides.

  9. Population pharmacokinetic/pharmacodynamic modeling of tumor growth kinetics in medullary thyroid cancer patients receiving cabozantinib. (United States)

    Miles, Dale R; Wada, David R; Jumbe, Nelson L; Lacy, Steven A; Nguyen, Linh T


    Nonlinear mixed effects models were developed to describe the relationship between cabozantinib exposure and target lesion tumor size in a phase III study of patients with progressive metastatic medullary thyroid cancer. These models used cabozantinib exposure estimates from a previously published population pharmacokinetic model for cabozantinib in cancer patients that was updated with data from healthy-volunteer studies. Semi-mechanistic models predict well for tumors with static, increasing, or decreasing growth over time, but they were not considered adequate for predicting tumor sizes in medullary thyroid cancer patients, among whom an early reduction in tumor size was followed by a late stabilization phase in those receiving cabozantinib. A semi-empirical tumor model adequately predicted tumor profiles that were assumed to have a net growth rate constant that was piecewise continuous in the regions of 0-110 and 110-280 days. Emax models relating average concentration to average change in tumor size predicted that an average concentration of 79 and 58 ng/ml, respectively, would yield 50% of the maximum possible tumor reduction during the first 110 days of dosing and during the subsequent 110-280 days of dosing. Simulations of tumor responses showed that daily doses of 60 mg or greater are expected to provide a similar tumor reduction. Both model evaluation of observed data and simulation results suggested that the two protocol-defined cabozantinib dose reductions from 140 to 100 mg/day and from 100 to 60 mg/day are not projected to result in a marked reduction in target lesion regrowth.

  10. Multicompartmental Pharmacokinetic Model of Tenofovir Delivery to the Rectal Mucosa by an Enema (United States)

    Gao, Yajing; Katz, David F.


    Rectal enemas that contain prophylactic levels of anti-HIV microbicides such as tenofovir have emerged as a promising dosage form to prevent sexually transmitted HIV infections. The enema vehicle is promising due to its likely ability to deliver a large amount of drug along the length of the rectal canal. Computational models of microbicide drug delivery by enemas can help their design process by determining key factors governing drug transport and, more specifically, the time history and degree of protection. They can also inform interpretations of experimental pharmacokinetic measures such as drug concentrations in biopsies. The present work begins rectal microbicide PK modeling, for enema vehicles. Results here show that a paramount factor in drug transport is the time of enema retention; direct connectivity between enema fluid and the fluid within rectal crypts is also important. Computations of the percentage of stromal volume protected by a single enema dose indicate that even with only a minute of enema retention, protection of 100% can be achieved after around 14 minutes post dose. Concentrations in biopsies are dependent on biopsy thickness; and control and/or knowledge of thickness could improve accuracy and decrease variability in biopsy measurements. Results here provide evidence that enemas are a promising dosage form for rectal microbicide delivery, and offer insights into their rational design. PMID:28114388

  11. Pharmacokinetics-pharmacodynamics of rifampin in an aerosol infection model of tuberculosis. (United States)

    Jayaram, Ramesh; Gaonkar, Sheshagiri; Kaur, Parvinder; Suresh, B L; Mahesh, B N; Jayashree, R; Nandi, Vrinda; Bharat, Sowmya; Shandil, R K; Kantharaj, E; Balasubramanian, V


    Limited information exists on the pharmacokinetic (PK)-pharmacodynamic (PD) relationships of drugs against Mycobacterium tuberculosis. Our aim was to identify the PK-PD parameter that best describes the efficacy of rifampin on the basis of in vitro and PK properties. Consistent with 83.8% protein binding by equilibrium dialysis, the rifampin MIC for M. tuberculosis strain H37Rv rose from 0.1 in a serum-free system to 1.0 mg/ml when it was tested in the presence of 50% serum. In time-kill studies, rifampin exhibited area under the concentration-time curve (AUC)-dependent killing in vitro, with maximal killing seen on all days and with the potency increasing steadily over a 9-day exposure period. MIC and time-kill studies performed with intracellular organisms in a macrophage monolayer model yielded similar results. By use of a murine aerosol infection model with dose ranging and dose fractionation over 6 days, the PD parameter that best correlated with a reduction in bacterial counts was found to be AUC/MIC (r(2) = 0.95), whereas the maximum concentration in serum/MIC (r(2) = 0.86) and the time that the concentration remained above the MIC (r(2) = 0.44) showed lesser degrees of correlation.

  12. Isoniazid pharmacokinetics-pharmacodynamics in an aerosol infection model of tuberculosis. (United States)

    Jayaram, Ramesh; Shandil, Radha K; Gaonkar, Sheshagiri; Kaur, Parvinder; Suresh, B L; Mahesh, B N; Jayashree, R; Nandi, Vrinda; Bharath, Sowmya; Kantharaj, E; Balasubramanian, V


    Limited data exist on the pharmacokinetic-pharmacodynamic (PK-PD) parameters of the bactericidal activities of the available antimycobacterial drugs. We report on the PK-PD relationships for isoniazid. Isoniazid exhibited concentration (C)-dependent killing of Mycobacterium tuberculosis H37Rv in vitro, with a maximum reduction of 4 log10 CFU/ml. In these studies, 50% of the maximum effect was achieved at a C/MIC ratio of 0.5, and the maximum effect did not increase with exposure times of up to 21 days. Conversely, isoniazid produced less than a 0.5-log10 CFU/ml reduction in two different intracellular infection models (J774A.1 murine macrophages and whole human blood). In a murine model of aerosol infection, isoniazid therapy for 6 days produced a reduction of 1.4 log10 CFU/lung. Dose fractionation studies demonstrated that the 24-h area under the concentration-time curve/MIC (r2 = 0.83) correlated best with the bactericidal efficacy, followed by the maximum concentration of drug in serum/MIC (r2 = 0.73).

  13. Pediatric Clinical Pharmacology of Voriconazole: Role of Pharmacokinetic/Pharmacodynamic Modeling in Pharmacotherapy. (United States)

    Kadam, Rajendra S; Van Den Anker, Johannes N


    Voriconazole is a potent antifungal agent used for the treatment of invasive fungal infections caused by Aspergillus and Candida species in adult and pediatric patients. Voriconazole has a narrow therapeutic index and a large intra- and inter-individual pharmacokinetics (PK) variability. Several factors including non-linear PK, age, body weight, cytochrome P450 2C19 genotype, concomitant drugs, liver function, and food are responsible for the large variability in voriconazole PK. A combination of a narrow therapeutic index with a large PK variability results in treatment failure in many patients at clinically recommended doses. There is an urgent need to establish an optimal dosing regimen for pediatric patients 60 %) treatment failure rates. Therapeutic drug monitoring is commonly used in clinical practice to optimize the voriconazole dosing regimens in pediatric patients, but it is associated with several practical limitations. Implementation of a PK model-guided individualized dose selection will help in reducing the PK variability and will improve therapeutic outcomes. In this review, we have summarized the covariates influencing the PK of voriconazole in adult and pediatric patients, emphasizing that the clearance of voriconazole is significantly different between adult and pediatric patients owing to developmental changes in the major clearance pathways. Moreover, we have provided the limitations of the current dosing regimens and have proposed a new dosing method using a PK model-guided dose individualization of voriconazole in pediatric patients.

  14. Physiologically Based Modelling of Dioxins. I. Validation of a rodent toxicokinetic model

    NARCIS (Netherlands)

    Zeilmaker MJ; Slob W


    In this report a rodent Physiologically Based PharmacoKinetic (PBPK) model for 2,3,7,8-tetrachlorodibenzodioxin is described. Validation studies, in which model simulations of TCDD disposition were compared with in vivo TCDD disposition in rodents exposed to TCDD, showed that the model adequately p

  15. Pharmacodynamics and pharmacokinetics of SQ109, a new diamine-based antitubercular drug. (United States)

    Jia, Lee; Tomaszewski, Joseph E; Hanrahan, Colleen; Coward, Lori; Noker, Patricia; Gorman, Gregory; Nikonenko, Boris; Protopopova, Marina


    SQ109 is a novel [1,2]-diamine-based ethambutol (EMB) analog developed from high-throughput combinatorial screening. The present study aimed at characterizing its pharmacodynamics and pharmacokinetics. The antimicrobial activity of SQ109 was confirmed in vitro (Mycobacterium tuberculosis-infected murine macrophages) and in vivo (M. tuberculosis-infected C57BL/6 mice) and compared to isoniazid (INH) and EMB. SQ109 showed potency and efficacy in inhibiting intracellular M. tuberculosis that was similar to INH, but superior to EMB. In vivo oral administration of SQ109 (0.1-25 mg kg(-1) day(-1)) to the mice for 28 days resulted in dose-dependent reductions of mycobacterial load in both spleen and lung comparable to that of EMB administered at 100 mg kg(-1) day(-1), but was less potent than INH at 25 mg kg(-1) day(-1). Monitoring of SQ109 levels in mouse tissues on days 1, 14 and 28 following 28-day oral administration (10 mg kg(-1) day(-1)) revealed that lungs and spleen contained the highest concentration of SQ109, at least 10 times above its MIC. Pharmacokinetic profiles of SQ109 in mice following a single administration showed its C(max) as 1038 (intravenous (i.v.)) and 135 ng ml(-1) (p.o.), with an oral T(max) of 0.31 h. The elimination t(1/2) of SQ109 was 3.5 (i.v.) and 5.2 h (p.o.). The oral bioavailability was 4%. However, SQ109 displayed a large volume of distribution into various tissues. The highest concentration of SQ109 was present in lung (>MIC), which was at least 120-fold (p.o.) and 180-fold (i.v.) higher than that in plasma. The next ranked tissues were spleen and kidney. SQ109 levels in most tissues after a single administration were significantly higher than that in blood. High tissue concentrations of SQ109 persisted for the observation period (10 h). This study demonstrated that SQ109 displays promising in vitro and in vivo antitubercular activity with favorable targeted tissue distribution properties.

  16. Pharmacokinetics/pharmacodynamic correlations of fluconazole in murine model of cryptococcosis. (United States)

    Santos, Julliana Ribeiro Alves; César, Isabela Costa; Costa, Marliete Carvalho; Ribeiro, Noelly Queiroz; Holanda, Rodrigo Assunção; Ramos, Lais Hott; Freitas, Gustavo José Cota; Paixão, Tatiane Alves; Pianetti, Gerson Antônio; Santos, Daniel Assis


    The emergence of fluconazole-resistant Cryptococcus gattii is a global concern, since this azole is the main antifungal used worldwide to treat patients with cryptococcosis. Although pharmacokinetic (PK) and pharmacodynamic (PD) indices are useful predictive factors for therapeutic outcomes, there is a scarcity of data regarding PK/PD analysis of antifungals in cryptococcosis caused by resistant strains. In this study, PK/PD parameters were determined in a murine model of cryptococcosis caused by resistant C. gattii. We developed and validated a suitable liquid chromatography-electrospray ionization tandem mass spectrometry method for PK studies of fluconazole in the serum, lungs, and brain of uninfected mice. Mice were infected with susceptible or resistant C. gattii, and the effects of different doses of fluconazole on the pulmonary and central nervous system fungal burden were determined. The peak levels in the serum, lungs, and brain were achieved within 0.5h. The AUC/MIC index (area under the curve/minimum inhibitory concentration) was associated with the outcome of anti-cryptococcal therapy. Interestingly, the maximum concentration of fluconazole in the brain was lower than the MIC for both strains. In addition, the treatment of mice infected with the resistant strain was ineffective even when high doses of fluconazole were used or when amphotericin B was tested, confirming the cross-resistance between these drugs. Altogether, our novel data provide the correlation of PK/PD parameters with antifungal therapy during cryptococcosis caused by resistant C. gattii.

  17. Glucosamine sulfate effect on the degenerated patellar cartilage: preliminary findings by pharmacokinetic magnetic resonance modeling

    Energy Technology Data Exchange (ETDEWEB)

    Marti-Bonmati, Luis [Dr Peset University Hospital, Radiology Department, Valencia (Spain); Hospital Quiron Valencia, Radiology Department, Valencia (Spain); Sanz-Requena, Roberto; Alberich-Bayarri, Angel [Hospital Quiron Valencia, Radiology Department, Valencia (Spain); Rodrigo, Jose Luis [Dr Peset University Hospital, Traumatology and Orthopedics Surgery Department, Valencia (Spain); Carot, Jose Miguel [Universidad Politecnica de Valencia, EIO Department, Valencia (Spain)


    Normal and degenerated cartilages have different magnetic resonance (MR) capillary permeability (K{sup trans}) and interstitial interchangeable volume (v{sub e}). Our hypothesis was that glucosamine sulfate treatment modifies these neovascularity abnormalities in osteoarthritis. Sixteen patients with patella degeneration, randomly distributed into glucosamine or control groups, underwent two 1.5-Tesla dynamic contrast-enhanced MR imaging studies (treatment initiation and after 6 months). The pain visual analog scale (VAS) and American Knee Society (AKS) score were used. A two-compartment pharmacokinetic model was used. Percentages of variations (postreatment-pretreatment/pretreatment) were compared (t-test for independent data). In the glucosamine group, pain and functional outcomes statistically improved (VAS: 7.3 {+-} 1.1 to 3.6 {+-} 1.3, p < 0.001; AKS: 18.6 {+-} 6.9 to 42.9 {+-} 2.7, p < 0.01). Glucosamine significantly increased K{sup trans} at 6 months (-54.4 {+-} 21.2% vs 126.7 {+-} 56.9%, p < 0.001, control vs glucosamine). In conclusion, glucosamine sulfate decreases pain while improving functional outcome in patients with cartilage degeneration. Glucosamine sulfate increases K{sup trans}, allowing its proposal as a surrogate imaging biomarker after 6 months of treatment. (orig.)

  18. Fiber optic-based fluorescence detection system for in vivo studies of exogenous chromophore pharmacokinetics (United States)

    Doiron, Daniel R.; Dunn, J. B.; Mitchell, W. L.; Dalton, Brian K.; Garbo, Greta M.; Warner, Jon A.


    The detection and quantification of the concentration of exogenous chromophores in-vivo by their fluorescence is complicated by many physical and geometrical parameters. Measurement of such signals is advantageous in determining the pharmacokinetics of photosensitizers such as those used in photodynamic therapy (PDT) or to assist in the diagnosis of tissue histological state. To overcome these difficulties a ratio based fiber optic contact fluorometer has been developed. This fluorescence detection system (FDS) uses the ratio of the fluorescence emission peak of the exogenous chromophore to that of endogenous chromophores, i.e. autofluorescence, to correct for a variety of parameters affecting the magnitude of the measured signals. By doing so it also minimizes the range of baseline measurements prior to exogenous drug injection, for various tissue types. Design of the FDS and results of its testing in animals and patients using the second generation photosensitizer Tin ethyletiopurpurin (SnET2) are presented. These results support the feasibility and usefulness of the Ratio FDS system.

  19. Programming of a flexible computer simulation to visualize pharmacokinetic-pharmacodynamic models. (United States)

    Lötsch, J; Kobal, G; Geisslinger, G


    Teaching pharmacokinetic-pharmacodynamic (PK/PD) models can be made more effective using computer simulations. We propose the programming of educational PK or PK/PD computer simulations as an alternative to the use of pre-built simulation software. This approach has the advantage of adaptability to non-standard or complicated PK or PK/PD models. Simplicity of the programming procedure was achieved by selecting the LabVIEW programming environment. An intuitive user interface to visualize the time courses of drug concentrations or effects can be obtained with pre-built elements. The environment uses a wiring analogy that resembles electrical circuit diagrams rather than abstract programming code. The goal of high interactivity of the simulation was attained by allowing the program to run in continuously repeating loops. This makes the program behave flexibly to the user input. The programming is described with the aid of a 2-compartment PK simulation. Examples of more sophisticated simulation programs are also given where the PK/PD simulation shows drug input, concentrations in plasma, and at effect site and the effects themselves as a function of time. A multi-compartmental model of morphine, including metabolite kinetics and effects is also included. The programs are available for download from the World Wide Web at http:// www. PKPDsimulation/content.html. For pharmacokineticists who only program occasionally, there is the possibility of building the computer simulation, together with the flexible interactive simulation algorithm for clinical pharmacological teaching in the field of PK/PD models.

  20. Substantial impact of altered pharmacokinetics in critically ill patients on the antibacterial effects of meropenem evaluated via the dynamic hollow-fiber infection model. (United States)

    Bergen, Phillip J; Bulitta, Jürgen B; Kirkpatrick, Carl M J; Rogers, Kate E; McGregor, Megan J; Wallis, Steven C; Paterson, David L; Nation, Roger L; Lipman, Jeffrey; Roberts, Jason A; Landersdorfer, Cornelia B


    Critically ill patients frequently have substantially altered pharmacokinetics compared to non-critically ill patients. We investigated the impact of pharmacokinetic alterations on bacterial killing and resistance for commonly used meropenem dosing regimens. A Pseudomonas aeruginosa isolate (MICmeropenem 0.25 mg/L) was studied in the hollow-fiber infection model (inoculum ∼10(7.5) CFU/mL; 10 days). Pharmacokinetic profiles representing critically ill patients with augmented renal clearance (ARC), normal, or impaired renal function (creatinine clearances of 285, 120 or ∼10 mL/min, respectively) were generated for three meropenem regimens (2g, 1g and 0.5g 8-hourly, 30 min infusion), plus 1g 12-hourly with impaired renal function. The time-course of total and less-susceptible populations and MICs were determined. Mechanism-based modeling (MBM) was performed using S-ADAPT. All dosing regimens across all renal functions produced similar initial bacterial killing (≤∼2.5 log10). For all regimens subjected to ARC regrowth occurred after 7h. For normal and impaired renal function bacterial killing continued until 23 to 47h whereafter regrowth occurred with 0.5g and 1g regimens with normal renal function (fT>5×MIC 56% and 69%, fCmin/MIC 5×MIC ≥82%, fCmin/MIC ≥2). The MBM successfully described bacterial killing and regrowth for all renal functions and regimens simultaneously. Optimized dosing regimens including extended infusions and/or combinations, supported by MBM and Monte Carlo simulations, should be evaluated in the context of ARC to maximize bacterial killing and suppress resistance emergence.

  1. The pharmacokinetic study of rutin in rat plasma based on an electrochemically reduced graphene oxide modified sensor$

    Institute of Scientific and Technical Information of China (English)

    Pei Zhang a; Yu-Qiang Gou b; Xia Gao a; Rui-Bin Bai a; Wen-Xia Chen a; Bo-Lu Sun a; Fang-Di Hu a; n; Wang-Hong Zhao c


    An electrochemical method based on a directly electrochemically reduced graphene oxide (ERGO) film coated on a glassy carbon electrode (GCE) was developed for the rapid and convenient determination of rutin in plasma. ERGO was modified on the surface of GCE by one-step electro-deposition method. Electrochemical behavior of rutin on ERGO/GCE indicated that rutin underwent a surface-controlled quasi-reversible process and the electrochemical parameters such as charge transfer coefficient (α), electron transfer number (n) and electrode reaction standard rate constant (ks) were 0.53, 2 and 3.4 s?1, respectively. The electrochemical sensor for rutin in plasma provided a wide linear response range of 4.70 ? 10 ? 7 ? 1.25 ? 10 ? 5 M with the detection limit (s/n ¼ 3) of 1.84 ? 10 ? 8 M. The assay was success-fully used to the pharmacokinetic study of rutin. The pharmacokinetic parameters such as elimination rate half-life (t1/2), area under curve (AUC), and plasma clearance (CL) were calculated to be 3.345 7 0.647 min, 5750 7 656.0 mg min/mL, and 5.891 7 0.458 mL/min/kg, respectively. The proposed method utilized a small sample volume of 10μL and had no complicated sample pretreatment (without deproteinization), which was simple, eco-friendly, and time-and cost-efficient for rutin pharmacokinetic studies.

  2. Multiscale Modeling of Antibody-Drug Conjugates: Connecting Tissue and Cellular Distribution to Whole Animal Pharmacokinetics and Potential Implications for Efficacy. (United States)

    Cilliers, Cornelius; Guo, Hans; Liao, Jianshan; Christodolu, Nikolas; Thurber, Greg M


    Antibody-drug conjugates exhibit complex pharmacokinetics due to their combination of macromolecular and small molecule properties. These issues range from systemic concerns, such as deconjugation of the small molecule drug during the long antibody circulation time or rapid clearance from nonspecific interactions, to local tumor tissue heterogeneity, cell bystander effects, and endosomal escape. Mathematical models can be used to study the impact of these processes on overall distribution in an efficient manner, and several types of models have been used to analyze varying aspects of antibody distribution including physiologically based pharmacokinetic (PBPK) models and tissue-level simulations. However, these processes are quantitative in nature and cannot be handled qualitatively in isolation. For example, free antibody from deconjugation of the small molecule will impact the distribution of conjugated antibodies within the tumor. To incorporate these effects into a unified framework, we have coupled the systemic and organ-level distribution of a PBPK model with the tissue-level detail of a distributed parameter tumor model. We used this mathematical model to analyze new experimental results on the distribution of the clinical antibody-drug conjugate Kadcyla in HER2-positive mouse xenografts. This model is able to capture the impact of the drug-antibody ratio (DAR) on tumor penetration, the net result of drug deconjugation, and the effect of using unconjugated antibody to drive ADC penetration deeper into the tumor tissue. This modeling approach will provide quantitative and mechanistic support to experimental studies trying to parse the impact of multiple mechanisms of action for these complex drugs.

  3. Randomized pharmacokinetic study comparing subcutaneous and intravenous palonosetron in cancer patients treated with platinum based chemotherapy.

    Directory of Open Access Journals (Sweden)

    Belen Sadaba

    Full Text Available BACKGROUND: Palonosetron is a potent second generation 5- hydroxytryptamine-3 selective antagonist which can be administered by either intravenous (IV or oral routes, but subcutaneous (SC administration of palonosetron has never been studied, even though it could have useful clinical applications. In this study, we evaluate the bioavailability of SC palonosetron. PATIENTS AND METHODS: Patients treated with platinum-based chemotherapy were randomized to receive SC or IV palonosetron, followed by the alternative route in a crossover manner, during the first two cycles of chemotherapy. Blood samples were collected at baseline and 10, 15, 30, 45, 60, 90 minutes and 2, 3, 4, 6, 8, 12 and 24 h after palonosetron administration. Urine was collected during 12 hours following palonosetron. We compared pharmacokinetic parameters including AUC0-24h, t1/2, and Cmax observed with each route of administration by analysis of variance (ANOVA. RESULTS: From October 2009 to July 2010, 25 evaluable patients were included. AUC0-24h for IV and SC palonosetron were respectively 14.1 and 12.7 ng × h/ml (p=0.160. Bioavalability of SC palonosetron was 118% (95% IC: 69-168. Cmax was lower with SC than with IV route and was reached 15 minutes following SC administration. CONCLUSIONS: Palonosetron bioavailability was similar when administered by either SC or IV route. This new route of administration might be specially useful for outpatient management of emesis and for administration of oral chemotherapy. TRIAL REGISTRATION: NCT01046240.

  4. Genetic algorithm guided population pharmacokinetic model development for simvastatin, concurrently or non-concurrently co-administered with amlodipine. (United States)

    Chaturvedula, Ayyappa; Sale, Mark E; Lee, Howard


    An automated model development was performed for simvastatin, co-administered with amlodipine concurrently or non-concurrently (i.e., 4 hours later) in 17 patients with coexisting hyperlipidemia and hypertension. The single objective hybrid genetic algorithm (SOHGA) was implemented in the NONMEM software by defining the search space for structural, statistical and covariate models. Candidate models obtained from the SOHGA runs were further assessed for biological plausibility and the precision of parameter estimates, followed by traditional backward elimination process for model refinement. The final population pharmacokinetic model shows that the elimination rate constant for simvastatin acid, the active form by hydrolysis of its lactone prodrug (i.e., simvastatin), is only 44% in the concurrent amlodipine administration group compared with the non-concurrent group. The application of SOHGA for automated model selection, combined with traditional model selection strategies, appears to save time for model development, which also can generate new hypotheses that are biologically more plausible.

  5. Pharmacokinetics and pharmacodynamics of oral oleylphosphocholine in a hamster model of visceral leishmaniasis

    NARCIS (Netherlands)

    Fortin, A.; Dorlo, T.P.C.; Matheeussen, A.; Hendrickx, S.; Cos, P.; Maes, L.


    INTRODUCTION Oleylphosphocholine (OlPC) is in the same chemical class as miltefosine (MIL) and was shown to be of superior efficacy and safety at equivalent doses (Fortin et al. 2012; 2014). In the current study, the pharmacokinetic (PK) properties of OlPC were evaluated in hamsters following single

  6. Pharmacokinetic-pharmacodynamic modelling of opioids in healthy human volunteers. a minireview. (United States)

    Ing Lorenzini, Kuntheavy; Daali, Youssef; Dayer, Pierre; Desmeules, Jules


    Pain is characterized by its multi-dimensional nature, explaining in part why the pharmacokinetic/pharmacodynamic (PK/PD) relationships are not straightforward for analgesics. The first part of this MiniReview gives an overview of PK, PD and PK/PD models, as well as of population approach used in analgesic studies. The second part updates the state-of-the-art in the PK/PD relationship of opioids, focusing on data obtained on experimental human pain models, a useful tool to characterize the PD of analgesics. For the so-called weak opioids such as codeine, experimental human studies showed that analgesia relies mainly upon biotransformation into morphine. However, the time-course of plasma concentrations of morphine did not always reflect the time-course of effects, the major site of action being the central nervous system. For tramadol, a correlation has been observed between the analgesic response and the PK of the (+)R-O-demethyl-tramadol metabolite. For 'stronger' opioids such as oxycodone, studies assessing the PK/PD of oxycodone suggested that active metabolite oxymorphone also strongly contributes to the analgesia and that analgesia may also be partially related through an action to peripherally located κ-opioid receptors. Different models have been proposed to describe the time-course of buprenorphine. An effect-compartment model was adopted to describe the PK/PD of morphine and its active metabolite, morphine-6-glucuronide (M6G). A longer blood-effect site equilibration half-life t(1/2) k(e0) was observed for M6G, suggesting a longer onset of action. The studies assessing the PK/PD of fentanyl and its derivatives showed a short t(1/2) k(e0) for analgesia, between 0.2 and 9 min., reflecting a short onset of effect. In conclusion, depending on the speed of transfer between the plasma and the effect site as well as the participation of active metabolites, the time-course of the analgesic effects can be close to the plasma concentrations (alfentanil and

  7. Pharmacokinetics and pharmacodynamics of ASP2151, a helicase-primase inhibitor, in a murine model of herpes simplex virus infection. (United States)

    Katsumata, Kiyomitsu; Chono, Koji; Kato, Kota; Ohtsu, Yoshiaki; Takakura, Shoji; Kontani, Toru; Suzuki, Hiroshi


    ASP2151 (amenamevir) is a helicase-primase inhibitor against herpes simplex virus 1 (HSV-1), HSV-2, and varicella zoster virus. Here, to determine and analyze the correlation between the pharmacodynamic (PD) and pharmacokinetic (PK) parameters of ASP2151, we examined the PD profile of ASP2151 using in vitro plaque reduction assay and a murine model of HSV-1 infection. ASP2151 inhibited the in vitro replication of HSV-1 with a mean 50% effective concentration (EC(50)) of 14 ng/ml. In the cutaneously HSV-1-infected mouse model, ASP2151 dose dependently suppressed intradermal HSV-1 growth, with the effect reaching a plateau at a dose of 30 mg/kg of body weight/day. The dose fractionation study showed that intradermal HSV-1 titers were below the detection limit in mice treated with ASP2151 at 100 mg/kg/day divided into two daily doses and at 30 or 100 mg/kg/day divided into three daily doses. The intradermal HSV-1 titer correlated with the maximum concentration of drug in serum (C(max)), the area under the concentration-time curve over 24 h (AUC(24h)), and the time during which the concentration of ASP2151 in plasma was above 100 ng/ml (T(>100)). The continuous infusion of ASP2151 effectively decreased intradermal HSV-1 titers below the limit of detection in mice in which the ASP2151 concentration in plasma reached 79 to 145 ng/ml. Our findings suggest that the antiviral efficacy of ASP2151 is most closely associated with the PK parameter T(>100) in HSV-1-infected mice. Based on these results, we propose that a plasma ASP2151 concentration exceeding 100 ng/ml for 21 to 24 h per day provides the maximum efficacy in HSV-1-infected mice.

  8. Improving pharmacokinetic-pharmacodynamic modeling to investigate anti-infective chemotherapy with application to the current generation of antimalarial drugs.

    Directory of Open Access Journals (Sweden)

    Katherine Kay

    Full Text Available Mechanism-based pharmacokinetic-pharmacodynamic (PK/PD modelling is the standard computational technique for simulating drug treatment of infectious diseases with the potential to enhance our understanding of drug treatment outcomes, drug deployment strategies, and dosing regimens. Standard methodologies assume only a single drug is used, it acts only in its unconverted form, and that oral drugs are instantaneously absorbed across the gut wall to their site of action. For drugs with short half-lives, this absorption period accounts for a significant period of their time in the body. Treatment of infectious diseases often uses combination therapies, so we refined and substantially extended the PK/PD methodologies to incorporate (i time lags and drug concentration profiles resulting from absorption across the gut wall and, if required, conversion to another active form; (ii multiple drugs within a treatment combination; (iii differing modes of action of drugs in the combination: additive, synergistic, antagonistic; (iv drugs converted to an active metabolite with a similar mode of action. This methodology was applied to a case study of two first-line malaria treatments based on artemisinin combination therapies (ACTs, artemether-lumefantrine and artesunate-mefloquine where the likelihood of increased artemisinin tolerance/resistance has led to speculation on their continued long-term effectiveness. We note previous estimates of artemisinin kill rate were underestimated by a factor of seven, both the unconverted and converted form of the artemisinins kill parasites and the extended PK/PD methodology produced results consistent with field observations. The simulations predict that a potentially rapid decline in ACT effectiveness is likely to occur as artemisinin resistance spreads, emphasising the importance of containing the spread of artemisinin resistance before it results in widespread drug failure. We found that PK/PD data is generally very

  9. Physiologically based pharmacokinetics joined with in vitro-in vivo extrapolation of ADME: a marriage under the arch of systems pharmacology. (United States)

    Rostami-Hodjegan, A


    Classic pharmacokinetics (PK) rarely takes into account the full knowledge of physiology and biology of the human body. However, physiologically based PK (PBPK) is built mainly from drug-independent "system" information. PBPK is not a new concept, but it has shown a very rapid rise in recent years. This has been attributed to a greater connectivity to in vitro-in vivo extrapolation (IVIVE) techniques for predicting drug absorption, distribution, metabolism, and excretion (ADME) and their variability in humans. The marriage between PBPK and IVIVE under the overarching umbrella of "systems biology" has removed many constraints related to cutoff approaches on prediction of ADME. PBPK-IVIVE linked models have repeatedly shown their value in guiding decisions when predicting the effects of intrinsic and extrinsic factors on PK of drugs. A review of the achievements and shortcomings of the models might suggest better strategies in extending the success of PBPK-IVIVE to pharmacodynamics (PD) and drug safety.

  10. Mixed Effects Modeling Using Stochastic Differential Equations: Illustrated by Pharmacokinetic Data of Nicotinic Acid in Obese Zucker Rats. (United States)

    Leander, Jacob; Almquist, Joachim; Ahlström, Christine; Gabrielsson, Johan; Jirstrand, Mats


    Inclusion of stochastic differential equations in mixed effects models provides means to quantify and distinguish three sources of variability in data. In addition to the two commonly encountered sources, measurement error and interindividual variability, we also consider uncertainty in the dynamical model itself. To this end, we extend the ordinary differential equation setting used in nonlinear mixed effects models to include stochastic differential equations. The approximate population likelihood is derived using the first-order conditional estimation with interaction method and extended Kalman filtering. To illustrate the application of the stochastic differential mixed effects model, two pharmacokinetic models are considered. First, we use a stochastic one-compartmental model with first-order input and nonlinear elimination to generate synthetic data in a simulated study. We show that by using the proposed method, the three sources of variability can be successfully separated. If the stochastic part is neglected, the parameter estimates become biased, and the measurement error variance is significantly overestimated. Second, we consider an extension to a stochastic pharmacokinetic model in a preclinical study of nicotinic acid kinetics in obese Zucker rats. The parameter estimates are compared between a deterministic and a stochastic NiAc disposition model, respectively. Discrepancies between model predictions and observations, previously described as measurement noise only, are now separated into a comparatively lower level of measurement noise and a significant uncertainty in model dynamics. These examples demonstrate that stochastic differential mixed effects models are useful tools for identifying incomplete or inaccurate model dynamics and for reducing potential bias in parameter estimates due to such model deficiencies.

  11. Pharmacokinetics and efficacy of PEGylated liposomal doxorubicin in an intracranial model of breast cancer.

    Directory of Open Access Journals (Sweden)

    Carey K Anders

    Full Text Available INTRODUCTION: Breast cancer brain metastases (BCBM are a challenging consequence of advanced BC. Nanoparticle agents, including liposomes, have shown enhanced delivery to solid tumors and brain. We compared pharmacokinetics (PK and efficacy of PEGylated liposomal doxorubicin (PLD with non-liposomal doxorubicin (NonL-doxo in an intracranial model of BC. METHODS: Athymic mice were inoculated intracerebrally with MDA-MB-231-BR-luciferase-expressing cells. Tumor-bearing mice were administered PLD or NonL-doxo at 6 mg/kg IV × 1 and were euthanized prior to and 0.083, 1, 3, 6, 24, 72 and 96 h post-treatment. Samples were processed to measure sum total doxorubicin via HPLC. PLD and NonL-doxo were administered IV weekly as single agents (6 mg/kg or in combination (4.5 mg/kg with the PARP inhibitor, ABT-888, PO 25 mg/kg/day. Efficacy was assessed by survival and bioluminescence. RESULTS: Treatment with PLD resulted in approximately 1,500-fold higher plasma and 20-fold higher intracranial tumor sum total doxorubicin AUC compared with NonL-doxo. PLD was detected at 96 h; NonL-doxo was undetectable after 24 h in plasma and tumor. Median survival of PLD-treated animals was 32 days (d, [CI] 31-38, which was significantly longer than controls (26d [CI 25-28]; p = 0.0012 or NonL-doxo treatment (23.5d [CI 18-28], p = 0.0002. Combination treatment with PLD/ABT-888 yielded improved survival compared to NonL-doxo/ABT-888 (35d [CI 31-38] versus 29.5d [CI 25-34]; p = 0.006. CONCLUSIONS: PLD provides both PK and efficacy advantage over NonL-doxo in the treatment of an in vivo model of BCBM. The results provide preclinical rationale to translate findings into early phase trials of PLD, with or without ABT-888, for patients with BCBM.

  12. Population pharmacokinetic/pharmacodynamic modelling of the hypothalamic-pituitary-gonadal axis

    DEFF Research Database (Denmark)

    Tornøe, Christoffer Wenzel


    -releasing hormone (GnRH) agonist triptorelin and GnRH antagonist degarelix in a combined model. The use of SDEs in non-linear mixed-effects modelling was investigated by implementing the Extended Kalman Filter in the NONMEM software. Non-linear mixed-effects models based on SDEs extend the first-stage model...... the production of receptors. The derived mechanism-based model of the HPG axis was able to account for the observed LH and testosterone concentration-time profiles following treatment with both GnRH agonist triptorelin and GnRH antago-nist degarelix thereby indicating that the model is sufficient at mimicking...

  13. Pharmacokinetic/pharmacodynamic-based optimization of levofloxacin administration in the treatment of MDR-TB. (United States)

    Ghimire, Samiksha; Van't Boveneind-Vrubleuskaya, Natasha; Akkerman, Onno W; de Lange, Wiel C M; van Soolingen, Dick; Kosterink, Jos G W; van der Werf, Tjip S; Wilffert, Bob; Touw, Daniel J; Alffenaar, Jan-Willem C


    The emergence of MDR-TB and XDR-TB has complicated TB treatment success. Among many factors that contribute to the development of resistance, low drug exposure is not the least important. This review summarizes the available information on pharmacokinetic properties of levofloxacin in relation to microbial susceptibilities, in order to optimize the dose and make general treatment recommendations. A total of 37 studies on adult (32 studies) and paediatric (5 studies) MDR-TB patients were included. Among the 32 adult studies, 19 were on susceptibility of Mycobacterium tuberculosis isolates to levofloxacin by MIC, 1 was on susceptibility of M. tuberculosis isolates to levofloxacin by MBC, 1 was on susceptibility of M. tuberculosis isolates to levofloxacin by mutant prevention concentration and 4 were on pharmacokinetics of levofloxacin, and 7 others were included. Likewise, out of five studies on children, two dealt with levofloxacin pharmacokinetic parameters, one reviewed CSF concentrations and two dealt with background information. In adult MDR-TB patients, standard dosing of once-daily 1000 mg levofloxacin in TB treatment did not consistently attain the target concentration (i.e. fAUC/MIC >100 and fAUC/MBC >100) in 80% of the patients with MIC and MBC of 1 mg/L, leaving them at risk of developing drug resistance. However, with an MIC of 0.5 mg/L, 100% of the patients achieved the target concentration. Similarly, paediatric patients failed consistently in achieving given pharmacokinetic/pharmacodynamic targets due to age-related differences, demanding a shift towards once daily dosing of 15-20 mg/kg. Therefore, we recommend therapeutic drug monitoring for patients with strains having MICs of ≥0.5 mg/L and suggest revising the cut-off value from 2 to 1 mg/L.

  14. Assessing the utility of an anti-malarial pharmacokinetic-pharmacodynamic model for aiding drug clinical development

    Directory of Open Access Journals (Sweden)

    Zaloumis Sophie


    Full Text Available Abstract Background Mechanistic within-host models relating blood anti-malarial drug concentrations with the parasite-time profile help in assessing dosing schedules and partner drugs for new anti-malarial treatments. A comprehensive simulation study to assess the utility of a stage-specific pharmacokinetic-pharmacodynamic (PK-PD model for predicting within-host parasite response was performed. Methods Three anti-malarial combination therapies were selected: artesunate-mefloquine, dihydroartemisinin-piperaquine, and artemether-lumefantrine. The PK-PD model included parameters to represent the concentration-time profiles of both drugs, the initial parasite burden and distribution across the parasite life cycle, and the parasite multiplication factor due to asexual reproduction. The model also included the maximal killing rate of each drug, and the blood drug concentration associated with half of that killing effect (in vivo EC50, derived from the in vitro IC50, the extent of binding to 0.5% Albumax present in the in vitro testing media, and the drugs plasma protein binding and whole blood to plasma partitioning ratio. All stochastic simulations were performed using a Latin-Hypercube-Sampling approach. Results The simulations demonstrated that the proportion of patients cured was highly sensitive to the in vivo EC50 and the maximal killing rate of the partner drug co-administered with the artemisinin derivative. The in vivo EC50 values that corresponded to on average 95% of patients cured were much higher than the adjusted values derived from the in vitro IC50. The proportion clinically cured was not strongly influenced by changes in the parameters defining the age distribution of the initial parasite burden (mean age of 4 to 16 hours and the parasite multiplication factor every life cycle (ranging from 8 to 12 fold/cycle. The median parasite clearance times, however, lengthened as the standard deviation of the initial parasite burden increased (i

  15. Pharmacokinetics & Neurophysiology (United States)

    Davis, Andrew S.; Salpekar, Jay A.


    Medications administered in clinical practice obtain their therapeutic effect only to the extent that the drug is present in the appropriate concentration at the desired site. To achieve this goal, the prescribing clinician must be aware of how a drug may interact with the physiology of the patient. Pharmacokinetics is the study of this process…

  16. The pharmacokinetic study of rutin in rat plasma based on an electrochemically reduced graphene oxide modified sensor

    Directory of Open Access Journals (Sweden)

    Pei Zhang


    Full Text Available An electrochemical method based on a directly electrochemically reduced graphene oxide (ERGO film coated on a glassy carbon electrode (GCE was developed for the rapid and convenient determination of rutin in plasma. ERGO was modified on the surface of GCE by one-step electro-deposition method. Electrochemical behavior of rutin on ERGO/GCE indicated that rutin underwent a surface-controlled quasi-reversible process and the electrochemical parameters such as charge transfer coefficient (α, electron transfer number (n and electrode reaction standard rate constant (ks were 0.53, 2 and 3.4 s−1, respectively. The electrochemical sensor for rutin in plasma provided a wide linear response range of 4.70×10−7−1.25×10−5 M with the detection limit (s/n=3 of 1.84×10−8 M. The assay was successfully used to the pharmacokinetic study of rutin. The pharmacokinetic parameters such as elimination rate half-life (t1/2, area under curve (AUC, and plasma clearance (CL were calculated to be 3.345±0.647 min, 5750±656.0 µg min/mL, and 5.891±0.458 mL/min/kg, respectively. The proposed method utilized a small sample volume of 10 μL and had no complicated sample pretreatment (without deproteinization, which was simple, eco-friendly, and time- and cost-efficient for rutin pharmacokinetic studies.

  17. A supermolecular curcumin for enhanced antiproliferative and proapoptotic activities: molecular characteristics, computer modeling and in vivo pharmacokinetics (United States)

    Tan, Qunyou; Wu, Jianyong; Li, Yi; Mei, Hu; Zhao, Chunjing; Zhang, Jingqing


    The supermolecular curcumin (SMCCM) exhibiting remarkably improved solubility and release characteristics was fabricated to increase the oral bioavailability in rat as well as the antiproliferative and proapoptotic activities of curcumin (CCM) against human lung adenocarcinoma cell A549. SMCCM was characterized by differential scanning calorimetry, Fourier transform infrared spectroscopy, morphology and structure, aqueous solubility, and release behavior in vitro. Computer modeling of the supermolecular structure was performed. The pharmacokinetics, antiproliferative and proapoptotic activities of SMCCM were evaluated. The mechanisms by which SMCCM inhibited proliferation and induced apoptosis were identified. The formation of SMCCM was testified and the supermolecular structure was studied by a computer modeling technique. Compared to free CCM, SMCCM with much higher aqueous solubility exhibited obviously enhanced release and more favorable pharmacokinetic profiles, and, furthermore, SMCCM showed higher anticancer efficacy, enhanced induction of G2/M-phase arrest and apoptosis in A549 cells, which might be involved with the increases in reactive oxygen species production and intracellular Ca2+ accumulation, and a decrease in mitochondrial membrane potential. SMCCM remarkably enhanced not only the oral bioavailability but also the antiproliferative and proapoptotic activities of CCM along with improved solubility and release characteristics of CCM.

  18. Valproate-induced reversible sensorineural hearing loss: a case report with serial audiometry and pharmacokinetic modelling during a valproate rechallenge. (United States)

    Yeap, Li-Ling; Lim, Kheng-Seang; Lo, Yoke-Lin; Bakar, Mohd Zukiflee Abu; Tan, Chong-Tin


    Hearing loss has been reported with valproic acid (VPA) use. However, this is the first case of VPA-induced hearing loss that was tested and confirmed with a VPA rechallenge, supported by serial audiometry and pharmacokinetic modelling. A 39-year-old truck driver with temporal lobe epilepsy was treated with VPA at 400 mg, twice daily, and developed hearing loss after each dose, but recovered within three hours. Hearing loss fully resolved after VPA discontinuation. Audiometry performed five hours after VPA rechallenge showed significant improvement in hearing thresholds. Pharmacokinetic modelling during the VPA rechallenge showed that hearing loss occurred at a level below the therapeutic range. Brainstem auditory evoked potential at three months after VPA discontinuation showed bilateral conduction defect between the cochlear and superior olivary nucleus, supporting a pre-existing auditory deficit. VPA may cause temporary hearing threshold shift. Pre-existing auditory defect may be a risk factor for VPA-induced hearing loss. Caution should be taken while prescribing VPA to patients with pre-existing auditory deficit.

  19. Drug-metabolism mechanism: Knowledge-based population pharmacokinetic approach for characterizing clobazam drug-drug interactions. (United States)

    Tolbert, Dwain; Bekersky, Ihor; Chu, Hui-May; Ette, Ene I


    A metabolic mechanism-based characterization of antiepileptic drug-drug interactions (DDIs) with clobazam in patients with Lennox-Gastaut syndrome (LGS) was performed using a population pharmacokinetic (PPK) approach. To characterize potential DDIs with clobazam, pharmacokinetic (PK) data from 153 patients with LGS in study OV-1012 (NCT00518713) and 18 healthy participants in bioavailability study OV-1017 were pooled. Antiepileptic drugs (AEDs) were grouped based on their effects on the cytochrome P450 (CYP) isozymes responsible for the metabolism of clobazam and its metabolite, N-desmethylclobazam (N-CLB): CYP3A inducers (phenobarbital, phenytoin, and carbamazepine), CYP2C19 inducers (valproic acid, phenobarbital, phenytoin, and carbamazepine), or CYP2C19 inhibitors (felbamate, oxcarbazepine). CYP3A4 inducers-which did not affect the oral clearance of clobazam-significantly increased the formation of N-CLB by 9.4%, while CYP2C19 inducers significantly increased the apparent elimination rate of N-CLB by 10.5%, resulting in a negligible net change in the PK of the active metabolite. CYP2C19 inhibitors did not affect N-CLB elimination. Because concomitant use of AEDs that are either CYP450 inhibitors or inducers with clobazam in the treatment of LGS patients had negligible to no effect on clobazam PK in this study, dosage adjustments may not be required for clobazam in the presence of the AEDs investigated here.

  20. Pharmacokinetic models of morphine and its metabolites in neonates:: Systematic comparisons of models from the literature, and development of a new meta-model. (United States)

    Knøsgaard, Katrine Rørbæk; Foster, David John Richard; Kreilgaard, Mads; Sverrisdóttir, Eva; Upton, Richard Neil; van den Anker, Johannes N


    Morphine is commonly used for pain management in preterm neonates. The aims of this study were to compare published models of neonatal pharmacokinetics of morphine and its metabolites with a new dataset, and to combine the characteristics of the best predictive models to design a meta-model for morphine and its metabolites in preterm neonates. Moreover, the concentration-analgesia relationship for morphine in this clinical setting was also investigated. A population of 30 preterm neonates (gestational age: 23-32weeks) received a loading dose of morphine (50-100μg/kg), followed by a continuous infusion (5-10μg/kg/h) until analgesia was no longer required. Pain was assessed using the Premature Infant Pain Profile. Five published population models were compared using numerical and graphical tests of goodness-of-fit and predictive performance. Population modelling was conducted using NONMEM® and the $PRIOR subroutine to describe the time-course of plasma concentrations of morphine, morphine-3-glucuronide, and morphine-6-glucuronide, and the concentration-analgesia relationship for morphine. No published model adequately described morphine concentrations in this new dataset. Previously published population pharmacokinetic models of morphine, morphine-3-glucuronide, and morphine-6-glucuronide were combined into a meta-model. The meta-model provided an adequate description of the time-course of morphine and the concentrations of its metabolites in preterm neonates. Allometric weight scaling was applied to all clearance and volume terms. Maturation of morphine clearance was described as a function of postmenstrual age, while maturation of metabolite elimination was described as a function of postnatal age. A clear relationship between morphine concentrations and pain score was not established.

  1. Influence of omeprazole on pharmacokinetics of domperidone given as free base and maleate salt in healthy Chinese patients

    Institute of Scientific and Technical Information of China (English)

    Yi-fan ZHANG; Xiao-yan CHEN; Xiao-jian DAI; Yi-ni ZHANG; Qi-zhi LIU; Hua-ling YU; Da-fang ZHONG


    Aim: To investigate the influence of omeprazole on the pharmacokinetics of domperidone given as free base and maleate salt. Methods: An open, randomized, 2-period crossover study with a washout period of 7 d was conducted in 10 healthy Chinese, male patients. In each study period, the patients were adminis-tered a single oral dose of l0 mg domperidone as free base or maleate salt on d 1,20 mg omeprazole twice daily on d 2 and 3, and once on d 4. A single dose of 10 mg domperidone as free base or maleate salt was taken at 4 h after administration of omeprazole on d 4. Plasma samples were collected on d 1 and 4 after the adminis- tration of domperidone, and the plasma concentrations of domperidone were de- termined by a sensitive liquid chromatography-tandem mass spectrometry method.Results: For free-base domperidone, pretreatment with omeprazole resulted in a 16% decrease in maximum concentration (Cmax), compared with administration alone (P<0.05). However, for maleate salt, with the exception of an increase in t1/2,no pharmacokinetic parameters were significantly changed. When the free base and maleate salt were administered alone, no differences were found in any param-eters between the 2 formulations. In contrast, when they were administered in the presence of omeprazole, the Cmax of domperidone given as free base was lower (25.9%) than that given as maleate salt (P<0.05). Conclusion: Pretreatment of omeprazole does not affect the absorption of domperidone maleate, but leads to a moderately decreased rate of absorption of the free base.

  2. Pharmacokinetic/pharmacodynamic relationship of cefquinome against Pasteurella multocida in a tissue-cage model in yellow cattle. (United States)

    Shan, Q; Yang, F; Wang, J; Ding, H; He, L; Zeng, Z


    The cephalosporin antimicrobial drug cefquinome was administered to yellow cattle intravenously (i.v.) and intramuscularly (i.m.) at a dose of 1 mg/kg of body weight in a two-period crossover study. The pharmacokinetic (PK) properties of cefquinome in serum, inflamed tissue-cage fluid (exudate), and noninflamed tissue-cage fluid (transudate) were studied using a tissue-cage model. The in vitro and ex vivo activities of cefquinome in serum, exudate, and transudate against a pathogenic strain of Pasteurella multocida (P. multocida) were determined. A concentration-independent antimicrobial activity of cefquinome was confirmed for levels lower than 4 × MIC. Integration of in vivo pharmacokinetic data with the in vitro MIC provided mean values for the time that drug levels remain above the MIC (T > MIC) in serum was 14.10 h after intravenous and 14.46 h after intramuscular dosing, indicating a likely high level of effectiveness in clinical infections caused by P. multocida of MIC 0.04 μg/mL or less. These data may be used as a rational basis for setting dosing schedules, which optimize clinical efficacy and minimize the opportunities for emergence of resistant organisms.

  3. Modelling hemoglobin and hemoglobin:haptoglobin complex clearance in a non-rodent species– pharmacokinetic and therapeutic implications

    Directory of Open Access Journals (Sweden)

    Felicitas S Boretti


    Full Text Available Preclinical studies suggest that haptoglobin (Hp supplementation could be an effective therapeutic modality during acute or chronic hemolytic diseases. Hp prevents Hb extravasation and neutralizes Hb’s oxidative and NO scavenging activity in the vasculature. Small animal models such as mouse, rat and guinea pig appear to be valuable to provide proof-of-concept for Hb neutralization by Hp in diverse pre-clinical conditions. However, these species differ significantly from human in the clearance of Hb:Hp complexes, which leads to long persistence of circulating Hb:Hp complexes after administration of human plasma derived Hp. Alternative animal models must therefore be explored to guide pre-clinical development of these potential therapeutics. In contrast to rodents, dogs have high Hp plasma concentrations comparable to human. In this study we show that like human macrophages, dog peripheral blood monocyte derived macrophages express a glucocorticoid inducible endocytic clearance pathways with a high specificity for the Hb:Hp complex. Evaluating the Beagle dog as a non-rodent model species we provide the first pharmacokinetic parameter estimates of free Hb and Hb:Hp phenotype complexes. The data reflect a drastically reduced volume of distribution (Vc of the complex compared to free Hb, increased exposures (Cmax and AUC and significantly reduced total body clearance (CL with a terminal half-life (t1/2 of approximately 12 hours. Distribution and clearance was identical for dog and human Hb (± glucocorticoid stimulation and for dimeric and multimeric Hp preparations bound to Hb. Collectively, our study supports the dog as a non-rodent animal model to study pharmacological and pharmacokinetic aspects of Hb clearance systems and apply the model to studying Hp therapeutics.

  4. [Comparison of the brain pharmacokinetics of nasal tetramethylpyrazine phosphate pH-sensitive in situ gel in normal rats and model rats]. (United States)

    Liu, Hong-Wei; Yan, Yi-Lin; Zhou, Li-Ling


    The study is to investigate the brain pharmacokinetics change of nasal tetramethylpyrazine phosphate (TMPP) pH-sensitive in situ gel in normal and model rats. Acute cerebral ischemia rat model was successfully established by middle cerebral artery occlusion (MCAO) method. Both normal and model rats were given nasal TMPP pH-sensitive in situ gel (10 mg x kg(-1)). Perfusates of brain striatum area were collected at each time point by microdialysis. The content of TMPP was determined by HPLC. The pharmacokinetics parameters were calculated by Kinetica 4.4 software at each time point of the brain drug concentration. The main pharmacokinetics parameters of TMPP were fitted with compartments 2. After nasal TMPP pH-sensitive in situ gel the values of C(max) and AUC of both components in brain showed as follows: the value of model group > that of normal group. Significant difference can be observed in the process of brain pharmacokinetics in normal and model rats after giving nasal TMPP pH-sensitive in situ gel.

  5. Solid Matrix Based Lipidic Nanoparticles in Oral Cancer Chemotherapy: Applications and Pharmacokinetics. (United States)

    Ahmad, Javed; Amin, Saima; Rahman, Mahfoozur; Rub, Rehan Abdur; Singhal, Madhur; Ahmad, Mohammad Zaki; Rahman, Ziyaur; Addo, Richard T; Ahmad, Farhan Jalees; Mushtaq, Gohar; Kamal, Mohammad Amjad; Akhter, Sohail


    Chemotherapeutic delivery by oral route in cancer patients has the potential to create "hospitalization free chemotherapy" which is a vision of oncologists, formulation scientists and patients. Such a therapeutic approach will improve patients' compliance, ease the burden of the patients' caregivers and significantly reduce the cost of treatment. In current clinical practice, chemotherapy carried out by intravenous injection or infusion leads to undesired side-effects such as plasma concentrations crossing the maximum safe concentration, rapid body clearance and lower bioavailability. Despite the presence of challenges such as poor aqueous solubility and stability of drugs and the presence of biological barriers like multidrug efflux transporter in the GI tract, oral cancer chemotherapy has the potential to surmount those obstacles. Lipid nanoparticles (LNPs) such as solid lipid nanoparticle, nanostructured lipid carriers, nano lipid-drug conjugates, mixed micelles, liposomes and nanoemulsions have shown some promising results for use in oral anticancer drug delivery through nanotechnological approach. LNPs demonstrate enhanced oral bioavailability owing to their ability to inhibit first pass metabolism via lymphatic absorption by chylomicron-linked and/or M-cell uptake. LNPs reduce the inter- and intrasubject pharmacokinetics variability of administrated drugs. Moreover, certain classes of phospholipids and surfactants used in the formulations of LNPs can suppress the P-glycoprotein efflux system. Here, we shall be discussing the biopharmaceutical challenges in oral cancer chemotherapy and how the LNPs may provide solutions to such challenges. The effect of GI tract environment on LNPs and pharmacokinetics shall also be discussed.

  6. Pharmacokinetics of fluconazole in cerebrospinal fluid and serum of rabbits: validation of an animal model used to measure drug concentrations in cerebrospinal fluid. (United States)

    Madu, A; Cioffe, C; Mian, U; Burroughs, M; Tuomanen, E; Mayers, M; Schwartz, E; Miller, M


    Complete concentration-time data describing the pharmacokinetics of fluconazole in the cerebrospinal fluid (CSF) following a single dose are not available for humans or animals. We studied the pharmacokinetics of fluconazole with an indwelling intracisternal needle as described by R.G. Dacey and M.A. Sande (Antimicrob. Agents Chemother. 6:437-441, 1974). To determine whether the presence of an intracisternal needle alters pharmacokinetics in the CSF, we validated this model with uninfected rabbits by measuring pharmacokinetic constants following direct intracisternal and intravenous administration of fluconazole. Following direct injection, there was no alteration of elimination rates in the CSF with increasing sample number or time. Following intravenous administration, the penetration and kinetic constants were the same in individual animals from which multiple CSF samples were obtained as in a composite subject constructed by pooling virgin samples from different animals. The presence of the intracisternal needle did not alter CSF chemistry or leukocyte counts, and erythrocyte contamination was < 0.001%. While drug concentrations were measured by a microbiological assay, we also compared the sensitivity and reproducibility of a high-performance liquid chromatography (HPLC) assay with those of the microbiological assay. Following a single intravenous dose, the maximum concentration of the drug in serum, the time to maximum concentration of the drug in serum, the terminal elimination half-life in the CSF, and the percent penetration by fluconazole were 6.12 micrograms/ml, 1 h, 9.0 h, and 84.3%, respectively. We conclude that the sampling of CSF via an indwelling needle does not alter fluconazole pharmacokinetics, cause inflammation, or alter chemical parameters; that the microbiological assay is at least equivalent in sensitivity and reproducibility to the HPLC assay; and that robust parameters describing the pharmacokinetics of fluconazole are possible with this

  7. Determination of a dosage regimen of colistin by pharmacokinetic/pharmacodynamic integration and modeling for treatment of G.I.T. disease in pigs. (United States)

    Guyonnet, J; Manco, B; Baduel, L; Kaltsatos, V; Aliabadi, M H F S; Lees, P


    Colistin is an antimicrobial drug of the polymyxin group and COLIVET SOLUTION is an aqueous solution containing colistin sulphate (2 x 10(6) IU/mL), formulated for oral administration. The target species is the pig, particularly the suckling and post weaning animal. This investigation was undertaken to provide pharmacokinetic and pharmacodynamic data on which to base the selection of dosage rate and interval of the solution for the treatment of porcine colibacillosis. Colistin absorption from the gastrointestinal tract of young pigs, when administered at dosage rates of 25,000, 50,000 and 100,000 IU/kg, was slight or absent. The drug was therefore restricted almost entirely to the required site of action. The colistin concentration-time profile within the jejunum and ileum was established, and this enabled determination of the pharmacokinetic variables, maximum concentration (C(max)) and area under curve (AUC) and derivation of the surrogate indices of antibacterial activity, C(max)/minimum inhibitory concentration (MIC) and AUC/MIC through integration of in vivo data with the results of in vitro potency studies for four strains of Escherichia coli. In the in vitro bacterial growth inhibition studies colistin acted by a concentration-dependent killing mechanism. Numerical values for the surrogate parameter AUC/MIC producing bactericidal and eradication effects of colistin against four strains of E. coli were established by PK-PD modeling based on the sigmoidal E(max) equation. These data were used to predict a daily dosage regimen for colistin.

  8. A population pharmacokinetic model for the complex systemic absorption of ropivacaine after femoral nerve block in patients undergoing knee surgery. (United States)

    Gaudreault, François; Drolet, Pierre; Fallaha, Michel; Varin, France


    Because of its slow systemic absorption and flip-flop kinetics, ropivacaine's pharmacokinetics after a peripheral nerve block has never been thoroughly characterized. The purpose of this study was to develop a population pharmacokinetic model for ropivacaine after loco-regional administration and to identify patient characteristics that may influence the drug's absorption and disposition. Frequent plasma samples were taken up to 93 h after a 100 mg dose given as femoral block for postoperative analgesia in 15 orthopedic patients. Ropivacaine plasma concentration-time data were analyzed using a nonlinear mixed effects modeling method. A one-compartment model with parallel inverse Gaussian and time-dependent inputs best described ropivacaine plasma concentration-time curves. Ropivacaine systemic absorption was characterized by a rapid phase (mean absorption time of 25 ± 4.8 min) followed by a much slower phase (half-life of 3.9 ± 0.65 h). Interindividual variability (IIV) for these parameters, 58 and 9 %, indicated that the initial absorption phase was more variable. The apparent volume of distribution (V/F = 77.2 ± 11.5 L, IIV = 26 %) was influenced by body weight (Δ 1.49 % per kg change) whereas the absorption rate constant (slower phase) of ropivacaine was affected by age (Δ 2.25 % per year change). No covariate effects were identified for the apparent clearance of the drug (CL/F =10.8 ± 1.0 L/h, 34  IIV = 34 %). These findings support our hypothesis that modeling a complex systemic absorption directly from plasma concentration-time curves exhibiting flip-flop kinetics is possible. Only the age-effect was considered as relevant for possible dosing adjustments.

  9. Pharmacokinetic/pharmaco-dynamic modelling and simulation of the effects of different cannabinoid receptor type 1 antagonists on (9)-tetrahydrocannabinol challenge tests

    NARCIS (Netherlands)

    Guan, Zheng; Klumpers, Linda E.; Oyetayo, Olubukayo-Opeyemi; Heuberger, Jules; van Gerven, Joop M. A.; Stevens, Jasper


    Aim: The severe psychiatric side effects of cannabinoid receptor type 1 (CB1) antagonists hampered their wide development but this might be overcome by careful management of drug development with pharmacokinetic/pharmacodynamic (PK/PD) analyses. PK/PD models suitable for direct comparison of differe

  10. Pharmacokinetic analysis of [11C]PBR28 in the rat model of herpes encephalitis: comparison with (R)-[11C]PK11195 for pre-clinical imaging

    NARCIS (Netherlands)

    Kopschina Feltes, Paula; Parente, Andrea; Vállez Garcia, David; Sijbesma, Jurgen; Moriguchi Jeckel, Cristina; Dierckx, Rudi; de Vries, Erik; Doorduin, Janine


    Aim: [11C]PBR28 is a second generation translocator protein (TSPO) ligand with supposedly better imaging characteristics than the most commonly used tracer [11C]PK11195. Surprisingly, only limited studies have evaluated the pharmacokinetic and binding profile of [11C]PBR28 in neuroinflammatory model

  11. Pharmacokinetic analysis of 11C-PBR28 in the rat model of herpes encephalitis (HSE): comparison with (R)-11C-PK11195

    NARCIS (Netherlands)

    Parente, Andrea; Kopschina Feltes, Paula; Vállez Garcia, David; Sijbesma, Jurgen; Moriguchi Jeckel, Cristina M; Dierckx, Rudi; de Vries, Erik F; Doorduin, Janine


    11C-PBR28 is a second generation TSPO tracer with supposedly superior characteristics than the most commonly used tracer for neuroinflammation, (R)-11C-PK11195. Despite its use in clinical research, no studies on the imaging properties and pharmacokinetic analysis of 11C-PBR28 in rodent models of ne

  12. Pharmacokinetic/pharmaco-dynamic modelling and simulation of the effects of different cannabinoid receptor type 1 antagonists on (9)-tetrahydrocannabinol challenge tests

    NARCIS (Netherlands)

    Guan, Zheng; Klumpers, Linda E.; Oyetayo, Olubukayo-Opeyemi; Heuberger, Jules; van Gerven, Joop M. A.; Stevens, Jasper


    AimThe severe psychiatric side effects of cannabinoid receptor type 1 (CB1) antagonists hampered their wide development but this might be overcome by careful management of drug development with pharmacokinetic/pharmacodynamic (PK/PD) analyses. PK/PD models suitable for direct comparison of different

  13. Simultaneous population pharmacokinetic modelling of darunavir and ritonavir Once daily in HIV-infected patients: evaluation of lower ritonavir dose

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    L Dickinson


    Full Text Available Purpose of study: Once-daily ritonavir-boosted darunavir (DRV/RTV is a preferred antiretroviral regimen for treatment-naïve patients. Population pharmacokinetic modelling of the interaction between DRV and RTV allows evaluation of alternative dosing strategies, particularly lower RTV doses (e.g. 800/50 mg once daily and assessment of factors that may influence DRV/RTV PK. Methods: Data were pooled from 3 DRV/RTV PK studies. Fifty-one HIV-infected patients (7 female stable on DRV/RTV (800/100 mg or 900/100 mg once daily; n=32 and 19, respectively were included. Median age, weight and baseline CD4 cell count were 39 yr (21–63, 74 kg (57–105 and 500 cells/mm3 (227–1129, respectively; 49 had undetectable viral load. Nonlinear mixed effects modelling (Monolix v.4.1.2 was applied simultaneously to DRV and RTV to determine PK parameters, interindividual variability and residual error. Covariates evaluated included: age, weight, sex and study. The model was validated by simulation and visual predictive check. DRV/RTV 800/50 mg once daily was simulated. Summary of results: RTV and DRV were described by a 1 and 2-compartment model, respectively with first-order absorption and lag-time. A maximum effect model, in which RTV inhibited DRV clearance (CL/F, best described the relationship between the two drugs. A RTV concentration of 0.33 mg/L was associated with 50% maximum inhibition of DRV CL/F with the maximum inhibitory effect fixed at 1. The population CL/F of DRV in the absence of RTV was 13.7L/h. Inclusion of weight on RTV CL/F and volume and age on DRV CL/F and study on DRV CL/F, volume and absorption improved the fit. Based on visual predictive check 93% and 91% of observed RTV and DRV concentrations were within the 95% prediction interval, indicative of an adequate model. Of 1000 simulated DRV troughs, 10% and 0% were below the MEC for treatment-experienced (<0.55 mg/L and naïve patients (<0.055 mg/L, respectively. For DRV/RTV 800/50 mg once

  14. PK-PD Modeling of Fluoroquinolones and ABC Transporters in Poultry

    NARCIS (Netherlands)

    Haritova, A.M.


    In the first part of this thesis advance pharmacokinetic models, based on an integration of pharmacokinetic and pharmacodynamic data for selected fluotoquinolones, are presented. The comparative investigations with danofloxacin mesylate and marbofloxacin indicated that with both fluoroquinolones a c

  15. Mechanistic pharmacokinetic-pharmacodynamic modeling of BACE1 inhibition in monkeys: development of a predictive model for amyloid precursor protein processing. (United States)

    Liu, Xingrong; Wong, Harvey; Scearce-Levie, Kimberly; Watts, Ryan J; Coraggio, Melis; Shin, Young G; Peng, Kun; Wildsmith, Kristin R; Atwal, Jasvinder K; Mango, Jason; Schauer, Stephen P; Regal, Kelly; Hunt, Kevin W; Thomas, Allen A; Siu, Michael; Lyssikatos, Joseph; Deshmukh, Gauri; Hop, Cornelis E C A


    This study was conducted to determine the pharmacokinetics (PK) and pharmacodynamics (PD) of two novel inhibitors of β-site amyloid precursor protein (APP)-cleaving enzyme (BACE1), GNE-629 [(4S,4a'S,10a'S)-2-amino-8'-(2-fluoropyridin-3-yl)-1-methyl-3',4',4a',10a'-tetrahydro-1'H-spiro[imidazole-4,10'-pyrano[4,3-b]chromen]-5(1H)-one] and GNE-892 [(R)-2-amino-1,3',3'-trimethyl-7'-(pyrimidin-5-yl)-3',4'-dihydro-2'H-spiro[imidazole-4,1'-naphthalen]-5(1H)-one], and to develop a PK-PD model to predict in vivo effects based solely on in vitro activity and PK. GNE-629 and GNE-892 concentrations and PD biomarkers including amyloid β (Aβ) in the plasma and cerebrospinal fluid (CSF), and secreted APPβ (sAPPβ) and secreted APPα (sAPPα) in the CSF were measured after a single oral administration of GNE-629 (100 mg/kg) or GNE-892 (30 or 100 mg/kg) in cynomolgus monkeys. A mechanistic PK-PD model was developed to simultaneously characterize the plasma Aβ and CSF Aβ, sAPPα, and sAPPβ using GNE-629 in vivo data. This model was used to predict the in vivo effects of GNE-892 after adjustments based on differences in in vitro cellular activity and PK. The PK-PD model estimated GNE-629 CSF and free plasma IC₅₀ of 0.0033 μM and 0.065 μM, respectively. These differences in CSF and free plasma IC₅₀ suggest that different mechanisms are involved in Aβ formation in these two compartments. The predicted in vivo effects for GNE-892 using the PK-PD model were consistent with the observed data. In conclusion, a PK-PD model was developed to mechanistically describe the effects of BACE1 inhibition on Aβ, sAPPβ, and sAPPα in the CSF, and Aβ in the plasma. This model can be used to prospectively predict in vivo effects of new BACE1 inhibitors using just their in vitro activity and PK data.

  16. Pharmacokinetics and tissue distribution after intravenous administration of a single dose of amphotericin B cochleates, a new lipid-based delivery system. (United States)

    Segarra, Ignacio; Movshin, Diane A; Zarif, Leila


    Model independent pharmacokinetic analysis of intravenous (iv) amphotericin B cochleates (CAMB), a new lipid-based drug delivery system, in mice (0.625 mg/kg) shows a two-phase disposition profile in blood [area under the curve of concentration versus time from time zero to infinity (AUC(0-infinity)) = 1.01 microg. h/mL, half-life (t((1/2))) = 11.68 h, volume of distribution at steady state (V(ss)) = 9.59 L/kg, clearance (CL) = 10.36 mL/min/kg and mean residence time from time 0 to infinity (MRT(0-infinity)) = 15.41 h). In target tissues, maximum time (t(max)) ranged from 2 min (spleen and lung) to 10 min (liver) and lungs presented the highest AMB concentration (16.4 microg. h/g) followed by liver (8.56 microg/g), and spleen (6.63 microg/g). In addition, liver and spleen presented the longest elution half-life (75.03 and 66.71 h, respectively), MRT(0-infinity) (98.4 and 86.3 h, respectively), and AMB exposure:liver AUC(0-infinity) = 474 and 116.4 microg. h/g for the spleen. The large V(ss) and the extensive tissue AUC indicate large and efficient ability of cochleates to penetrate and deliver AMB. Differences in tissue uptake mechanism and pharmacokinetic data suggest a crucial role of macrophages in CAMB clearance from blood as well as an essential role of the liver and the spleen in AMB distribution to target tissues.

  17. Development of olmesartan medoxomil lipid-based nanoparticles and nanosuspension: preparation, characterization and comparative pharmacokinetic evaluation. (United States)

    B, Arun; D, Narendar; Veerabrahma, Kishan


    The aim was to enhance the oral bioavailability of olmesartan medoxomil (OM) by preparing solid lipid nanoparticles (SLNs) and comparing with nanosuspension (OM-NS). OM-SLNs and OM-NS were prepared by known methods. Prepared SLNs were evaluated for physical characters and in vivo pharmacokinetic (PK) performance in rats. OM-NS showed more than four-fold increase in the solubility. During DSC and XRD studies, drug incorporated in SLNs was found to be in amorphous form. The relative bioavailability of OM-SLN and OM-NS was 7.21- and 3.52-fold when compared with that of coarse suspension. Further, OM-SLNs also increased the oral bioavailability by two-fold over that of OM-NS.

  18. Assessment of Bioequivalence of Weak Base Formulations Under Various Dosing Conditions Using Physiologically Based Pharmacokinetic Simulations in Virtual Populations. Case Examples: Ketoconazole and Posaconazole. (United States)

    Cristofoletti, Rodrigo; Patel, Nikunjkumar; Dressman, Jennifer B


    Postabsorptive factors which can affect systemic drug exposure are assumed to be dependent on the active pharmaceutical ingredient (API), and thus independent of formulation. In contrast, preabsorptive factors, for example, hypochlorhydria, might affect systemic exposure in both an API and a formulation-dependent way. The aim of this study was to evaluate whether the oral absorption of 2 poorly soluble, weakly basic APIs, ketoconazole (KETO) and posaconazole (POSA), would be equally sensitive to changes in dissolution rate under the following dosing conditions-coadministration with water, with food, with carbonated drinks, and in drug-induced hypochlorhydria. The systems-components of validated absorption and PBPK models for KETO and POSA were modified to simulate the above-mentioned clinical scenarios. Virtual bioequivalence studies were then carried out to investigate whether formulation effects on the plasma profile vary with the dosing conditions. The slow precipitation of KETO upon reaching the upper part of the small intestine renders its absorption more sensitive to the completeness of gastric dissolution and thus to the gastric environment than POSA, which is subject to extensive precipitation in response to a pH shift. The virtual bioequivalence studies showed that hypothetical test and reference formulations containing KETO would be bioequivalent only if the microenvironment in the stomach enables complete gastric dissolution. We conclude that physiologically based pharmacokinetic modeling and simulation has excellent potential to address issues close to bedside such as optimizing dosing conditions. By studying virtual populations adapted to various clinical situations, clinical strategies to reduce therapeutic failures can be identified.

  19. Pharmacokinetic and Toxicological Evaluation of a Zinc Gluconate-Based Chemical Sterilant Using In Vitro and In Silico Approaches (United States)

    Araujo-Lima, Carlos F.; Nunes, Rafael J. M.; Carpes, Raphael M.


    Sclerosing agents as zinc gluconate-based chemical sterilants (Infertile®) are used for chemical castration. This solution is injected into the animal testis, but there are not enough evidences of its safety profiles for the receivers. The present work aimed to establish the pharmacokinetics and toxicological activity of Infertile, using in vitro and in silico approaches. The evaluation at the endpoint showed effects in a dose-dependent manner. Since necrosis is potentially carcinogenic, the possible cell death mechanism could be apoptosis. Our data suggested that Infertile at 60 mM presented risk for animal health. Even though Infertile is a licensed product by the Brazilian Ministry of Agriculture, Livestock and Supply, it presented a high mutagenic potential. We suggest that the optimal dose must be less than 6 mM, once, at this concentration, no mutagenicity or genotoxicity was observed. PMID:28197414

  20. Integrative pharmacokinetic-pharmacodynamic modeling and simulation of amenamevir (ASP2151) for treatment of recurrent genital herpes. (United States)

    Takada, Akitsugu; Katashima, Masataka; Kaibara, Atsunori; Chono, Koji; Katsumata, Kiyomitsu; Sawamoto, Taiji; Suzuki, Hiroshi; Yano, Yoshitaka


    Amenamevir is a novel drug that targets the viral helicase-primase complex. While dose-dependent efficacy had been observed in non-clinical studies, no clear dose dependence has been observed in humans. We therefore developed a pharmacokinetic/pharmacodynamic (PK/PD) model to explain this inconsistency between species and to clarify the immune-related healing of amenamevir in humans. The model consisted of a non-linear kinetic model for a virtual number of virus plaques as a built-in biomarker. Lesion score was defined as an endpoint of antiviral efficacy, and logit model analysis was applied to the ordered-categorical lesion score. The modeling results suggested the time course profiles of lesion score could be explained with the efficacy terms in the logit model, using change in number of virus plaques as an indicator of the effects of amenamevir and time elapsed as an indicator of the healing of the immune response. In humans, the PD effect was almost dose-independent, and immune-related healing may have been the driving force behind the reduction in lesion scores. Drug efficacy is occasionally masked in diseases healed by the immune response, such as genital herpes. The PK/PD model proposed in the present study must be useful for explanation the PK/PD relationship of such drugs.

  1. Pharmacokinetic and nephroprotective benefits of using Schisandra chinensis extracts in a cyclosporine A-based immune-suppressive regime

    Directory of Open Access Journals (Sweden)

    Lai Q


    the very same addition of SCE. SCE was also able to increase the systemic exposure of CsA in rats. The renoprotective effects of SCE were thought to be mediated by its antiapoptotic and antioxidant abilities, which caused the attenuation of CsA-induced autophagic cell death. All in all, these findings suggest the prospective use of SCE as an effective adjunct in a CsA-based immunosuppressive regimen.Keywords: Schisandra chinensis extracts, cyclosporine A, pharmacokinetics, nephroprotective, oxidative stress, apoptosis, autophagy

  2. A mechanism-based approach for absorption modeling: the Gastro-Intestinal Transit Time (GITT) model. (United States)

    Hénin, Emilie; Bergstrand, Martin; Standing, Joseph F; Karlsson, Mats O


    Absorption models used in the estimation of pharmacokinetic drug characteristics from plasma concentration data are generally empirical and simple, utilizing no prior information on gastro-intestinal (GI) transit patterns. Our aim was to develop and evaluate an estimation strategy based on a mechanism-based model for drug absorption, which takes into account the tablet movement through the GI transit. This work is an extension of a previous model utilizing tablet movement characteristics derived from magnetic marker monitoring (MMM) and pharmacokinetic data. The new approach, which replaces MMM data with a GI transit model, was evaluated in data sets where MMM data were available (felodipine) or not available (diclofenac). Pharmacokinetic profiles in both datasets were well described by the model according to goodness-of-fit plots. Visual predictive checks showed the model to give superior simulation properties compared with a standard empirical approach (first-order absorption rate + lag-time). This model represents a step towards an integrated mechanism-based NLME model, where the use of physiological knowledge and in vitro–in vivo correlation helps fully characterize PK and generate hypotheses for new formulations or specific populations.

  3. Transform-both-sides nonlinear models for in vitro pharmacokinetic experiments. (United States)

    Latif, A H M Mahbub; Gilmour, Steven G


    Transform-both-sides nonlinear models have proved useful in many experimental applications including those in pharmaceutical sciences and biochemistry. The maximum likelihood method is commonly used to fit transform-both-sides nonlinear models, where the regression and transformation parameters are estimated simultaneously. In this paper, an analysis of variance-based method is described in detail for estimating transform-both-sides nonlinear models from randomized experiments. It estimates the transformation parameter from the full treatment model and then the regression parameters are estimated conditionally on this estimate of the transformation parameter. The analysis of variance method is computationally simpler compared with the maximum likelihood method of estimation and allows a more natural separation of different sources of lack of fit. Simulation studies show that the analysis of variance method can provide unbiased estimators of complex transform-both-sides nonlinear models, such as transform-both-sides random coefficient nonlinear regression models and transform-both-sides fixed coefficient nonlinear regression models with random block effects.

  4. Propofol Pharmacokinetics and Estimation of Fetal Propofol Exposure during Mid-Gestational Fetal Surgery: A Maternal-Fetal Sheep Model.

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    Pornswan Ngamprasertwong

    Full Text Available Measuring fetal drug concentrations is extremely difficult in humans. We conducted a study in pregnant sheep to simultaneously describe maternal and fetal concentrations of propofol, a common intravenous anesthetic agent used in humans. Compared to inhalational anesthesia, propofol supplemented anesthesia lowered the dose of desflurane required to provide adequate uterine relaxation during open fetal surgery. This resulted in better intraoperative fetal cardiac outcome. This study describes maternal and fetal propofol pharmacokinetics (PK using a chronically instrumented maternal-fetal sheep model.Fetal and maternal blood samples were simultaneously collected from eight mid-gestational pregnant ewes during general anesthesia with propofol, remifentanil and desflurane. Nonlinear mixed-effects modeling was performed by using NONMEM software. Total body weight, gestational age and hemodynamic parameters were tested in the covariate analysis. The final model was validated by bootstrapping and visual predictive check.A total of 160 propofol samples were collected. A 2-compartment maternal PK model with a third fetal compartment appropriately described the data. Mean population parameter estimates for maternal propofol clearance and central volume of distribution were 4.17 L/min and 37.7 L, respectively, in a typical ewe with a median heart rate of 135 beats/min. Increase in maternal heart rate significantly correlated with increase in propofol clearance. The estimated population maternal-fetal inter-compartment clearance was 0.0138 L/min and the volume of distribution of propofol in the fetus was 0.144 L. Fetal propofol clearance was found to be almost negligible compared to maternal clearance and could not be robustly estimated.For the first time, a maternal-fetal PK model of propofol in pregnant ewes was successfully developed. This study narrows the gap in our knowledge in maternal-fetal PK model in human. Our study confirms that maternal heart

  5. Modeling of pharmacokinetics of cocaine in human reveals the feasibility for development of enzyme therapies for drugs of abuse.

    Directory of Open Access Journals (Sweden)

    Fang Zheng

    Full Text Available A promising strategy for drug abuse treatment is to accelerate the drug metabolism by administration of a drug-metabolizing enzyme. The question is how effectively an enzyme can actually prevent the drug from entering brain and producing physiological effects. In the present study, we have developed a pharmacokinetic model through a combined use of in vitro kinetic parameters and positron emission tomography data in human to examine the effects of a cocaine-metabolizing enzyme in plasma on the time course of cocaine in plasma and brain of human. Without an exogenous enzyme, cocaine half-lives in both brain and plasma are almost linearly dependent on the initial cocaine concentration in plasma. The threshold concentration of cocaine in brain required to produce physiological effects has been estimated to be 0.22±0.07 µM, and the threshold area under the cocaine concentration versus time curve (AUC value in brain (denoted by AUC2(∞ required to produce physiological effects has been estimated to be 7.9±2.7 µM·min. It has been demonstrated that administration of a cocaine hydrolase/esterase (CocH/CocE can considerably decrease the cocaine half-lives in both brain and plasma, the peak cocaine concentration in brain, and the AUC2(∞. The estimated maximum cocaine plasma concentration which a given concentration of drug-metabolizing enzyme can effectively prevent from entering brain and producing physiological effects can be used to guide future preclinical/clinical studies on cocaine-metabolizing enzymes. Understanding of drug-metabolizing enzymes is key to the science of pharmacokinetics. The general insights into the effects of a drug-metabolizing enzyme on drug kinetics in human should be valuable also in future development of enzyme therapies for other drugs of abuse.

  6. Safety, pharmacokinetic, and efficacy studies of oral DB868 in a first stage vervet monkey model of human African trypanosomiasis.

    Directory of Open Access Journals (Sweden)

    John K Thuita

    Full Text Available There are no oral drugs for human African trypanosomiasis (HAT, sleeping sickness. A successful oral drug would have the potential to reduce or eliminate the need for patient hospitalization, thus reducing healthcare costs of HAT. The development of oral medications is a key objective of the Consortium for Parasitic Drug Development (CPDD. In this study, we investigated the safety, pharmacokinetics, and efficacy of a new orally administered CPDD diamidine prodrug, 2,5-bis[5-(N-methoxyamidino-2-pyridyl]furan (DB868; CPD-007-10, in the vervet monkey model of first stage HAT. DB868 was well tolerated at a dose up to 30 mg/kg/day for 10 days, a cumulative dose of 300 mg/kg. Mean plasma levels of biomarkers indicative of liver injury (alanine aminotransferase, aspartate aminotransferase were not significantly altered by drug administration. In addition, no kidney-mediated alterations in creatinine and urea concentrations were detected. Pharmacokinetic analysis of plasma confirmed that DB868 was orally available and was converted to the active compound DB829 in both uninfected and infected monkeys. Treatment of infected monkeys with DB868 began 7 days post-infection. In the infected monkeys, DB829 attained a median C(max (dosing regimen that was 12-fold (3 mg/kg/day for 7 days, 15-fold (10 mg/kg/day for 7 days, and 31-fold (20 mg/kg/day for 5 days greater than the IC50 (14 nmol/L against T. b. rhodesiense STIB900. DB868 cured all infected monkeys, even at the lowest dose tested. In conclusion, oral DB868 cured monkeys with first stage HAT at a cumulative dose 14-fold lower than the maximum tolerated dose and should be considered a lead preclinical candidate in efforts to develop a safe, short course (5-7 days, oral regimen for first stage HAT.

  7. Pharmacokinetic/pharmacodynamic relationship of marbofloxacin against Pasteurella multocida in a tissue-cage model in yellow cattle. (United States)

    Shan, Q; Wang, J; Yang, F; Ding, H; Liang, C; Lv, Z; Li, Z; Zeng, Z


    The fluoroquinolone antimicrobial drug marbofloxacin was administered to yellow cattle intravenously and intramuscularly at a dose of 2 mg/kg of body weight in a two-period crossover study. The pharmacokinetic properties of marbofloxacin in serum, inflamed tissue-cage fluid (exudate), and noninflamed tissue-cage fluid (transudate) were studied by using a tissue-cage model. The in vitro and ex vivo activities of marbofloxacin in serum, exudate, and transudate against a pathogenic strain of Pasteurella multocida (P. multocida) were determined. Integration of in vivo pharmacokinetic data with the in vitro MIC provided mean values for the area under the curve (AUC)/MIC for serum, exudate, and transudate of 155.75, 153.00, and 138.88, respectively, after intravenous dosing and 160.50, 151.00, and 137.63, respectively, after intramuscular dosing. After intramuscular dosing, the maximum concentration/MIC ratios for serum, exudate, and transudate were 21.13, 9.13, and 8.38, respectively. The ex vivo growth inhibition data after intramuscular dosing were fitted to the inhibitory sigmoid Emax equation to provide the values of AUC/MIC required to produce bacteriostasis, bactericidal activity, and elimination of bacteria. The respective values for serum were 17.25, 31.29, and 109.62, and slightly lower values were obtained for transudate and exudate. It is proposed that these findings might be used with MIC50 or MIC90 data to provide a rational approach to the design of dosage schedules which optimize efficacy in respect of bacteriological as well as clinical cures.

  8. Pharmacokinetics of SPECT radiopharmaceuticals for imaging hypoxic tissues. (United States)

    Wiebe, L I; Stypinski, D


    Although hypoxia has been known for decades to play an important role in the outcome of radiotherapy in oncology, and inspite of the contribution of hypoxia to a myriad of pathologies that involve vascular disease, the selective imaging of hypoxic tissue has attained prominence only within the past decade. Contemporary research in the hypoxia imaging field is based largely on radiosensitizer research of the 1960's and 1970's. Early sensitizer research identified a family of nitro-organic compounds, the N-1 substituted 2-nitroimidazoles as candidate drugs. The early champion, and still the reference standard for therapeutic radiosensitization of hypoxic tumor cells is misonidazole (MISO). Its peripheral neurotoxicity led to failure in clinical studies, but its biological, biophysical and biochemical properties have been investigated in detail and serve as a basis for further design, not only of sensitizers, but of diagnostic radiopharmaceuticals for imaging tissue hypoxia. Pharmacokinetic characterization of radiopharmaceuticals, specifically radiopharmaceuticals for imaging tissue hypoxia, has not been a central theme in their development. The advent of PET, through which quantitative determinations first became possible, opened the field for both descriptive and analytical radiopharmacokinetic studies. In SPECT, however, this approach is still undergoing refinement. This paper addresses some of the underlying issues in radiopharmaceutical pharmacokinetics. There is a paucity of published radiopharmacokinetic data for SPECT hypoxia imaging agents. Consequently, the pharmacokinetic issues for MISO are presented as a basis for development of pharmacokinetics for the chemically-related imaging agents. Properties of an hypoxia marker are described from a pharmacokinetic viewpoint, a theoretical model for descriptive pharmacokinetics is introduced and finally, recent pharmacokinetic studies from our laboratory are described.

  9. NanoFerrite particle based radioimmunonanoparticles: binding affinity and in vivo pharmacokinetics. (United States)

    Natarajan, A; Gruettner, C; Ivkov, R; DeNardo, G L; Mirick, G; Yuan, A; Foreman, A; DeNardo, S J


    Dextran and PEG-coated iron oxide nanoparticles (NP), when suitably modified to enable conjugation with molecular targeting agents, provide opportunities to target cancer cells. Monoclonal antibodies, scFv, and peptides conjugated to 20 nm NP have been reported to target cancer for imaging and alternating magnetic field (AMF) therapy. The physical characteristics of NPs can affect their in vivo performance. Surface morphology, surface charge density, and particle size are considered important factors that determine pharmacokinetics, toxicity, and biodistribution. New NanoFerrite (NF) particles having improved specific AMF absorption rates and diameters of 30 and 100 nm were studied to evaluate the variation in their in vitro and in vivo characteristics in comparison to the previously studied 20 nm superparamagnetic iron oxide (SPIO) NP. SPIO NP 20 nm and NF NP 30 and 100 nm were conjugated to (111)In-DOTA-ChL6, a radioimmunoconjugate. Radioimmunoconjugates were conjugated to NPs using 25 microg of RIC/mg of NP by carbodiimide chemistry. The radioimmunonanoparticles (RINP) were purified and characterized by PAGE, cellulose acetate electrophoresis (CAE), live cell binding assays, and pharmacokinetics in athymic mice bearing human breast cancer (HBT 3477) xenografts. RINP (2.2 mg) were injected iv and whole body; blood and tissue data were collected at 4, 24, and 48 h. The preparations used for animal study were >90% monomeric by PAGE and CAE. The immunoreactivity of the RINP was 40-60% compared to (111)In-ChL6. Specific activities of the doses were 20-25 microCi/2.2 mg and 6-11 microg of mAb/2.2 mg of NP. Mean tumor uptakes (% ID/g +/- SD) of each SPIO 20 nm, NF 30 nm, and 100 nm RINP at 48 h were 9.00 +/- 0.8 (20 nm), 3.0 +/- 0.3 (30 nm), and 4.5 +/- 0.8 (100 nm), respectively; the ranges of tissue uptakes were liver (16-32 +/- 1-8), kidney (7.0-15 +/- 1), spleen (8-17 +/- 3-8), lymph nodes 5-6 +/- 1-2), and lung (2.0-4 +/- 0.1-2). In conclusion, this study

  10. Bioequivalence and Population Pharmacokinetic Modeling of Two Forms of Antibiotic, Cefuroxime Lysine and Cefuroxime Sodium, after Intravenous Infusion in Beagle Dogs

    Directory of Open Access Journals (Sweden)

    Longshan Zhao


    Full Text Available To investigate the bioequivalence and the population pharmacokinetics of cefuroxime lysine and cefuroxime sodium in healthy beagle dogs. A randomized 2-period crossover design in 18 healthy beagle dogs after receiving 20, 40, and 80 mg/kg of cefuroxime lysine or cefuroxime sodium was conducted. A 3-compartment open model was used as the basic model for the population pharmacokinetic study. Both of the antibiotics exhibited dose-proportional pharmacokinetics over the dose range of 20–80 mg/kg. The mean relative bioavailability of cefuroxime lysine versus cefuroxime sodium was 1.05 (range, 0.71 to 1.42, with a significant difference between males and females. The estimates of population pharmacokinetic of CL, V1, Q2, V2, Q3, V3 were 3.74 mL/h, 1.70 mL, 29.5 mL/min, 3.58 mL, 0.31 mL/min, and 158 mL for cefuroxime lysine and 4.10 mL/h, 1.00 mL, 38.5 mL/min, 4.19 mL, 0.06 mL/min, and 13.6 mL for cefuroxime sodium, respectively. The inter-individual variability was determined to be less than 29.1%. A linear pharmacokinetic was revealed for cefuroxime lysine and cefuroxime sodium in dogs after intravenous infusion, and the bioequivalence of these forms of the antibiotic was observed with the significant gender-related differences in mean relative bioavailability of cefuroxime lysine versus cefuroxime sodium.

  11. Development of a physiology-directed population pharmacokinetic and pharmacodynamic model for characterizing the impact of genetic and demographic factors on clopidogrel response in healthy adults. (United States)

    Jiang, Xi-Ling; Samant, Snehal; Lewis, Joshua P; Horenstein, Richard B; Shuldiner, Alan R; Yerges-Armstrong, Laura M; Peletier, Lambertus A; Lesko, Lawrence J; Schmidt, Stephan


    Clopidogrel (Plavix®), is a widely used antiplatelet agent, which shows high inter-individual variability in treatment response in patients following the standard dosing regimen. In this study, a physiology-directed population pharmacokinetic/pharmacodynamic (PK/PD) model was developed based on clopidogrel and clopidogrel active metabolite (clop-AM) data from the PAPI and the PGXB2B studies using a step-wise approach in NONMEM (version 7.2). The developed model characterized the in vivo disposition of clopidogrel, its bioactivation into clop-AM in the liver and subsequent platelet aggregation inhibition in the systemic circulation reasonably well. It further allowed the identification of covariates that significantly impact clopidogrel's dose-concentration-response relationship. In particular, CYP2C19 intermediate and poor metabolizers converted 26.2% and 39.5% less clopidogrel to clop-AM, respectively, compared to extensive metabolizers. In addition, CES1 G143E mutation carriers have a reduced CES1 activity (82.9%) compared to wild-type subjects, which results in a significant increase in clop-AM formation. An increase in BMI was found to significantly decrease clopidogrel's bioactivation, whereas increased age was associated with increased platelet reactivity. Our PK/PD model analysis suggests that, in order to optimize clopidogrel dosing on a patient-by-patient basis, all of these factors have to be considered simultaneously, e.g. by using quantitative clinical pharmacology tools.

  12. Herb drug interaction: effect of Manix® on pharmacokinetic parameters of pefloxacin in rat model (United States)

    Odunke, Nduka Sunday; Eleje, Okonta; Christiana, Abba Chika; Peter, Ihekwereme Chibueze; Uchenna, Ekwedigwe; Matthew, Okonta


    Objective To evaluate the effect of Manix®, the commonly used polyherbal formulation on pefloxacin pharmacokinetic parameters. Methods Microbiological assay was employed using clinical isolate of Escherichia coli samples from hospitalized patients. Results Manix® altered the bioavailability parameters of pefloxacin as thus, maximal concentration (Cmax) of pefloxacin (0.91±0.31) µg/mL occurred at time to reach maximal concentration (tmax) 4.0 h while in the group that received Manix® alongside pefloxacin Cmax was (0.22±0.08) µg/mL at tmax 1.0 h respectively. The area under curve of pefloxacin alone was (7.83±5.14) µg/h/mL while with Manix® was (2.60±0.08) µg/h/mL. There was a significant difference between Cmax, tmax and area under curve between pefloxacin alone and pefloxacin after Manix® pre-treatment (P<0.05). Conclusions The concurrent use of Manix® and pefloxacin has been found to compromise the therapeutic effectiveness of pefloxacin which could lead to poor clinical outcomes in patients. PMID:25183119

  13. On the accuracy of estimation of basic pharmacokinetic parameters by the traditional noncompartmental equations and the prediction of the steady-state volume of distribution in obese patients based upon data derived from normal subjects. (United States)

    Berezhkovskiy, Leonid M


    The steady-state and terminal volumes of distribution, as well as the mean residence time of drug in the body (V(ss), V(β), and MRT) are the common pharmacokinetic parameters calculated using the drug plasma concentration-time profile C(p) (t) following intravenous (i.v. bolus or constant rate infusion) drug administration. These calculations are valid for the linear pharmacokinetic system with central elimination (i.e., elimination rate being proportional to drug concentration in plasma). Formally, the assumption of central elimination is not normally met because the rate of drug elimination is proportional to the unbound drug concentration at elimination site, although equilibration between systemic circulation and the site of clearance for majority of small molecule drugs is fast. Thus, the assumption of central elimination is practically quite adequate. It appears reasonable to estimate the extent of possible errors in determination of these pharmacokinetic parameters due to the absence of central elimination. The comparison of V(ss), V(β), and MRT calculated by exact equations and the commonly used ones was made considering a simplified physiologically based pharmacokinetic model. It was found that if the drug plasma concentration profile is detected accurately, determination of drug distribution volumes and MRT using the traditional noncompartmental calculations of these parameters from C(p) (t) yields the values very close to that obtained from exact equations. Though in practice, the accurate measurement of C(p) (t), especially its terminal phase, may not always be possible. This is particularly applicable for obtaining the distribution volumes of lipophilic compounds in obese subjects, when the possibility of late terminal phase at low drug concentration is quite likely, specifically for compounds with high clearance. An accurate determination of V(ss) is much needed in clinical practice because it is critical for the proper selection of drug treatment

  14. Pharmacokinetic Properties of Cytokines in Their Targeted Delivery Based on Autologous Erythrocyte Pharmacocytes

    Directory of Open Access Journals (Sweden)

    Zhaxybay Zhumadilov


    Full Text Available Introduction. Using autologous erythrocytes as drug carriers for targeted delivery of cytokines to the sites of inflammation could potentially provide new opportunities for treatment of patients with purulent diseases. The targeted characteristic of erythrocytes is associated with the nature of purulent inflammation, where a large amount of erythrocytes is phagocytized and drugs encapsulated into the erythrocytes could be easily released. On the other hand, autologous erythrocytes meet all the criteria for the ideal drug carrier. They are nontoxic, not immunogenic, and able to bear a large number of drug molecules while preserving an original conformation of the drugs. Thus, in this study, we aimed to analyze pharmacokinetic profiles of IL-1β encapsulated into erythrocytes’ ghosts (pharmacocytes in comparison to intravenously injected free IL-1β.Material and methods. Albino rats were randomly divided into two groups, each group receiving a different kind of IV injection via the tail vein. Group A (control received 500 µg of free IL-1β, and group B received an injection of 1 ml of pharmacocytes loaded with 500 µg of test substance. At fixed time points after injection (15, 30, 60, 180, 540, 720, and 1,440 minutes serum samples were collected. Homogenates of liver, spleen, lung, heart, kidney, and adipose tissue were obtained 24 hours after injections. Concentration of the tested substance in the collected organs and blood plasma were measured by ELISA. Results. We have observed an increased half-life period (T1/2 for encapsulated IL-1β compared to the control. T1/2 for free IL-1β was one hour, while administration of loaded pharmacocytes allowed the half-life period to increase by more than 15 fold (1,043.40 ± 137.92 min preserving high level of IL-1β activity in the blood samples up to 24 hours. The increased time of IL-1β presence in the body when administered in the form of pharmacocytes could be explained by reduction of

  15. Physiologically Based Pharmacokinetic Predictions of Tramadol Exposure Throughout Pediatric Life: an Analysis of the Different Clearance Contributors with Emphasis on CYP2D6 Maturation. (United States)

    T'jollyn, Huybrecht; Snoeys, Jan; Vermeulen, An; Michelet, Robin; Cuyckens, Filip; Mannens, Geert; Van Peer, Achiel; Annaert, Pieter; Allegaert, Karel; Van Bocxlaer, Jan; Boussery, Koen


    This paper focuses on the retrospective evaluation of physiologically based pharmacokinetic (PBPK) techniques used to mechanistically predict clearance throughout pediatric life. An intravenous tramadol retrograde PBPK model was set up in Simcyp® using adult clearance values, qualified for CYP2D6, CYP3A4, CYP2B6, and renal contributions. Subsequently, the model was evaluated for mechanistic prediction of total, CYP2D6-related, and renal clearance predictions in very early life. In two in vitro pediatric human liver microsomal (HLM) batches (1 and 3 months), O-desmethyltramadol and N-desmethyltramadol formation rates were compared with CYP2D6 and CYP3A4 activity, respectively. O-desmethyltramadol formation was mediated only by CYP2D6, while N-desmethyltramadol was mediated in part by CYP3A4. Additionally, the clearance maturation of the PBPK model predictions was compared to two in vivo maturation models (Hill and exponential) based on plasma concentration data, and to clearance estimations from a WinNonlin® fit of plasma concentration and urinary excretion data. Maturation of renal and CYP2D6 clearance is captured well in the PBPK model predictions, but total tramadol clearance is underpredicted. The most pronounced underprediction of total and CYP2D6-mediated clearance was observed in the age range of 2-13 years. In conclusion, the PBPK technique showed to be a powerful mechanistic tool capable of predicting maturation of CYP2D6 and renal tramadol clearance in early infancy, although some underprediction occurs between 2 and 13 years for total and CYP2D6-mediated tramadol clearance.

  16. The use of error-category mapping in pharmacokinetic model analysis of dynamic contrast-enhanced MRI data. (United States)

    Gill, Andrew B; Anandappa, Gayathri; Patterson, Andrew J; Priest, Andrew N; Graves, Martin J; Janowitz, Tobias; Jodrell, Duncan I; Eisen, Tim; Lomas, David J


    This study introduces the use of 'error-category mapping' in the interpretation of pharmacokinetic (PK) model parameter results derived from dynamic contrast-enhanced (DCE-) MRI data. Eleven patients with metastatic renal cell carcinoma were enrolled in a multiparametric study of the treatment effects of bevacizumab. For the purposes of the present analysis, DCE-MRI data from two identical pre-treatment examinations were analysed by application of the extended Tofts model (eTM), using in turn a model arterial input function (AIF), an individually-measured AIF and a sample-average AIF. PK model parameter maps were calculated. Errors in the signal-to-gadolinium concentration ([Gd]) conversion process and the model-fitting process itself were assigned to category codes on a voxel-by-voxel basis, thereby forming a colour-coded 'error-category map' for each imaged slice. These maps were found to be repeatable between patient visits and showed that the eTM converged adequately in the majority of voxels in all the tumours studied. However, the maps also clearly indicated sub-regions of low Gd uptake and of non-convergence of the model in nearly all tumours. The non-physical condition ve ≥ 1 was the most frequently indicated error category and appeared sensitive to the form of AIF used. This simple method for visualisation of errors in DCE-MRI could be used as a routine quality-control technique and also has the potential to reveal otherwise hidden patterns of failure in PK model applications.

  17. Methodology developed for the simultaneous measurement of bone formation and bone resorption in rats based on the pharmacokinetics of fluoride. (United States)

    Lupo, Maela; Brance, Maria Lorena; Fina, Brenda Lorena; Brun, Lucas Ricardo; Rigalli, Alfredo


    This paper describes a novel methodology for the simultaneous estimation of bone formation (BF) and resorption (BR) in rats using fluoride as a nonradioactive bone-seeker ion. The pharmacokinetics of flouride have been extensively studied in rats; its constants have all been characterized. This knowledge was the cornerstone for the underlying mathematical model that we used to measure bone fluoride uptake and elimination rate after a dose of fluoride. Bone resorption and formation were estimated by bone fluoride uptake and elimination rate, respectively. ROC analysis showed that sensitivity, specificity and area under the ROC curve were not different from deoxypiridinoline and bone alkaline phosphatase, well-known bone markers. Sprague-Dawley rats with modified bone remodelling (ovariectomy, hyper, and hypocalcic diet, antiresorptive treatment) were used to validate the values obtained with this methodology. The results of BF and BR obtained with this technique were as expected for each biological model. Although the method should be performed under general anesthesia, it has several advantages: simultaneous measurement of BR and BF, low cost, and the use of compounds with no expiration date.

  18. A Bloch-McConnell simulator with pharmacokinetic modeling to explore accuracy and reproducibility in the measurement of hyperpolarized pyruvate (United States)

    Walker, Christopher M.; Bankson, James A.


    Magnetic resonance imaging (MRI) of hyperpolarized (HP) agents has the potential to probe in-vivo metabolism with sensitivity and specificity that was not previously possible. Biological conversion of HP agents specifically for cancer has been shown to correlate to presence of disease, stage and response to therapy. For such metabolic biomarkers derived from MRI of hyperpolarized agents to be clinically impactful, they need to be validated and well characterized. However, imaging of HP substrates is distinct from conventional MRI, due to the non-renewable nature of transient HP magnetization. Moreover, due to current practical limitations in generation and evolution of hyperpolarized agents, it is not feasible to fully experimentally characterize measurement and processing strategies. In this work we use a custom Bloch-McConnell simulator with pharmacokinetic modeling to characterize the performance of specific magnetic resonance spectroscopy sequences over a range of biological conditions. We performed numerical simulations to evaluate the effect of sequence parameters over a range of chemical conversion rates. Each simulation was analyzed repeatedly with the addition of noise in order to determine the accuracy and reproducibility of measurements. Results indicate that under both closed and perfused conditions, acquisition parameters can affect measurements in a tissue dependent manner, suggesting that great care needs to be taken when designing studies involving hyperpolarized agents. More modeling studies will be needed to determine what effect sequence parameters have on more advanced acquisitions and processing methods.

  19. Investigation of ifosfamide and chloroacetaldehyde renal toxicity through integration of in vitro liver-kidney microfluidic data and pharmacokinetic-system biology models. (United States)

    Leclerc, Eric; Hamon, Jeremy; Bois, Frederic Yves


    We have integrated in vitro and in silico data to describe the toxicity of chloroacetaldehyde (CAA) on renal cells via its production from the metabolism of ifosfamide (IFO) by hepatic cells. A pharmacokinetic (PK) model described the production of CAA by the hepatocytes and its transport to the renal cells. A system biology model was coupled to the PK model to describe the production of reactive oxygen species (ROS) induced by CAA in the renal cells. In response to the ROS production, the metabolism of glutathione (GSH) and its depletion were modeled by the action of an NFE2L2 gene-dependent pathway. The model parameters were estimated in a Bayesian context via Markov Chain Monte Carlo (MCMC) simulations based on microfluidic experiments and literature in vitro data. Hepatic IFO and CAA in vitro intrinsic clearances were estimated to be 1.85 x 10(-9) μL s(-1) cell(-1) and 0.185 x 10(-9) μL s(-1) cell(-1) ,respectively (corresponding to an in vivo intrinsic IFO clearance estimate of 1.23 l h(-1) , to be compared to IFO published values ranging from 3 to 10 l h(-1) ). After model calibration, simulations made at therapeutic doses of IFO showed CAA renal intracellular concentrations ranging from 11 to 131 μM. Intracellular CAA concentrations above 70 μM induced intense ROS production and GSH depletion. Those responses were time and dose dependent, showing transient and non-linear kinetics. Those results are in agreement with literature data reporting that intracellular CAA toxic concentrations range from 35 to 320 μM, after therapeutic ifosfamide dosing. The results were also consistent with in vitro CAA renal cytotoxicity data.

  20. Physiologically based pharmacokinetics in Drug Development and Regulatory Science: A workshop report (Georgetown University, Washington, DC, May 29–30, 2002)


    Rowland, Malcolm; Balant, Luc; Peck,Carl


    A 2-day workshop on “Physiologically Based Pharmacokinetics (PBPK) in Drug Development and Regulatory Science” came to a successful conclusion on May 30, 2002, in Washington, DC. More than 120 international participants from the environmental and predominantly pharmaceutical industries, Food and Drug Administration (FDA), and universities attended this workshop, organized by the Center for Drug Development Science, Georgetown University, Washington, DC. The first of its kind specifically devo...

  1. Armodafinil and modafinil in patients with excessive sleepiness associated with shift work disorder: a pharmacokinetic/pharmacodynamic model for predicting and comparing their concentration-effect relationships. (United States)

    Darwish, Mona; Bond, Mary; Ezzet, Farkad


    Armodafinil, the longer lasting R-isomer of racemic modafinil, improves wakefulness in patients with excessive sleepiness associated with shift work disorder (SWD). Pharmacokinetic studies suggest that armodafinil achieves higher plasma concentrations than modafinil late in a dose interval following equal oral doses. Pooled Multiple Sleep Latency Test (MSLT) data from 2 randomized, double-blind, placebo-controlled trials in 463 patients with SWD, 1 with armodafinil 150 mg/d and 1 with modafinil 200 mg/d (both administered around 2200 h before night shifts), were used to build a pharmacokinetic/pharmacodynamic model. Predicted plasma drug concentrations were obtained by developing and applying a population pharmacokinetic model using nonlinear mixed-effects modeling. Armodafinil 200 mg produced a plasma concentration above the EC(50) (4.6 µg/mL) for 9 hours, whereas modafinil 200 mg did not exceed the EC(50). Consequently, armodafinil produced greater increases in predicted placebo-subtracted MSLT times of 0.5-1 minute (up to 10 hours after dosing) compared with modafinil. On a milligram-to-milligram basis, armodafinil 200 mg consistently increased wakefulness more than modafinil 200 mg, including times late in the 8-hour shift.

  2. Using Akaike's information theoretic criterion in mixed-effects modeling of pharmacokinetic data: a simulation study [version 3; referees: 2 approved, 1 approved with reservations

    Directory of Open Access Journals (Sweden)

    Erik Olofsen


    Full Text Available Akaike's information theoretic criterion for model discrimination (AIC is often stated to "overfit", i.e., it selects models with a higher dimension than the dimension of the model that generated the data. However, with experimental pharmacokinetic data it may not be possible to identify the correct model, because of the complexity of the processes governing drug disposition. Instead of trying to find the correct model, a more useful objective might be to minimize the prediction error of drug concentrations in subjects with unknown disposition characteristics. In that case, the AIC might be the selection criterion of choice. We performed Monte Carlo simulations using a model of pharmacokinetic data (a power function of time with the property that fits with common multi-exponential models can never be perfect - thus resembling the situation with real data. Prespecified models were fitted to simulated data sets, and AIC and AICc (the criterion with a correction for small sample sizes values were calculated and averaged. The average predictive performances of the models, quantified using simulated validation sets, were compared to the means of the AICs. The data for fits and validation consisted of 11 concentration measurements each obtained in 5 individuals, with three degrees of interindividual variability in the pharmacokinetic volume of distribution. Mean AICc corresponded very well, and better than mean AIC, with mean predictive performance. With increasing interindividual variability, there was a trend towards larger optimal models, but with respect to both lowest AICc and best predictive performance. Furthermore, it was observed that the mean square prediction error itself became less suitable as a validation criterion, and that a predictive performance measure should incorporate interindividual variability. This simulation study showed that, at least in a relatively simple mixed-effects modelling context with a set of prespecified models

  3. The Tofts model in frequency domain: fast and robust determination of pharmacokinetic maps for dynamic contrast enhancement MRI (United States)

    Vajuvalli, Nithin N.; Chikkemenahally, Dharmendra Kumar K.; Nayak, Krupa N.; Bhosale, Manoj G.; Geethanath, Sairam


    Dynamic contrast enhancement magnetic resonance imaging (DCE-MRI) is a well-established method for non-invasive detection and therapeutic monitoring of pathologies through administration of intravenous contrast agent. Quantification of pharmacokinetic (PK) maps can be achieved through application of compartmental models relevant to the pathophysiology of the tissue under interrogation. The determination of PK parameters involves fitting of time-concentration data to these models. In this work, the Tofts model in frequency domain (TM-FD) is applied to a weakly vascularized tissue such as the breast. It is derived as a convolution-free model from the conventional Tofts model in the time domain (TM-TD). This reduces the dimensionality of the curve-fitting problem from two to one. The approaches of TM-FD and TM-TD were applied to two kinds of in silico phantoms and six in vivo breast DCE data sets with and without the addition of noise. The results showed that computational time taken to estimate PK maps using TM-FD was 16-25% less than with TM-TD. Normalized root mean square error (NRMSE) calculation and Pearson correlation analyses were performed to validate robustness and accuracy of the TM-FD and TM-TD approaches. These compared with ground truth values in the case of phantom studies for four different temporal resolutions. Results showed that NRMSE values for TM-FD were significantly lower than those of TM-TD as validated by a paired t-test along with reduced computational time. This approach therefore enables online evaluation of PK maps by radiologists in a clinical setting, aiding in the evaluation of 3D and/or increased coverage of the tissue of interest.

  4. Pharmacokinetic and nephroprotective benefits of using Schisandra chinensis extracts in a cyclosporine A-based immune-suppressive regime. (United States)

    Lai, Qiao; Wei, Jiabao; Mahmoodurrahman, Mohammed; Zhang, Chenxue; Quan, Shijian; Li, Tongming; Yu, Yang


    Cyclosporine A (CsA) is a powerful immunosuppressive drug. However, nephrotoxicity resulting from its long-term usage has hampered its prolonged therapeutic usage. Schisandra chinensis extracts (SCE) have previously been used in traditional Chinese medicine and more recently coadministered with Western medicine for the treatment of CsA-induced side effects in the People's Republic of China. This study aimed to investigate the possible effects of SCE on the pharmacokinetics of CsA in rats and elucidate the potential mechanisms by which it hinders the development of CsA-induced nephrotoxicity. A liquid chromatography/tandem mass spectrometry method was developed and validated for determining the effect of SCE on the pharmacokinetics of CsA. Male Sprague Dawley rats, which were administered with CsA (25 mg/kg/d) alone or in combination with SCE (54 mg/kg/d and 108 mg/kg/d) for 28 days, were used to evaluate the nephroprotective effects of SCE. Our study showed that SCE increased the mean blood concentration of CsA. Furthermore, we found that the concomitant administration of SCE alongside CsA prevented the disruption of catalase activity and reduction in creatinine, urea, renal malondialdehyde, and glutathione peroxidase levels that would have otherwise occurred in the absence of SCE administration. SCE treatment markedly suppressed the expression of 4-hydroxynonenal, Bcl-2-associated X protein, cleaved caspase 3, and autophagy-related protein LC3 A/B. On the other hand, the expression of heme oxygenase-1, nuclear factor erythroid 2-related factor 2 (Nrf2), and P-glycoprotein was enhanced by the very same addition of SCE. SCE was also able to increase the systemic exposure of CsA in rats. The renoprotective effects of SCE were thought to be mediated by its antiapoptotic and antioxidant abilities, which caused the attenuation of CsA-induced autophagic cell death. All in all, these findings suggest the prospective use of SCE as an effective adjunct in a CsA-based

  5. Understanding Variability in Posaconazole Exposure Using an Integrated Population Pharmacokinetic Analysis


    Dolton, Michael J; Brüggemann, Roger J. M.; Burger, David M.; McLachlan, Andrew J


    Posaconazole oral suspension is widely used for antifungal prophylaxis and treatment in immunocompromised patients, with highly variable pharmacokinetics reported in patients due to inconsistent oral absorption. This study aimed to characterize the pharmacokinetics of posaconazole in adults and investigate factors that influence posaconazole pharmacokinetics byusing a population pharmacokinetic approach. Nonlinear mixed-effects modeling was undertaken for two posaconazole studies in patients ...

  6. Population pharmacokinetics and pharmacodynamics in anesthesia, intensive care and pain medicine

    NARCIS (Netherlands)

    Heeremans, Eleonora H.; Proost, Johannes H.; Eleveld, Douglas J.; Absalom, Anthony R.; Struys, Michel M. R. F.


    Purpose of review Population modeling is a relatively new pharmacological discipline, the development of which has largely been stimulated by the need for accurate models for the pharmacokinetics and dynamics of anesthetic agents. Recent findings Population-based modeling is now considered superior

  7. Animal model of undernutrition for the evaluation of drug pharmacokinetics Modelo de desnutrición animal para la evaluación de estudios de farmacocinética


    M. Merino-Sanjuán; A. Catalán-Latorre; A. Nácher; S. Miralles-Arnau; N. V. Jiménez-Torres


    Background: Protein energy malnutrition is a public health problem affecting a great number of people. Pathophysiological imbalances in malnourished individuals have a profound impact on drug pharmacokinetics. Objective: To develop an animal model of undernutrition using male Wistar rats to be used to assess, in further studies, the impact of nutritional status on the oral bioavailability and pharmacokinetics of drugs. Desing: Animals were randomly assigned to one of two groups and fed differ...

  8. Development of a nanogel formulation for transdermal delivery of tenoxicam: a pharmacokinetic-pharmacodynamic modeling approach for quantitative prediction of skin absorption. (United States)

    Elkomy, Mohammed H; El Menshawe, Shahira F; Eid, Hussein M; Ali, Ahmed M A


    This study investigates potentials of solid lipid nanoparticles (SLN)-based gel for transdermal delivery of tenoxicam (TNX) and describes a pharmacokinetic-pharmacodynamic (PK-PD) modeling approach for predicting concentration-time profile in skin. A 2(3) factorial design was adopted to study the effect of formulation factors on SLN properties and determine the optimal formulation. SLN-gel tolerability was investigated using rabbit skin irritation test. Its anti-inflammatory activity was assessed by carrageenan-induced rat paw edema test. A published Hill model for in vitro inhibition of COX-2 enzyme was fitted to edema inhibition data. Concentration in skin was represented as a linear spline function and coefficients were estimated using non-linear regression. Uncertainty in predicted concentrations was assessed using Monte Carlo simulations. The optimized SLN was spherical vesicles (58.1 ± 3.1 nm) with adequate entrapment efficiency (69.6 ± 2.6%). The SLN-gel formulation was well-tolerated. It increased TNX activity and skin level by 40 ± 13.5, and 227 ± 116%, respectively. Average Cmax and AUC0-24 predicted by the model were 2- and 3.6-folds higher than the corresponding values computed using in vitro permeability data. SLN-gel is a safe and efficient carrier for TNX across skin in the treatment of inflammatory disorders. PK-PD modeling is a promising approach for indirect quantitation of skin deposition from PD activity data.

  9. Population pharmacokinetic modeling of itraconazole and hydroxyitraconazole for oral SUBA-itraconazole and sporanox capsule formulations in healthy subjects in fed and fasted states. (United States)

    Abuhelwa, Ahmad Y; Foster, David J R; Mudge, Stuart; Hayes, David; Upton, Richard N


    Itraconazole is an orally active antifungal agent that has complex and highly variable absorption kinetics that is highly affected by food. This study aimed to develop a population pharmacokinetic model for itraconazole and the active metabolite hydroxyitraconazole, in particular, quantifying the effects of food and formulation on oral absorption. Plasma pharmacokinetic data were collected from seven phase I crossover trials comparing the SUBA-itraconazole and Sporanox formulations of itraconazole. First, a model of single-dose itraconazole data was developed, which was then extended to the multidose data. Covariate effects on itraconazole were then examined before extending the model to describe hydroxyitraconazole. The final itraconazole model was a 2-compartment model with oral absorption described by 4-transit compartments. Multidose kinetics was described by total effective daily dose- and time-dependent changes in clearance and bioavailability. Hydroxyitraconazole was best described by a 1-compartment model with mixed first-order and Michaelis-Menten elimination for the single-dose data and a time-dependent clearance for the multidose data. The relative bioavailability of SUBA-itraconazole compared to that of Sporanox was 173% and was 21% less variable between subjects. Food resulted in a 27% reduction in bioavailability and 58% reduction in the transit absorption rate constant compared to that with the fasted state, irrespective of the formulation. This analysis presents the most extensive population pharmacokinetic model of itraconazole and hydroxyitraconazole in the literature performed in healthy subjects. The presented model can be used for simulating food effects on itraconazole exposure and for performing prestudy power analysis and sample size estimation, which are important aspects of clinical trial design of bioequivalence studies.

  10. Population pharmacokinetic modelling of tramadol using inverse Gaussian function for the assessment of drug absorption from prolonged and immediate release formulations. (United States)

    Brvar, Nina; Mateović-Rojnik, Tatjana; Grabnar, Iztok


    This study aimed to develop a population pharmacokinetic model for tramadol that combines different input rates with disposition characteristics. Data used for the analysis were pooled from two phase I bioavailability studies with immediate (IR) and prolonged release (PR) formulations in healthy volunteers. Tramadol plasma concentration-time data were described by an inverse Gaussian function to model the complete input process linked to a two-compartment disposition model with first-order elimination. Although polymorphic CYP2D6 appears to be a major enzyme involved in the metabolism of tramadol, application of a mixture model to test the assumption of two and three subpopulations did not reveal any improvement of the model. The final model estimated parameters with reasonable precision and was able to estimate the interindividual variability of all parameters except for the relative bioavailability of PR vs. IR formulation. Validity of the model was further tested using the nonparametric bootstrap approach. Finally, the model was applied to assess absorption kinetics of tramadol and predict steady-state pharmacokinetics following administration of both types of formulations. For both formulations, the final model yielded a stable estimate of the absorption time profiles. Steady-state simulation supports switching of patients from IR to PR formulation.

  11. Modeling hepatitis C virus kinetics under therapy using pharmacokinetic and pharmacodynamic information

    Energy Technology Data Exchange (ETDEWEB)

    Perelson, Alan S [Los Alamos National Laboratory; Shudo, Emi [Los Alamos National Laboratory; Ribeiro, Ruy M [Los Alamos National Laboratory


    Mathematical models have proven helpful in analyzing the virological response to antiviral therapy in hepatitis C virus (HCY) infected subjects. Objective: To summarize the uses and limitations of different models for analyzing HCY kinetic data under pegylated interferon therapy. Methods: We formulate mathematical models and fit them by nonlinear least square regression to patient data in order estimate model parameters. We compare the goodness of fit and parameter values estimated by different models statistically. Results/Conclusion: The best model for parameter estimation depends on the availability and the quality of data as well as the therapy used. We also discuss the mathematical models that will be needed to analyze HCV kinetic data from clinical trials with new antiviral drugs.

  12. Pharmacodynamic and pharmacokinetic profiling of delafloxacin in a murine lung model against community-acquired respiratory tract pathogens. (United States)

    Thabit, Abrar K; Crandon, Jared L; Nicolau, David P


    Increasing antimicrobial resistance in community-acquired pneumonia (CAP) pathogens has contributed to infection-related morbidity and mortality. Delafloxacin is a novel fluoroquinolone with broad-spectrum activity against Gram-positive and -negative organisms, including Streptococcus pneumoniae and methicillin-resistant Staphylococcus aureus (MRSA). This study aimed to define the pharmacodynamic profile of delafloxacin against CAP pathogens using a neutropenic murine lung infection model. Five S. pneumoniae, 2 methicillin-susceptible S. aureus (MSSA), 2 MRSA and 2 Klebsiella pneumoniae isolates were studied. Delafloxacin doses varied from 0.5 mg/kg/day to 640 mg/kg/day and were given as once-daily to every 3 h regimens over the 24-h treatment period. Efficacy was measured as the change in log10 CFU at 24 h compared with 0-h controls. Plasma and bronchopulmonary pharmacokinetic studies were conducted. Delafloxacin demonstrated potent in vitro and in vivo activity. Delafloxacin demonstrated high penetration into the lung compartment, as epithelial lining fluid concentrations were substantially higher than free drug in plasma. The ratio of the area under the free drug concentration-time curve to the minimum inhibitory concentration of the infecting organism (fAUC/MIC) was the parameter that best correlated with the efficacy of the drug, and the magnitude required to achieve 1 log10 CFU reduction was 31.8, 24.7, 0.4 and 9.6 for S. pneumoniae, MRSA, MSSA and K. pneumoniae, respectively. The observed in vivo efficacy of delafloxacin was supported by the high pulmonary disposition of the compound. The results derived from this pre-clinical lung model support the continued investigation of delafloxacin for the treatment of community-acquired lower respiratory tract infections.

  13. Formulation, stability and pharmacokinetics of sugar-based salmon calcitonin-loaded nanoporous/nanoparticulate microparticles (NPMPs) for inhalation. (United States)

    Amaro, Maria Inês; Tewes, Frederic; Gobbo, Oliviero; Tajber, Lidia; Corrigan, Owen I; Ehrhardt, Carsten; Healy, Anne Marie


    A challenge exists to produce dry powder inhaler (DPI) formulations with appropriate formulation stability, biological activity and suitable physicochemical and aerosolisation characteristics that provide a viable alternative to parenteral formulations. The present study aimed to produce sugar-based nanoporous/nanoparticulate microparticles (NPMPs) loaded with a therapeutic peptide - salmon calcitonin (sCT). The physicochemical properties of the powders and their suitability for pulmonary delivery of sCT were determined. Production of powders composed of sCT loaded into raffinose or trehalose with or without hydroxypropyl-β-cyclodextrin was carried out using a laboratory scale spray dryer. Spray dried microparticles were spherical, porous and of small geometric size (≤2 μm). Aerodynamic assessment showed that the fine particle fraction (FPF) less than 5 μm ranged from 45 to 86%, depending on the formulation. The mass median aerodynamic diameter (MMAD) varied between 1.9 and 4.7 μm. Compared to unprocessed sCT, sCT:raffinose composite systems presented a bioactivity of approximately 100% and sCT:trehalose composite systems between 70-90% after spray drying. Storage stability studies demonstrated composite systems with raffinose to be more stable than those containing trehalose. These sugar-based salmon calcitonin-loaded NPMPs retain reasonable sCT bioactivity and have micromeritic and physicochemical properties which indicate their suitability for pulmonary delivery. Formulations presented a similar pharmacokinetic profile to sCT solution. Hence the advantage of a dry powder formulation is its non-invasive delivery route and ease of administration of the sCT.

  14. Pharmacokinetics and pharmacodynamics utilizing unbound target tissue exposure as part of a disposition-based rationale for lead optimization of benzoxaboroles in the treatment of Stage 2 Human African Trypanosomiasis. (United States)

    Wring, Stephen; Gaukel, Eric; Nare, Bakela; Jacobs, Robert; Beaudet, Beth; Bowling, Tana; Mercer, Luke; Bacchi, Cyrus; Yarlett, Nigel; Randolph, Ryan; Parham, Robin; Rewerts, Cindy; Platner, Jacob; Don, Robert


    SUMMARY This review presents a progression strategy for the discovery of new anti-parasitic drugs that uses in vitro susceptibility, time-kill and reversibility measures to define the therapeutically relevant exposure required in target tissues of animal infection models. The strategy is exemplified by the discovery of SCYX-7158 as a potential oral treatment for stage 2 (CNS) Human African Trypanosomiasis (HAT). A critique of current treatments for stage 2 HAT is included to provide context for the challenges of achieving target tissue disposition and the need for establishing pharmacokinetic-pharmacodynamic (PK-PD) measures early in the discovery paradigm. The strategy comprises 3 stages. Initially, compounds demonstrating promising in vitro activity and selectivity for the target organism over mammalian cells are advanced to in vitro metabolic stability, barrier permeability and tissue binding assays to establish that they will likely achieve and maintain therapeutic concentrations during in-life efficacy studies. Secondly, in vitro time-kill and reversibility kinetics are employed to correlate exposure (based on unbound concentrations) with in vitro activity, and to identify pharmacodynamic measures that would best predict efficacy. Lastly, this information is used to design dosing regimens for pivotal pharmacokinetic-pharmacodyamic studies in animal infection models.

  15. Comparing the cardiovascular therapeutic indices of glycopyrronium and tiotropium in an integrated rat pharmacokinetic, pharmacodynamic and safety model

    Energy Technology Data Exchange (ETDEWEB)

    Trifilieff, Alexandre; Ethell, Brian T. [Respiratory Disease Area, Novartis Institutes for Biomedical Research, Wimblehurst Road, Horsham, West Sussex RH12 5AB (United Kingdom); Sykes, David A. [Respiratory Disease Area, Novartis Institutes for Biomedical Research, Wimblehurst Road, Horsham, West Sussex RH12 5AB (United Kingdom); School of Life Sciences, Queen' s Medical Centre, University of Nottingham, Nottingham, NG7 2UH (United Kingdom); Watson, Kenny J.; Collingwood, Steve [Respiratory Disease Area, Novartis Institutes for Biomedical Research, Wimblehurst Road, Horsham, West Sussex RH12 5AB (United Kingdom); Charlton, Steven J. [Respiratory Disease Area, Novartis Institutes for Biomedical Research, Wimblehurst Road, Horsham, West Sussex RH12 5AB (United Kingdom); School of Life Sciences, Queen' s Medical Centre, University of Nottingham, Nottingham, NG7 2UH (United Kingdom); Kent, Toby C., E-mail: [Respiratory Disease Area, Novartis Institutes for Biomedical Research, Wimblehurst Road, Horsham, West Sussex RH12 5AB (United Kingdom)


    Long acting inhaled muscarinic receptor antagonists, such as tiotropium, are widely used as bronchodilator therapy for chronic obstructive pulmonary disease (COPD). Although this class of compounds is generally considered to be safe and well tolerated in COPD patients the cardiovascular safety of tiotropium has recently been questioned. We describe a rat in vivo model that allows the concurrent assessment of muscarinic antagonist potency, bronchodilator efficacy and a potential for side effects, and we use this model to compare tiotropium with NVA237 (glycopyrronium bromide), a recently approved inhaled muscarinic antagonist for COPD. Anaesthetized Brown Norway rats were dosed intratracheally at 1 or 6 h prior to receiving increasing doses of intravenous methacholine. Changes in airway resistance and cardiovascular function were recorded and therapeutic indices were calculated against the ED{sub 50} values for the inhibition of methacholine-induced bronchoconstriction. At both time points studied, greater therapeutic indices for hypotension and bradycardia were observed with glycopyrronium (19.5 and 28.5 fold at 1 h; > 200 fold at 6 h) than with tiotropium (1.5 and 4.2 fold at 1 h; 4.6 and 5.5 fold at 6 h). Pharmacokinetic, protein plasma binding and rat muscarinic receptor binding properties for both compounds were determined and used to generate an integrated model of systemic M{sub 2} muscarinic receptor occupancy, which predicted significantly higher M{sub 2} receptor blockade at ED{sub 50} doses with tiotropium than with glycopyrronium. In our preclinical model there was an improved safety profile for glycopyrronium when compared with tiotropium. - Highlights: • We use an in vivo rat model to study CV safety of inhaled muscarinic antagonists. • We integrate protein and receptor binding and PK of tiotropium and glycopyrrolate. • At ED{sub 50} doses for bronchoprotection we model systemic M{sub 2} receptor occupancy. • Glycopyrrolate demonstrates lower M

  16. Application of pharmacokinetic modelling for 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure assessment. (United States)

    Ruiz, P; Aylward, L L; Mumtaz, M


    Polychlorinated dibenzo-p-dioxins, polychlorinated dibenzofurans, and mono- and non-ortho polychlorinated biphenyls (dioxin-like PCBs) are identified as a family or group of organic compounds known as 'dioxins' or dioxin-like chemicals (DLCs). The most toxic member of this group is 2,3,7,8-tetrachlorodibenzo-(p)-dioxin (TCDD). Historically, DLCs have caused a variety of negative human health effects, but a disfiguring skin condition known as chloracne is the only health effect reported consistently. As part of translational research to make computerized models accessible to health risk assessors, the Concentration- and Age-Dependent Model (CADM) for TCDD was recoded in the Berkeley Madonna simulation language. The US Agency for Toxic Substances and Disease Registry's computational toxicology laboratory used the recoded model to predict TCDD tissue concentrations at different exposure levels. The model simulations successfully reproduced the National Health and Nutrition Examination Survey (NHANES) 2001-2002 TCDD data in age groups from 6 to 60 years and older, as well as in other human datasets. The model also enabled the estimation of lipid-normalized serum TCDD concentrations in breastfed infants. The model performed best for low background exposures over time compared with a high acute poisoning case that could due to the large dose and associated liver toxicity. Hence, this model may be useful for interpreting human biomonitoring data as a part of an overall DLC risk assessment.

  17. Determination of robust ocular pharmacokinetic parameters in serum and vitreous humor of albino rabbits following systemic administration of ciprofloxacin from sparse data sets by using IT2S, a population pharmacokinetic modeling program. (United States)

    Drusano, G L; Liu, W; Perkins, R; Madu, A; Madu, C; Mayers, M; Miller, M H


    Robust determination of the concentration-time profile of anti-infective agents in certain specialized compartments is often limited by the inability to obtain more than a single sample from such a site in any one subject. Vitreous humor and cerebrospinal fluid are obvious examples for which the determination of concentrations of anti-infective agents is limited. Advances in pharmacodynamics have pointed out the importance of understanding the profiles of drugs in the plasma and in specialized compartments in order to dose the drugs to obtain the best patient outcomes. Advances in population pharmacokinetic modeling hold the promise of allowing proper estimation of drug penetration into the vitreous (or other specialized compartment) with only a single vitreous sample, in conjunction with plasma sampling. We have developed a rabbit model which allows multiple samples of vitreous to be obtained without breaking down the blood-vitreous barrier. We have employed this model to test the hypothesis that robust estimates of vitreous penetration by the fluoroquinolone ciprofloxacin can be obtained from a traditional intensive plasma sampling set plus a single vitreous sample. We studied 33 rabbits which were receiving 40 mg of ciprofloxacin per kg of body weight intravenously as short infusions and from which multiple plasma and vitreous samples were obtained and assayed for ciprofloxacin content by high-performance liquid chromatography. Data were analyzed by the iterative two-stage population modeling technique (IT2S), employing the iterative two-stage program of Forrest et al. (Antimicrob. Agents Chemother. 37:1065-1072, 1993). Two data sets were analyzed: all plasma and vitreous samples versus all plasma samples and the initially obtained single vitreous sample. The pharmacokinetic parameter values identified were used to calculate the percent vitreous penetration as the ratio of the area under the concentration-time curve for the vitreous to that for the plasma. The

  18. Pharmacokinetic-pharmacodynamic modeling of rifampicin-mediated Cyp3a11 induction in steroid and xenobiotic X receptor humanized mice. (United States)

    Raybon, Joseph J; Pray, Devin; Morgan, Daniel G; Zoeckler, Mary; Zheng, Ming; Sinz, Michael; Kim, Sean


    The purpose of this study was to develop a mechanistic pharmacokinetic-pharmacodynamic (PK-PD) model to describe the effects of rifampicin on hepatic Cyp3a11 RNA, enzymatic activity, and triazolam pharmacokinetics. Rifampicin was administered to steroid and xenobiotic X receptor (SXR) humanized mice at 10 mg/kg p.o. (every day for 3 days) followed by triazolam (4 mg/kg p.o.) 24 h after the last dose of rifampicin. Rifampicin and triazolam concentrations and Cyp3a11 RNA expression and activity in the liver were measured over the 4-day period. Elevations in Cyp3a11 RNA expression were observed 24 h after the first dose of rifampicin, reaching a maximum (∼10 times baseline) after the third dose and were sustained until day 4 and began declining 48 h after the last rifampicin dose. Similar changes in enzymatic activity were also observed. The triazolam serum area under the curve (AUC) was 5-fold lower in mice pretreated with rifampicin, consistent with enzyme induction. The final PK-PD model incorporated rifampicin liver concentration as the driving force for the time-delayed Cyp3a11 induction governed by in vitro potency estimates, which in turn regulated the turnover of enzyme activity. The PK-PD model was able to recapitulate the delayed induction of Cyp3a11 mRNA and enzymatic activity by rifampicin. Furthermore, the model was able to accurately anticipate the reduction in the triazolam plasma AUC by integrating a ratio of the predicted induced enzyme activity and basal activity into the equations describing triazolam pharmacokinetics. In conjunction with the SXR humanized mouse model, this mathematical approach may serve as a tool for predicting clinically relevant drug-drug interactions via pregnane X receptor-mediated enzyme induction and possibly extended to other induction pathways (e.g., constitutive androstane receptor).

  19. Pharmacokinetics, pharmacodynamics, and efficacy of a small-molecule SMN2 splicing modifier in mouse models of spinal muscular atrophy (United States)

    Zhao, Xin; Feng, Zhihua; Ling, Karen K. Y.; Mollin, Anna; Sheedy, Josephine; Yeh, Shirley; Petruska, Janet; Narasimhan, Jana; Dakka, Amal; Welch, Ellen M.; Karp, Gary; Chen, Karen S.; Metzger, Friedrich; Ratni, Hasane; Lotti, Francesco; Tisdale, Sarah; Naryshkin, Nikolai A.; Pellizzoni, Livio; Paushkin, Sergey; Ko, Chien-Ping; Weetall, Marla


    Spinal muscular atrophy (SMA) is caused by the loss or mutation of both copies of the survival motor neuron 1 (SMN1) gene. The related SMN2 gene is retained, but due to alternative splicing of exon 7, produces insufficient levels of the SMN protein. Here, we systematically characterize the pharmacokinetic and pharmacodynamics properties of the SMN splicing modifier SMN-C1. SMN-C1 is a low-molecular weight compound that promotes the inclusion of exon 7 and increases production of SMN protein in human cells and in two transgenic mouse models of SMA. Furthermore, increases in SMN protein levels in peripheral blood mononuclear cells and skin correlate with those in the central nervous system (CNS), indicating that a change of these levels in blood or skin can be used as a non-invasive surrogate to monitor increases of SMN protein levels in the CNS. Consistent with restored SMN function, SMN-C1 treatment increases the levels of spliceosomal and U7 small-nuclear RNAs and corrects RNA processing defects induced by SMN deficiency in the spinal cord of SMNΔ7 SMA mice. A 100% or greater increase in SMN protein in the CNS of SMNΔ7 SMA mice robustly improves the phenotype. Importantly, a ∼50% increase in SMN leads to long-term survival, but the SMA phenotype is only partially corrected, indicating that certain SMA disease manifestations may respond to treatment at lower doses. Overall, we provide important insights for the translation of pre-clinical data to the clinic and further therapeutic development of this series of molecules for SMA treatment. PMID:26931466

  20. Pharmacokinetics of human recombinant tissue-type plasminogen activator, administered intra-abdominally, in a rat peritonitis model

    NARCIS (Netherlands)

    van Goor, Harry; Bom, VJJ; van der Meer, J; Sluiter, WJ; Geerards, S; de Graaf, JS; Bleichrodt, RP; van der Schaaf, W


    Human recombinant tissue-type plasminogen activator (rtPA), administered intraperitoneally, may promote intraabdominal fibrinolysis in peritonitis, thereby preventing adhesion and abscess formation. The pharmacokinetics of a single intraperitoneal dose of 0.5 or 2.0 mg/ml human rtPA were assessed in

  1. Pharmacokinetic model for diazepam and its major metabolite desmethyldiazepam following diazepam administration. (United States)

    Jack, M L; Colburn, W A


    A five-compartment open model was used to simulate the blood concentration profiles of diazepam and its metabolite, desmethyldiazepam, following single- and multiple-dose administrations of diazepam. The parameter estimates for diazepam were previously reported literature values. The parameters estimates for the metabolite were calculated from literature values of blood concentrations of desmethyldiazepam following the administration of clorazepate. The five-compartment open model suggests that approximately 50% of the administered diazepam is biotransformed to desmethyldiazepam, and that the elimination profile of the metabolite is not altered by the presence of the drug. The model may also be readily adapted to predict the concentrations of diazepam and desmethyldiazepam in cerebrospinal fluid following the administration of diazepam by simply correcting the blood or plasma concentrations of the drug and metabolite for the degree of plasma protein binding.

  2. Improvement of "hit-to-lead" optimization by integration of in vitro HTS experimental models for early determination of pharmacokinetic properties. (United States)

    Kariv, Ilona; Rourick, Robyn A; Kassel, Daniel B; Chung, Thomas D Y


    Development of predictive in vitro surrogate methods for traditional approaches assessing bioavailability and pharmacokinetics of lead compounds must be made to both keep pace with high-throughput (HT) lead identification and to mitigate the high costs associated with progression of compounds with poor chances of developmental success. Indeed opportunities for improvement still exist in the lead optimization phase versus the lead identification phase, where HT methodologies have been nearly optimized. Review of examples, limitations, and development of high-throughput microtiterplate-based assays for evaluating metabolic liabilities, such as in vitro radiometric and fluorometric assays for inhibition of cytochrome p450 (CYP) activity, determination of stability of a compound in liver microsomes, or cloned CYPs coupled to reconstituting systems are described. Parallel approaches to improve speed, resolution, sample preparation, as well as data analysis using LC/MS and LC/MS/MS approaches and technologies to assess compound integrity and biotransformation by automation and multiplexing are also discussed. Realization of the benefits in automation of cell-based models for determining drug permeability to predict drug absorption are still hampered by bottlenecks in analytical analysis of compounds. The implementation and limitations of surrogate physiochemical methods for passive adsorption such as immobilized artificial membranes (IAM) and parallel artificial membrane permeation assays (PAMPA), and compound solubility by laser nephelometry are reviewed as well. Additionally, data from a high-throughput 96-well equilibrium dialysis device, showing good correlation to classical methods, is presented. Finally, the impact of improvements in these downstream bottlenecks in lead optimization and preclinical drug discovery are discussed in this review.

  3. Pharmacokinetic Modeling of Manganese I. Dose-Dependencies of Uptake and Elimination

    Energy Technology Data Exchange (ETDEWEB)

    Teeguarden, Justin G.; Dorman, David C.; Covington, Tammie R.; Clewell, III, H. J.; Andersen, Melvin E.


    ABSTRACT Homeostatic mechanisms controlling uptake, storage, and elimination of dietary manganese (Mn) afford protection against fluctuations in tissue manganese (Mn) levels. Homeostatic control of inhaled Mn is less well understood, but important in assessing likely risks of Mn inhalation. We have used two compartmental kinetic models to characterize the influence of Mn exposure level and route (oral, inhalation) on uptake, elimination and transport of Mn. The models were fitted to or used to interpret data from five whole body Mn elimination studies, from one dietary Mn balance study, and from two biliary elimination studies, one acute and one chronic. As dietary Mn concentrations increased from low-sufficiency (1.5 ppm) to sufficiency (20 ppm), control of Mn uptake shifts from the intestine (principally), to more proportional control by both intestinal tissues and the liver. Using a 2-compartment distribution model, the increased elimination of 54Mn tracer doses in response to increases in dietary (rats and mice) or inhaled Mn (rats) resulted from increases in Mn elimination rate constants rather than changes in intercompartmental transfer rate constants between a central compartment and deep compartment. The PK analysis also indicated differential control of absorption in single gavage oral dose studies versus continuous high oral doses in the feed. The gavage study indicated increased elimination rate constants and the chronic study had reduced rate constants for absorption. These dose-dependencies in uptake and elimination are necessary inputs for comprehensive PK models guiding human health risk assessments with Mn.

  4. Model-based geostatistics

    CERN Document Server

    Diggle, Peter J


    Model-based geostatistics refers to the application of general statistical principles of modeling and inference to geostatistical problems. This volume provides a treatment of model-based geostatistics and emphasizes on statistical methods and applications. It also features analyses of datasets from a range of scientific contexts.

  5. Pharmacokinetics in patients with chronic liver disease and hepatic safety of incretin-based therapies for the management of type 2 diabetes mellitus. (United States)

    Scheen, André J


    Patients with type 2 diabetes mellitus have an increased risk of chronic liver disease (CLD) such as non-alcoholic fatty liver disease and steatohepatitis, and about one-third of cirrhotic patients have diabetes. However, the use of several antidiabetic agents, such as metformin and sulphonylureas, may be a concern in case of hepatic impairment (HI). New glucose-lowering agents targeting the incretin system are increasingly used for the management of type 2 diabetes. Incretin-based therapies comprise oral inhibitors of dipeptidyl peptidase-4 (DPP-4) (gliptins) or injectable glucagon-like peptide-1 (GLP-1) receptor agonists. This narrative review summarises the available data regarding the use of both incretin-based therapies in patients with HI. In contrast to old glucose-lowering agents, they were evaluated in specifically designed acute pharmacokinetic studies in patients with various degrees of HI and their hepatic safety was carefully analysed in large clinical trials. Only mild changes in pharmacokinetic characteristics of DPP-4 inhibitors were observed in patients with different degrees of HI, presumably without major clinical relevance. GLP-1 receptor agonists have a renal excretion rather than liver metabolism. Specific pharmacokinetic data in patients with HI are only available for liraglutide. No significant changes in liver enzymes were reported with DPP-4 inhibitors or GLP-1 receptor agonists, alone or in combination with various other glucose-lowering agents, in clinical trials up to 2 years in length. On the contrary, preliminary data suggested that incretin-based therapies may be beneficial in patients with CLD, more particularly in the presence of non-alcoholic fatty liver disease. Nevertheless, caution should be recommended, especially in patients with advanced cirrhosis, because of a lack of clinical experience with incretin-based therapies in these vulnerable patients.

  6. The Use of Spreadsheets for Pharmacokinetic Simulations

    Directory of Open Access Journals (Sweden)

    Joseph Chamberlain


    Full Text Available The use of simple spreadsheets is described to create simulations of complex pharmacokinetic phenomena. The basics of spreadsheets are first described and are developed to demonstrate classical pharmacokinetics without the use of differential or integral calculus. Using standard spreadsheet commands, the technique is shown to be applicable to the full range of advanced pharmacokinetic simulations. Demonstrations of the effect of a variety of physiological eventualities are included to show the versatility of the technique. The technique is very simple to use and is always in the complete control of the modeller.

  7. Pharmacokinetics of Two Alkaloids after Oral Administration of Rhizoma Coptidis Extract in Normal Rats and Irritable Bowel Syndrome Rats

    Directory of Open Access Journals (Sweden)

    Zipeng Gong


    Full Text Available A comparative pharmacokinetic study of berberine and palmatine after oral administration of Rhizoma Coptidis extract (96 mg/kg, containing berberine 22 mg/kg and palmatine 5 mg/kg based on body weight was performed in normal and postinflammation irritable bowel syndrome (PI-IBS rats, induced by intracolonic instillation of acetic acid and restraint stress. Quantification of berberine and palmatine in rat plasma was achieved by using a sensitive and rapid UPLC-MS/MS method. Plasma samples were collected at 13 different time points and the pharmacokinetic parameters were analyzed by WinNonlin software. The significant differences in the pharmacokinetic behaviors, such as Cmax⁡, AUC(0–t, Vd/F, and CL/F, of berberine and palmatine were found between normal and PI-IBS model rats. The results indicated that PI-IBS pathological conditions in rats could alter the pharmacokinetic behavior of drug. Preclinical pharmacokinetic studies are usually carried out on healthy animals. However, we should pay more attention to the fact that the change of pharmacokinetic behavior plays an important role on efficacy. It is essential to investigate the pharmacokinetics of the drug in disease status.

  8. [Pharmacokinetics of carbapenems]. (United States)

    Suchánková, H; Rychlíčková, J; Urbánek, K


    Carbapenems, beta-lactam antibiotics, are ideal candidates for the treatment of serious nosocomial infections including sepsis for their exceptionally broad antibacterial spectrum and high efficiency. They are administered parenterally by intravenous infusion. Carbapenems penetrate well and rapidly into many different tissue compartments and the interstitial fluid. They are metabolized by renal dihydropeptidase-1. Therefore, imipenem must be co-administered with an inhibitor of dihydropeptidase-1. Other carbapenems registered in the Czech Republic (meropenem, ertapenem and doripenem) are more stable to this enzyme. Carbapenems are mainly eliminated via the kidneys and dose adjustment in patients with renal impairment is necessary. The elimination half-life of most carbapenems is around 1 hour with the exception of ertapenem, with 3.8-hour half-life, which allows its once-daily use. Carbapenems are a group of antibiotics with time-dependent effect. Their typical pharmaceutical property is a limited stability in solution after dilution. Administration in the prolonged infusion appears to be a convenient strategy to achieve higher efficiency. Pharmacokinetic parameters of carbapenems may vary individually, especially in critically ill patients and those treated by renal replacement therapy. Therefore, individualization of dosing regimens based on knowledge of pharmacokinetic parameters of individual patients may be useful.

  9. Pharmacokinetic Models for the Elimination of Drinking Water Contaminants from the Body, (United States)


    for the MFO and GSH pathways in B6C3F1 mice .111-5 111-4 Log (total area under curve) for animals dosed with trichloroethylene in oil plotted against...values 8XE - Ethylene glycol monomethyl ethgr EPA = Environmental Protection Agency exp - Exponential function g - Gram GSH = Glutathione S-transferase...the laboratory are often available. The earliest PBPK models were developed for cancer I chemotherapeutic agents such as methotraxate and cisplatin

  10. Pharmacokinetic assessment of an oligopeptide-based enteral formula in abdominal surgery patients. (United States)

    Ziegler, F; Nitenberg, G; Coudray-Lucas, C; Lasser, P; Giboudeau, J; Cynober, L


    The specific effect of the molecular form of the nitrogen supply (oligopeptides and whole proteins) on amino acid kinetics during enteral feeding after surgery has not been assessed previously. In a prospective, randomized study, patients having undergone esophagectomy or gastrectomy for cancer received jejunal infusions of oligopeptide-based or whole-protein-based complete formulas (OPD and WPD, respectively) during two 9-h periods on 2 consecutive days in a crossover design. The OPD and WPD had identical energy compositions and amino acid profiles. Amino acid peripheral bioavailability (measurements of area under the curve of arterial blood concentrations), amino acid arteriovenous differences, and insulin and glucagon responses were measured. Amino acid peripheral bioavailability was higher (leucine: 54%, P bioavailability than the corresponding WPD. These results could be useful for a better definition of clinical indications of semi-elemental diets.

  11. Pharmacokinetic aspects and in vitro–in vivo correlation potential for lipid-based formulations



    Lipid-based formulations have been an attractive choice among novel drug delivery systems for enhancing the solubility and bioavailability of poorly soluble drugs due to their ability to keep the drug in solubilized state in the gastrointestinal tract. These formulations offer multiple advantages such as reduction in food effect and inter-individual variability, ease of preparation, and the possibility of manufacturing using common excipients available in the market. Despite these advantages,...

  12. Strategies for preclinical pharmacokinetic investigation in streptozotocin-induced diabetes mellitus (DMIS) and alloxan-induced diabetes mellitus (DMIA) rat models: case studies and perspectives. (United States)

    Srinivas, Nuggehally R


    Preclinical rodent models that manifest type 2 diatetes mellitus using either streptozotocin (DMIS) or alloxan (DMIA) have been well established. Both DMIS and DMIA models have served as key experimental tools to evaluate and understand the pharmacokinetic disposition of scores of drugs and therefore some key questions with respect to absorption, metabolism or elimination of drugs can be answered during the development of full-blown diabetes in the animal models. The choice of the right preclinical rodent model and adaptation of the appropriate experimental design could help to generate data to enable go or no-go decision on the clinical candidate. Also, such models may help to understand the risk potential from a drug-drug interaction perspective. The review provides an overview of the strategies and perspectives of institutionalizing DMIS and/or DMIA rat models using relevant case studies.

  13. Explicit reformulations of the Lambert W-omega function for calculations of the solutions to one-compartment pharmacokinetic models with Michaelis-Menten elimination kinetics. (United States)

    Goličnik, Marko


    The exact closed-form solutions to the integrated rate equations for one-compartment pharmacokinetic models that obey Michaelis-Menten elimination kinetics were derived recently (Tang and Xiao in J Pharmacokin Pharmacodyn 34:807-827, 2007). These solutions are expressed in terms of the Lambert W(x)-omega function; however, unfortunately, most of the available computer programs are not set up to handle equations that involve the W(x) function. Therefore, in this article, I provide alternative explicit analytical equations expressed in terms of elementary mathematical functions that accurately approximate exact solutions and can be simply calculated using any optional standard software.

  14. Combined use of pharmacokinetic modeling and a steady-state delivery approach allows early assessment of IkappaB kinase-2 (IKK-2) target safety and efficacy. (United States)

    Chiang, Po-Chang; Kishore, Nandini N; Thompson, David C


    NF-kappaB activation is clearly linked to the pathogenesis of multiple inflammatory diseases including arthritis. The prominent role of IkappaB kinase-2 (IKK-2) in regulating NF-kappaB signaling in response to proinflammatory stimuli has made IKK-2 a primary anti-inflammation therapeutic target. PHA-408, a potent and selective IKK-2 inhibitor, was identified internally and used for our studies to assess this target. In early in vivo studies, PHA-408 demonstrated efficacy at high doses; however, the correlation between PHA-408 exposure and efficacy could not be established using standard dosing paradigms for the rat disease models. Similar concerns arose from early in vivo safety studies where appropriate NOAEL margins were not achieved. Following a full investigation of the physicochemical properties of the molecule and pharmacokinetic modeling, an oral steady-state delivery strategy was designed to administer PHA-408 to the rat for both efficacy and safety studies. Using this steady-state delivery, a clear dose-response relationship was established between plasma concentrations of PHA-408 and efficacy in the rat arthritis model. The same steady-state delivery approach was used to demonstrate the target safety. In summary, a combination of pharmacokinetic modeling with a steady-state delivery approach allowed us to establish confidence in both the mechanism and safety of the target.

  15. Pharmacokinetic-Pharmacodynamic Model To Evaluate Intramuscular Tetracycline Treatment Protocols To Prevent Antimicrobial Resistance in Pigs

    DEFF Research Database (Denmark)

    Ahmad, Amais; Græsbøll, Kaare; Christiansen, Lasse Engbo


    High instances of antimicrobial resistance are linked to both routine and excessive antimicrobial use, but excessive or inappropriate use represents an unnecessary risk. The competitive growth advantages of resistant bacteria may be amplified by the strain dynamics; in particular, the extent...... protocol for intramuscular administration of tetracycline and the composition of bacterial strains in a pig affect the level of resistance in the intestine of a pig. Predictions were generated by a mathematical model of competitive growth of Escherichia coli strains in pigs under specified plasma...... concentration profiles of tetracycline. All dosing regimens result in a clear growth advantage for resistant strains. Short treatment duration was found to be preferable, since it allowed less time for resistant strains to outcompete the susceptible ones. Dosing frequency appeared to be ineffective at reducing...

  16. Pharmacokinetic-Pharmacodynamic Model To Evaluate Intramuscular Tetracycline Treatment Protocols To Prevent Antimicrobial Resistance in Pigs

    DEFF Research Database (Denmark)

    Ahmad, Amais; Græsbøll, Kaare; Christiansen, Lasse Engbo;


    to which resistant strains outcompete susceptible strains under antimicrobial pressure may depend not only on the antimicrobial treatment strategies but also on the epidemiological parameters, such as the composition of the bacterial strains in a pig. This study evaluated how variation in the dosing...... protocol for intramuscular administration of tetracycline and the composition of bacterial strains in a pig affect the level of resistance in the intestine of a pig. Predictions were generated by a mathematical model of competitive growth of Escherichia coli strains in pigs under specified plasma......High instances of antimicrobial resistance are linked to both routine and excessive antimicrobial use, but excessive or inappropriate use represents an unnecessary risk. The competitive growth advantages of resistant bacteria may be amplified by the strain dynamics; in particular, the extent...

  17. [Interspecies allometric scaling in pharmacokinetics of drugs]. (United States)

    Sylvia, M


    Allometric scaling is an empirical examination of the relationships between the pharmacokinetic parameters and size (usually body weight, ratio of organ- and body weight, breathing number, etc.). Interspecies pharmacokinetics tend to approximate, the organism, as the sum of organs and tissues according to material balance. The allometric equations for the pharmacokinetic parameters were applied to scale the data with respect to pharmacokinetic time and remove the chronological time dependency. When the data of at least three species are available, the pharmacokinetic parameters can be fit according to body weight in log-log regression. Allometric scaling is not applicable in all cases, only when the selected species has similar physiological behaviour, such as protein-binding, metabolism, etc. Valuable information for the evaluation of the effect and the biopharmaceutical characteristics may emerge from more creative data analysis based on all result collected during the preclinical evaluation of a new drug. Author examined the applicability of the interspecies scaling method in the case of a new drug depogen, using drotaverin as reference. The pharmacokinetic data were collected from mouse, rat and dog and during the evaluation human data were applied too. The usual pharmacokinetic parameters were determined (MRT, MAT, beta, etc.), the results of allometric analysis were collected and the standard deviation of measured and calculated values were given.

  18. Application of a whole-body pharmacokinetic model for targeted radionuclide therapy to NM404 and FLT (United States)

    Grudzinski, Joseph J.; Floberg, John M.; Mudd, Sarah R.; Jeffery, Justin J.; Peterson, Eric T.; Nomura, Alice; Burnette, Ronald R.; Tomé, Wolfgang A.; Weichert, Jamey P.; Jeraj, Robert


    We have previously developed a model that provides relative dosimetry estimates for targeted radionuclide therapy (TRT) agents. The whole-body and tumor pharmacokinetic (PK) parameters of this model can be noninvasively measured with molecular imaging, providing a means of comparing potential TRT agents. Parameter sensitivities and noise will affect the accuracy and precision of the estimated PK values and hence dosimetry estimates. The aim of this work is to apply a PK model for TRT to two agents with different magnitudes of clearance rates, NM404 and FLT, explore parameter sensitivity with respect to time and investigate the effect of noise on parameter precision and accuracy. Twenty-three tumor bearing mice were injected with a ‘slow-clearing’ agent, 124I-NM404 (n = 10), or a ‘fast-clearing’ agent, 18F-FLT (3‧-deoxy-3‧-fluorothymidine) (n = 13) and imaged via micro-PET/CT pseudo-dynamically or dynamically, respectively. Regions of interest were drawn within the heart and tumor to create time-concentration curves for blood pool and tumor. PK analysis was performed to estimate the mean and standard error of the central compartment efflux-to-influx ratio (k12/k21), central elimination rate constant (kel), and tumor influx-to-efflux ratio (k34/k43), as well as the mean and standard deviation of the dosimetry estimates. NM404 and FLT parameter estimation results were used to analyze model accuracy and parameter sensitivity. The accuracy of the experimental sampling schedule was compared to that of an optimal sampling schedule found using Cramer-Rao lower bounds theory. Accuracy was assessed using correlation coefficient, bias and standard error of the estimate normalized to the mean (SEE/mean). The PK parameter estimation of NM404 yielded a central clearance, kel (0.009 ± 0.003 h-1), normal body retention, k12/k21 (0.69 ± 0.16), tumor retention, k34/k43 (1.44 ± 0.46) and predicted dosimetry, Dtumor (3.47 ± 1.24 Gy). The PK parameter estimation of FLT

  19. Sample-size calculations for multi-group comparison in population pharmacokinetic experiments. (United States)

    Ogungbenro, Kayode; Aarons, Leon


    This paper describes an approach for calculating sample size for population pharmacokinetic experiments that involve hypothesis testing based on multi-group comparison detecting the difference in parameters between groups under mixed-effects modelling. This approach extends what has been described for generalized linear models and nonlinear population pharmacokinetic models that involve only binary covariates to more complex nonlinear population pharmacokinetic models. The structural nonlinear model is linearized around the random effects to obtain the marginal model and the hypothesis testing involving model parameters is based on Wald's test. This approach provides an efficient and fast method for calculating sample size for hypothesis testing in population pharmacokinetic models. The approach can also handle different design problems such as unequal allocation of subjects to groups and unbalanced sampling times between and within groups. The results obtained following application to a one compartment intravenous bolus dose model that involved three different hypotheses under different scenarios showed good agreement between the power obtained from NONMEM simulations and nominal power.

  20. Testis dosimetry in individual patients by combining a small-scale dosimetry model and pharmacokinetic modeling-application of 111In-Ibritumomab Tiuxetan (Zevalin®) (United States)

    Meerkhan, Suaad A.; Sjögreen-Gleisner, Katarina; Larsson, Erik; Strand, Sven-Erik; Jönsson, Bo-Anders


    A heterogeneous distribution of radionuclides emitting low-energy electrons in the testicles may result in a significant difference between an absorbed dose to the radiosensitive spermatogonia and the mean absorbed dose to the whole testis. This study focused on absorbed dose distribution in patients at a finer scale than normally available in clinical dosimetry, which was accomplished by combining a small-scale dosimetry model with patient pharmacokinetic data. The activity in the testes was measured and blood sampling was performed for patients that underwent pre-therapy imaging with 111In-Zevalin®. Using compartment modeling, testicular activity was separated into two components: vascular and extravascular. The uncertainty of absorbed dose due to geometry variations between testicles was explored by an assumed activity micro-distribution and by varying the radius of the interstitial tubule. Results showed that the absorbed dose to germ cells might be strongly dependent on the location of the radioactive source, and may exceed the absorbed dose to the whole testis by as much as a factor of two. Small-scale dosimetry combined with compartmental analysis of clinical data proved useful for gauging tissue dosimetry and interpreting how intrinsic geometric variation influences the absorbed dose.

  1. Development of Liposomal Formulation for Delivering Anticancer Drug to Breast Cancer Stem-Cell-Like Cells and its Pharmacokinetics in an Animal Model. (United States)

    Ahmad, Ajaz; Mondal, Sujan Kumar; Mukhopadhyay, Debabrata; Banerjee, Rajkumar; Alkharfy, Khalid M


    The objective of the present study is to develop a liposomal formulation for delivering anticancer drug to breast cancer stem-cell-like cells, ANV-1, and evaluate its pharmacokinetics in an animal model. The anticancer drug ESC8 was used in dexamethasone (Dex)-associated liposome (DX) to form ESC8-entrapped liposome named DXE. ANV-1 cells showed high-level expression of NRP-1. To enhance tumor regression, we additionally adapted to codeliver the NRP-1 shRNA-encoded plasmid using the established DXE liposome. In vivo efficacy of DXE-NRP-1 was carried out in mice bearing ANV-1 cells as xenograft tumors and the extent of tumor growth inhibition was evaluated by tumor-size measurement. A significant difference in tumor volume started to reveal between DXE-NRP-1 group and DXE-Control group. DXE-NRP-1 group showed ∼4 folds and ∼2.5 folds smaller tumor volume than exhibited by untreated and DXE-Control-treated groups, respectively. DXE disposition was evaluated in Sprague-Dawley rats following an intraperitoneal dose (3.67 mg/kg of ESC8 in DXE). The plasma concentrations of ESC8 in the DXE formulation were measured by liquid chromatography mass spectrometry and pharmacokinetic parameters were determined using a noncompartmental analysis. ESC8 had a half-life of 11.01 ± 0.29 h, clearance of 2.10 ± 3.63 L/kg/h, and volume of distribution of 33.42 ± 0.83 L/kg. This suggests that the DXE liposome formulation could be administered once or twice daily for therapeutic efficacy. In overall, we developed a potent liposomal formulation with favorable pharmacokinetic and tumor regressing profile that could sensitize and kill highly aggressive and drug-resistive cancer stem-cell-like cells.

  2. Population stochastic modelling (PSM)-An R package for mixed-effects models based on stochastic differential equations

    DEFF Research Database (Denmark)

    Klim, Søren; Mortensen, Stig Bousgaard; Kristensen, Niels Rode


    likelihood estimation of a time-inhomogeneous stochastic differential model of glucose dynamics, Math. Med. Biol. 25 (June(2)) (2008) 141-155]. PK/PD models are traditionally based ordinary differential equations (ODES) with an observation link that incorporates noise. This state-space formulation only......The extension from ordinary to stochastic differential equations (SDEs) in pharmacokinetic and pharmacodynamic (PK/PD) modelling is an emerging field and has been motivated in a number of articles [N.R. Kristensen, H. Madsen, S.H. Ingwersen, Using stochastic differential equations for PK/PD model...... development, J. Pharmacokinet. Pharmacodyn. 32 (February(l)) (2005) 109-141; C.W. Tornoe, R.V Overgaard, H. Agerso, H.A. Nielsen, H. Madsen, E.N. Jonsson, Stochastic differential equations in NONMEM: implementation, application, and comparison with ordinary differential equations, Pharm. Res. 22 (August(8...

  3. A simulation study of sampling time point designing for therapeutic drug monitoring based on a population pharmacokinetic model%治疗药物监测中基于群体药动学模型设计采样方案的仿真研究

    Institute of Scientific and Technical Information of China (English)

    张扬; 周颖; 张相林; 刘晓; 崔一民; 卢炜


    Aim To develop a method to estimate population pharmacokinetic parameters with the limited sampling time points provided clinically during therapeutic drug monitoring.Methods Various simulations were attempted using a one-compartment open model wim the first order absorption to determine PK parameter estimates with different sampling strategies as a validation of the method.The estimated parameters were further verified by comparing to the observed values.Results The sampleS collected at the single time point close to the non-informative sampling time point designed bvtllis method led to bias and inaccurate parameter estimations.Furthermore,the relationship between the estimated non-informative sampljng time points and the values of the parameter was examined.The non-informative sampling time points have been developed under some typical OCCasions and the results were plotted to show the tendency.As a result,one non,informative time point was demonstrated to be appropriate for clearance and two for both Vohme of distribution and constant of absorption in the present studv.It was found that the estimates of the non-informarive sampling time points developed in the method increase with increases of volume of distribution and the decrease of clearance and constant of absorption.Conclusion A rational sampling strategy during therapeutic drug monitoring can be established using the method present in the study.%目的 建立一种预测在治疗药物监测中需要避免的、只能提供很少信息的"最小信息采样点"的方法.方法 进行了一系列基于一室开放模型的仿真, 并且通过比较不同采样方案中预测参数效果的差异来验证建立的预测最小信息采样点的方法是否合理.我们比较了每种采样方案中各个参数的预测值和真实值(仿真值), 通过两者的接近程度来评价该采样方案,预测值和真实值越接近说明通过该方案采样获得的信息量越大,这

  4. Alteration in Intrapulmonary Pharmacokinetics of Aerosolized Model Compounds Due to Disruption of the Alveolar Epithelial Barriers Following Bleomycin-Induced Pulmonary Fibrosis in Rats. (United States)

    Togami, Kohei; Chono, Sumio; Tada, Hitoshi


    Idiopathic pulmonary fibrosis is a lethal lung disease that is characterized by the accumulation of extracellular matrix and a change in lung structure. In this study, intrapulmonary pharmacokinetics of aerosolized model compounds were evaluated using rats with bleomycin-induced pulmonary fibrosis. Aerosol formulations of indocyanine green, 6-carboxyfluorescein (6-CF), and fluorescein isothiocyanate dextrans (FD; 4.4, 10, 70, and 250 kDa) were administered to rat lungs using a MicroSprayer. Indocyanine green fluorescence signals were significantly weaker in fibrotic lungs than in control lungs and 6-CF and FD concentrations in the plasma of pulmonary fibrotic animals were markedly higher than in the plasma of control animals. Moreover, disrupted epithelial tight junctions, including claudins-1, -3, and -5, were observed in pulmonary fibrotic lesions using immunofluorescence microscopy. In addition, destruction of tight junctions on model alveolar epithelial cells (NCI-H441) by transforming growth factor-β1 treatment enhanced the permeability of 6-CF and FDs through NCI-H441 cell monolayers. These results indicate that aerosolized drugs are easily distributed into the plasma after leakage through damaged tight junctions of alveolar epithelium. Therefore, the development of delivery systems for anti-fibrotic agents to improve intrapulmonary pharmacokinetics may be necessary for effective idiopathic pulmonary fibrosis therapy.

  5. Physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model for aldicarb and its metabolites in rats and human using exposure-related dose Estimating Model (ERDEM)%应用ERDEM模型为涕灭威及其代谢物构建大鼠和人的PBPK/PD模型研究

    Institute of Scientific and Technical Information of China (English)

    巢迎妍; 张辉; 张晓菲


    Objective To construct the PBPK/PD models for aldicarb in rats and humans to help understandits disposition in both species in order to use the models for risk assessment purposes due to aldicarb exposure. MethodsThe PBPK/PD models were constructed using the ERDEM ( Exposure-related dose estimating model ) platform. Themodel structures for both species included a full gastrointestinal compartment, liver metabolism, urinary excretion, fecalelimination,and bimolecular acetylcholinesterase ( AChE ) inhibition by aldicarb and its two oxidized metabolites, aldi-carb sulfoxide and aldicarb sulfone. Experimentally reported values or estimation of physiological, biochemical, and physicochemical parameters were obtained from the open literature or optimized by fitting to the experimental data. Results The rat model simulation of oral exposure of 0. 4 mg/kg aldicarb indicated that aldicarb had an overall half-life of 1. 35 h,and 96. 6% of the dose was excreted in urine compared to the measured 91. 6% at 144 h after oral exposure. AChE activity in blood was inhibited to 31 % of the control level at 0. 35 h in the rat model compared to the measured 42. 5% at 0. 5 h after oral exposure of 0. 33 mg/kg aldicarb. In the human model,the simulation showed that the minimum blood AChE activity was 76. 9% at 1 h compared to the measured 75. 3% after a 0. 05 mg/kg dose of aldicarb. Conclusion The ERDEM model simulations for both species were consistent with the experimental data. Therefore, the models constructed in the ERDEM platform may be helpful in evaluating human health risk due to aldicarb exposure.%目的 为构建涕灭威在大鼠和人的生理药代动力学/药效学(PBPK/PD)模型,以进一步了解涕灭威在两物种体内的转化过程,从而用于其风险评估.方法 采用暴露相关的剂量估算模型(Exposure-related dose estimating model,ERDEM)的构建平台进行模型构建.两个物种的模型结构均包括完整的胃肠道、肝脏代谢、尿排泄

  6. Modelling the Effect of Exercise on Insulin Pharmacokinetics in "Continuous Subcutaneous Insulin Infusion" Treated Type 1 Diabetes Patients

    DEFF Research Database (Denmark)

    Duun-Henriksen, Anne Katrine; Juhl, Rune; Schmidt, Signe

    transformation is used to ensure non-negative state values. A special focus is put on the structural identiflability of the base model, while the posterior identiflability is checked for all models from the conditional likelihood profiles. Results: The first model is disregarded due to the small number...... of observations during the exercise bout. From likelihood-ratio tests and information criteria, the third model is appointed as the best model to model the relationship between exercise and the insulin absorption. The posterior identiflability check showed that it was not possible to identify the variance...

  7. Pharmacokinetics and PBPK Models

    Energy Technology Data Exchange (ETDEWEB)

    Corley, Richard A.


    Since the landmark report Pesticides in the Diets of Infants and Children (NRC 1993), children at all stages of development, from fertilization through postnatal maturation, have explicitly been identified as an area of emphasis in human health risk assessments. Exposure to drugs or chemicals at any point in development has the potential for causing irreversible changes that can be unique to each stage of development (Grabowski and Daston 1983; Rodier 1978; Wilson 1973). While exposures of a developing embryo or fetus are mediated by the mother, postnatal exposures consist of maternal influences via breastfeeding as well as environmental factors (Figure 1). As a result, risk assessments for developmental toxicity must consider the sources as well as timing of potential exposures to adequately protect children when they may be the most exposed or the most sensitive to adverse consequences (NRC 1993).

  8. Pharmacokinetics of Aminoglycosides

    Institute of Scientific and Technical Information of China (English)

    Lokangu Lombo(Congo); HE Hua


    The Pharmacokinetics informations of aminoglycosides, their monograph and clinical Pharmacokinetics parameters are reported in this review. The Aminoglycosides are highly polarity and in reserve for serious infections caused by aerobic gram-negative bacteria and some gram-positive bacteria but their toxicity are major limitations in clinical use.

  9. Pharmacokinetics and clinical use of incretin-based therapies in patients with chronic kidney disease and type 2 diabetes. (United States)

    Scheen, André J


    The prevalence of chronic kidney disease (CKD) of stages 3-5 (glomerular filtration rate [GFR] <60 mL/min) is about 25-30 % in patients with type 2 diabetes mellitus (T2DM). While most oral antidiabetic agents have limitations in patients with CKD, incretin-based therapies are increasingly used for the management of T2DM. This review analyses (1) the influence of CKD on the pharmacokinetics of dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists; and (2) the efficacy/safety profile of these agents in clinical practice when prescribed in patients with both T2DM and CKD. Most DPP-4 inhibitors (sitagliptin, vildagliptin, saxagliptin, alogliptin) are predominantly excreted by the kidneys. Thereby, pharmacokinetic studies showed that total exposure to the drug is increased in proportion to the decline of GFR, leading to recommendations for appropriate dose reductions according to the severity of CKD. In these conditions, clinical studies reported a good efficacy and safety profile in patients with CKD. In contrast, linagliptin is eliminated by a predominantly hepatobiliary route. As a pharmacokinetic study showed only minimal influence of decreased GFR on total exposure, no dose adjustment of linagliptin is required in the case of CKD. The experience with GLP-1 receptor agonists in patients with CKD is more limited. Exenatide is eliminated by renal mechanisms and should not be given in patients with severe CKD. Liraglutide is not eliminated by the kidney, but it should be used with caution because of the limited experience in patients with CKD. Only limited pharmacokinetic data are also available for lixisenatide, exenatide long-acting release (LAR) and other once-weekly GLP-1 receptor agonists in current development. Several case reports of acute renal failure have been described with GLP-1 receptor agonists, probably triggered by dehydration resulting from gastrointestinal adverse events. However, increasing GLP-1 may

  10. Long-term pharmacokinetic efficacy and safety of low-dose ritonavir as a booster and atazanavir pharmaceutical formulation based on solid dispersion system in rats. (United States)

    Fukushima, Keizo; Haraya, Kenta; Terasaka, Shuichi; Ito, Yukako; Sugioka, Nobuyuki; Takada, Kanji


    Atazanavir (ATV) is clinically coadministered with low-dose ritonavir (RTV), which boosts the oral bioavailability (BA) of ATV by inhibiting cytochrome P450 (CYP) 3A, and P-glycoprotein (Pgp) via the same metabolic pathway; however, it is well known that in the chronic phase, the inhibition effect of RTV on Pgp and CYP3A becomes an induction effect. In this study, we investigated the long-term efficacy and safety of RTV-boosted ATV in rats with a clinical relevant dosage of ATV and RTV, 7 mg/kg and 2 mg/kg, respectively, and drew a direct comparison with RTV-boosted ATV and the previously reported ATV pharmaceutical formulation based on a solid dispersion system (ATV-SLS SD+G). Rats received RTV-boosted ATV or ATV-SLS SD+G for 14 d in the pharmacokinetic study. In addition, after 14-d repeated administration of each formulation, cyclosporine A (CyA) was administered to rats and Western blot analysis of Pgp and CYP3A was performed to investigate the impact on pharmacokinetic interaction of each ATV formulation. After repeated administration of both formulations, there was no significant difference between ATV pharmacokinetic parameters on day 1 and 14; therefore, it was considered that the long-term efficacy of both ATV formulations was maintained. However, after treatment with RTV-boosted ATV, the Cmax and AUC0-infinity of the following CyA significantly decreased to 49% and 47% in comparison to the control, respectively, and the Pgp expression in the small intestine by Western blot analysis was approximately 2-fold higher than the control, whereas after treatment with ATV pharmaceutical formulation, neither significant alteration of CyA nor notable change in the expression of intestinal Pgp and hepatic CYP3A was observed. Therefore, it was considered that the BA of CyA after treatment with RTV-boosted ATV would decrease by the induction effect of RTV in chronic phase as described above. The results of this study revealed that the chronic use of low-dose RTV as a

  11. Population pharmacokinetics of rifampin in the treatment of Mycobacterium tuberculosis in Asian elephants. (United States)

    Egelund, E F; Isaza, R; Brock, A P; Alsultan, A; An, G; Peloquin, C A


    The objective of this study was to develop a population pharmacokinetic model for rifampin in elephants. Rifampin concentration data from three sources were pooled to provide a total of 233 oral concentrations from 37 Asian elephants. The population pharmacokinetic models were created using Monolix (version 4.2). Simulations were conducted using ModelRisk. We examined the influence of age, food, sex, and weight as model covariates. We further optimized the dosing of rifampin based upon simulations using the population pharmacokinetic model. Rifampin pharmacokinetics were best described by a one-compartment open model including first-order absorption with a lag time and first-order elimination. Body weight was a significant covariate for volume of distribution, and food intake was a significant covariate for lag time. The median Cmax of 6.07 μg/mL was below the target range of 8-24 μg/mL. Monte Carlo simulations predicted the highest treatable MIC of 0.25 μg/mL with the current initial dosing recommendation of 10 mg/kg, based upon a previously published target AUC0-24/MIC > 271 (fAUC > 41). Simulations from the population model indicate that the current dose of 10 mg/kg may be adequate for MICs up to 0.25 μg/mL. While the targeted AUC/MIC may be adequate for most MICs, the median Cmax for all elephants is below the human and elephant targeted ranges.

  12. Fisher information matrix for nonlinear mixed effects multiple response models: evaluation of the appropriateness of the first order linearization using a pharmacokinetic/pharmacodynamic model. (United States)

    Bazzoli, Caroline; Retout, Sylvie; Mentré, France


    We focus on the Fisher information matrix used for design evaluation and optimization in nonlinear mixed effects multiple response models. We evaluate the appropriateness of its expression computed by linearization as proposed for a single response model. Using a pharmacokinetic-pharmacodynamic (PKPD) example, we first compare the computation of the Fisher information matrix with approximation to one derived from the observed matrix on a large simulation using the stochastic approximation expectation-maximization algorithm (SAEM). The expression of the Fisher information matrix for multiple responses is also evaluated by comparison with the empirical information obtained through a replicated simulation study using the first-order linearization estimation methods implemented in the NONMEM software (first-order (FO), first-order conditional estimate (FOCE)) and the SAEM algorithm in the MONOLIX software. The predicted errors given by the approximated information matrix are close to those given by the information matrix obtained without linearization using SAEM and to the empirical ones obtained with FOCE and SAEM. The simulation study also illustrates the accuracy of both FOCE and SAEM estimation algorithms when jointly modelling multiple responses and the major limitations of the FO method. This study highlights the appropriateness of the approximated Fisher information matrix for multiple responses, which is implemented in PFIM 3.0, an extension of the R function PFIM dedicated to design evaluation and optimization. It also emphasizes the use of this computing tool for designing population multiple response studies, as for instance in PKPD studies or in PK studies including the modelling of the PK of a drug and its active metabolite.

  13. Pharmacokinetics of mitragynine in man

    Directory of Open Access Journals (Sweden)

    Trakulsrichai S


    the study without adverse reactions. The median duration of abuse was 1.75 years. We analyzed one subject separately due to the abnormal behavior of blood concentration. From data of nine subjects, the pharmacokinetic parameters established were time to reach the maximum plasma concentration (0.83±0.35 hour, terminal half-life (23.24±16.07 hours, and the apparent volume of distribution (38.04±24.32 L/kg. The urine excretion of unchanged form was 0.14%. The pharmacokinetics were observed to be oral two-compartment model. Conclusion: This was the first pharmacokinetic study in humans, which demonstrated linearity and was consistent with the oral two-compartment model with a terminal half-life of about 1 day. The pharmacokinetic linearity and parameters reported are necessary pharmacological information of Kratom, and there is a possibility for it to be developed medically as a pain killer or better opioid substitute in the future. Keywords: kratom, human, pharmacokinetics

  14. Pharmacokinetics of Cannabinoids

    Directory of Open Access Journals (Sweden)

    Iain J McGilveray


    Full Text Available Delta-9-tetrahydrocannabinol (Δ-9-THC is the main psychoactive ingredient of cannabis (marijuana. The present review focuses on the pharmacokinetics of THC, but also includes known information for cannabinol and cannabidiol, as well as the synthetic marketed cannabinoids, dronabinol (synthetic THC and nabilone. The variability of THC in plant material (0.3% to 30% leads to variability in tissue THC levels from smoking, which is, in itself, a highly individual process. THC bioavailability averages 30%. With a 3.55% THC cigarette, a peak plasma level of 152±86.3 ng/mL occured approximately 10 min after inhalation. Oral THC, on the other hand, is only 4% to 12% bioavailable and absorption is highly variable. THC is eliminated from plasma in a multiphasic manner, with low amounts detectable for over one week after dosing. A major active 11-hydroxy metabolite is formed after both inhalation and oral dosing (20% and 100% of parent, respectively. THC is widely distributed, particularly to fatty tissues, but less than 1% of an administered dose reaches the brain, while the spleen and body fat are long-term storage sites. The elimination of THC and its many metabolites (from all routes occurs via the feces and urine. Metabolites persist in the urine and feces for severalweeks. Nabilone is well absorbed and the pharmacokinetics, although variable, appear to be linear from oral doses of 1 mg to 4 mg (these doses show a plasma elimination half-life of approximately 2 h. As with THC, there is a high first-pass effect, and the feces to urine ratio of excretion is similar to other cannabinoids. Pharmacokineticpharmacodynamic modelling with plasma THC versus cardiac and psychotropic effects show that after equilibrium is reached, the intensity of effect is proportional to the plasma THC profile. Clinical trials have found that nabilone produces less tachycardia and less euphoria than THC for a similar antiemetic response.

  15. Web Based VRML Modelling

    NARCIS (Netherlands)

    Kiss, S.


    Presents a method to connect VRML (Virtual Reality Modeling Language) and Java components in a Web page using EAI (External Authoring Interface), which makes it possible to interactively generate and edit VRML meshes. The meshes used are based on regular grids, to provide an interaction and modeling

  16. Population pharmacokinetic/pharmacodynamic (PK/PD) modelling of the hypothalamic-pituitary-gonadal axis following treatment with GnRH analogues

    DEFF Research Database (Denmark)

    Tornøe, Christoffer Wenzel; Agersø, Henrik; Senderovitz, Thomas;


    Aims To develop a population pharmacokinetic/pharmacodynamic (PK/PD) model of the hypothalamic-pituitary-gonadal (HPG) axis describing the changes in luteinizing hormone (LH) and testosterone concentrations following treatment with the gonadotropin-releasing hormone (GnRH) agonist triptorelin...... and the GnRH receptor blocker degarelix. Methods Fifty-eight healthy subjects received single subcutaneous or intramuscular injections of 3.75 mg of triptorelin and 170 prostate cancer patients received multiple subcutaneous doses of degarelix of between 120 and 320 mg. All subjects were pooled...... for the different dynamic responses observed after administration of both GnRH agonists and GnRH receptor blockers, suggesting that the model adequately characterizes the underlying physiology of the endocrine system....

  17. PBPK modeling and simulation in drug research and development


    Xiaomei Zhuang; Chuang Lu


    Physiologically based pharmacokinetic (PBPK) modeling and simulation can be used to predict the pharmacokinetic behavior of drugs in humans using preclinical data. It can also explore the effects of various physiologic parameters such as age, ethnicity, or disease status on human pharmacokinetics, as well as guide dose and dose regiment selection and aid drug–drug interaction risk assessment. PBPK modeling has developed rapidly in the last decade within both the field of academia and the phar...

  18. Lisdexamfetamine: A pharmacokinetic review. (United States)

    Comiran, Eloisa; Kessler, Félix Henrique; Fröehlich, Pedro Eduardo; Limberger, Renata Pereira


    Lisdexamfetamine (LDX) is a d-amphetamine (d-AMPH) pro-drug used to treat Attention Deficit and Hyperactivity Disorder (ADHD) and Binge Eating Disorder (BED) symptoms. The in vivo pharmacodynamics of LDX is the same as that of its active product d-AMPH, although there are a few qualitative and quantitative differences due to pharmacokinetics. Due to the specific pharmacokinetics of the long-acting stimulants, this article revises the pharmacokinetic studies on LDX, the newest amphetamine pro-drug. The Medline/Pubmed, Science Direct and Biblioteca Virtual em Saúde (Lilacs and Ibecs) (2007-2016) databases were searched for articles and their list of references. As for basic pharmacokinetics studies, since LDX is a newly developed medication, there are few results concerning biotransformation, distribution and the use of different biological matrices for analysis. This is the first robust review on this topic, gathering data from all clinical pharmacokinetics studies available in the literature. The particular pharmacokinetics of LDX plays a major role in studying this pro-drug, since this knowledge was essential to understand some reports on clinical effects in literature, e.g. the small likelihood of reducing the effect by interactions, the effect of long duration use and the still questionable reduction of the potential for abuse. In general the already well-known pharmacokinetic properties of amphetamine make LDX relatively predictable, simplifying the use of LDX in clinical practice.

  19. Density-based Monte Carlo filter and its applications in nonlinear stochastic differential equation models. (United States)

    Huang, Guanghui; Wan, Jianping; Chen, Hui


    Nonlinear stochastic differential equation models with unobservable state variables are now widely used in analysis of PK/PD data. Unobservable state variables are usually estimated with extended Kalman filter (EKF), and the unknown pharmacokinetic parameters are usually estimated by maximum likelihood estimator. However, EKF is inadequate for nonlinear PK/PD models, and MLE is known to be biased downwards. A density-based Monte Carlo filter (DMF) is proposed to estimate the unobservable state variables, and a simulation-based M estimator is proposed to estimate the unknown parameters in this paper, where a genetic algorithm is designed to search the optimal values of pharmacokinetic parameters. The performances of EKF and DMF are compared through simulations for discrete time and continuous time systems respectively, and it is found that the results based on DMF are more accurate than those given by EKF with respect to mean absolute error.

  20. Allometric scaling of marbofloxacin pharmacokinetics: a retrospective analysis. (United States)

    Yohannes, S; Hossain, Md Akil; Kim, J Y; Lee, S J; Kwak, D M; Suh, J W; Park, S C


    The association between physiologically dependent pharmacokinetic parameters (CL(B), T1/2beta, Vd(ss)) of marbofloxacin and body weight was studied in eight animal species based on allometric equation Y = aWb, where 'Y' is the pharmacokinetic parameter, 'W' is body weight, 'a' is allometric coefficient (intercept) and 'b' is the exponent that describes relation between pharmacokinetic parameter and body weight. The body clearance of marbofloxacin has shown significant (P marbofloxacin in animal species that have not been studied yet. However further study considering large sample size and other parameters influencing pharmacokinetics of marbofloxacin is recommended.

  1. Pharmacokinetics of [{sup 18}F]flutemetamol in wild-type rodents and its binding to beta amyloid deposits in a mouse model of Alzheimer's disease

    Energy Technology Data Exchange (ETDEWEB)

    Snellman, Anniina; Lopez-Picon, Francisco R.; Haaparanta-Solin, Merja [University of Turku, MediCity/PET Preclinical Laboratory, Turku PET Centre, Turku (Finland); Rokka, Johanna; Eskola, Olli [University of Turku, Radiopharmaceutical Chemistry Laboratory, Turku PET Centre, Turku (Finland); Wilson, Ian; Farrar, Gill [GE Healthcare Medical Diagnostics, Little Chalfont, Buckinghamshire (United Kingdom); Scheinin, Mika [University of Turku, Department of Pharmacology, Drug Development and Therapeutics, Turku (Finland); Turku University Hospital, Unit of Clinical Pharmacology, Turku (Finland); Solin, Olof [University of Turku, Radiopharmaceutical Chemistry Laboratory, Turku PET Centre, Turku (Finland); Aabo Akademi University, Accelerator Laboratory, Turku PET Centre, Turku (Finland); Rinne, Juha O. [University of Turku and Turku University Hospital, Turku PET Centre, Turku (Finland)


    The aim of this study was to investigate the potential of [{sup 18}F]flutemetamol as a preclinical PET tracer for imaging {beta}-amyloid (A{beta}) deposition by comparing its pharmacokinetics to those of [{sup 11}C]Pittsburgh compound B ([{sup 11}C]PIB) in wild-type Sprague Dawley rats and C57Bl/6N mice. In addition, binding of [{sup 18}F]flutemetamol to A{beta} deposits was studied in the Tg2576 transgenic mouse model of Alzheimer's disease. [{sup 18}F]Flutemetamol biodistribution was evaluated using ex vivo PET methods and in vivo PET imaging in wild-type rats and mice. Metabolism and binding of [{sup 11}C]PIB and [{sup 18}F]flutemetamol to plasma proteins were analysed using thin-layer chromatography and ultrafiltration methods, respectively. Radiation dose estimates were calculated from rat ex vivo biodistribution data. The binding of [{sup 18}F]flutemetamol to A{beta} deposits was also studied using ex vivo and in vitro autoradiography. The location of A{beta} deposits in the brain was determined with thioflavine S staining and immunohistochemistry. The pharmacokinetics of [{sup 18}F]flutemetamol resembled that of [{sup 11}C]PIB in rats and mice. In vivo studies showed that both tracers readily entered the brain, and were excreted via the hepatobiliary pathway in both rats and mice. The metabolism of [{sup 18}F]flutemetamol into radioactive metabolites was faster than that of [{sup 11}C]PIB. [{sup 18}F]Flutemetamol cleared more slowly from the brain than [{sup 11}C]PIB, particularly from white matter, in line with its higher lipophilicity. Effective dose estimates for [{sup 11}C]PIB and [{sup 18}F]flutemetamol were 2.28 and 6.65 {mu}Sv/MBq, respectively. Autoradiographs showed [{sup 18}F]flutemetamol binding to fibrillar A{beta} deposits in the brain of Tg2576 mice. Based on its pharmacokinetic profile, [{sup 18}F]flutemetamol showed potential as a PET tracer for preclinical imaging. It showed good brain uptake and was bound to A{beta} deposits in the

  2. Application of back-propagation artificial neural network and curve estimation in pharmacokinetics of losartan in rabbit. (United States)

    Lin, Bin; Lin, Gaotong; Liu, Xianyun; Ma, Jianshe; Wang, Xianchuan; Lin, Feiyan; Hu, Lufeng


    In order to develop pharmacokinetic model, a well-known multilayer feed-forward algorithm back-propagation artificial neural networks (BP-ANN) was applied to the pharmacokinetics of losartan in rabbit. The plasma concentrations of losartan in twelve rabbits, which were divided into two groups and given losartan 2 mg/kg by intravenous (Iv) and intragastrical (Ig) administration, were determined by LC-MS. The BP-ANN model included one input layer, hidden layers, and one output layer was constructed and compared with curve estimation based on the time-concentration data of losartan. The results showed the BP-ANN model had high goodness of fit index and good coherence (R > 0.99) between forecasted concentration and measured concentration both in Iv and Ig administration. The residuals of each concentrations generated by BP-ANN model were all smaller than Curve estimation. The pharmacokinetic result showed there was no significant difference between measured and simulated pharmacokinetic parameters including AUC(0-t), AUC(0-∞), MRT(0-t), MRT(0-∞), T1/2 V and Cmax (P > 0.05). In conclusion, the BP-ANN model has remarkably accurate predictions ability, which better than Curve estimation, and can be used as a utility tool in pharmacokinetic experiment.

  3. Antihyperalgesic effect of the GABA(A) ligand clobazam in a neuropathic pain model in mice: a pharmacokinetic-pharmacodynamic study. (United States)

    Besson, Marie; Daali, Youssef; Di Lio, Alessandra; Dayer, Pierre; Zeilhofer, Hanns Ulrich; Desmeules, Jules


    Facilitation of spinal GABAergic inhibition with benzodiazepines (BZDs) reverses pain sensitization in animals; however, the use of BZDs in man is limited by their sedative effect. The antihyperalgesic effects of GABA(A) agonists are mediated by GABA(A) receptors containing α2 subunits, whereas sedation is linked to α1 subunit-containing receptors. α2 and α3 selective GABA(A) receptor modulators have been tested in animals but are not yet available for use in human beings. Clobazam is a 1,5-BZD, which exhibits less cognitive side effects than other benzodiazepines. Here, we studied its antihyperalgesic effects in a mouse model of neuropathic pain. Clobazam showed a dose-dependent antihyperalgesic effect in the chronic constriction injury (CCI) model of neuropathic pain, peaking at 1 hr after administration and lasting for 4 hr with no relevant sedation at a dose of 3 mg/kg. At higher doses, the antihyperalgesic effect was stronger, but sedation became significant. The blood and brain kinetics of clobazam were linear over the range of doses tested with a short half-life of the parent compound and a ready penetration of the blood-brain barrier. Clobazam blood concentrations decreased rapidly, falling below the limit of detection at 120 min. after drug application. Its main metabolite, N-desmethyl-clobazam, showed more delayed and prolonged pharmacokinetics, partly explaining why antihyperalgesia persisted when clobazam was no longer detectable in the blood. Considering its therapeutic margin and its pharmacokinetic properties, clobazam would be a valuable compound to assess the role of the GABAergic pathway in pain transmission in human beings.

  4. Integration of pharmacokinetic and NRF2 system biology models to describe reactive oxygen species production and subsequent glutathione depletion in liver microfluidic biochips after flutamide exposure. (United States)

    Leclerc, Eric; Hamon, Jeremy; Legendre, Audrey; Bois, Frederic Y


    We present a systems biology analysis of rat primary hepatocytes response after exposure to 10 μM and 100 μM flutamide in liver microfluidic biochips. We coupled an in vitro pharmacokinetic (PK) model of flutamide to a system biology model of its reactive oxygen species (ROS) production and scavenging by the Nrf2 regulated glutathione production. The PK model was calibrated using data on flutamide kinetics, hydroxyflutamide and glutathione conjugates formation in microfluidic conditions. The parameters of Nrf2-related gene activities and the subsequent glutathione depletion were calibrated using microarray data from our microfluidic experiments and literature information. Following a 10 μM flutamide exposure, the model predicted a recovery time to baseline levels of glutathione (GSH) and ROS in agreement with our experimental observations. At 100 μM, the model predicted that metabolism saturation led to an important accumulation of flutamide in cells, a high ROS production and complete GSH depletion. The high levels of ROS predicted were consistent with the necrotic switch observed by transcriptomics, and the high cell mortality we had experimentally observed. The model predicted a transition between recoverable GSH depletion and deep GSH depletion at about 12.5 μM of flutamide (single perfusion exposure). Our work shows that in vitro biochip experiments can provide supporting information for complex in silico modeling including data from extra cellular and intra cellular levels. We believe that this approach can be an efficient strategy for a global integrated methodology in predictive toxicology.

  5. Calibration and validation of a physiologically based model for soman intoxication in the rat, marmoset, guinea pig and pig. (United States)

    Chen, Kaizhen; Seng, Kok-Yong


    A physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model has been developed for low, medium and high levels of soman intoxication in the rat, marmoset, guinea pig and pig. The primary objective of this model was to describe the pharmacokinetics of soman after intravenous, intramuscular and subcutaneous administration in the rat, marmoset, guinea pig, and pig as well as its subsequent pharmacodynamic effects on blood acetylcholinesterase (AChE) levels, relating dosimetry to physiological response. The reactions modelled in each physiologically realistic compartment are: (1) partitioning of C(±)P(±) soman from the blood into the tissue; (2) inhibition of AChE and carboxylesterase (CaE) by soman; (3) elimination of soman by enzymatic hydrolysis; (4) de novo synthesis and degradation of AChE and CaE; and (5) aging of AChE-soman and CaE-soman complexes. The model was first calibrated for the rat, then extrapolated for validation in the marmoset, guinea pig and pig. Adequate fits to experimental data on the time course of soman pharmacokinetics and AChE inhibition were achieved in the mammalian models. In conclusion, the present model adequately predicts the dose-response relationship resulting from soman intoxication and can potentially be applied to predict soman pharmacokinetics and pharmacodynamics in other species, including human.

  6. [{sup 186}Re]Liposomal doxorubicin (Doxil): in vitro stability, pharmacokinetics, imaging and biodistribution in a head and neck squamous cell carcinoma xenograft model

    Energy Technology Data Exchange (ETDEWEB)

    Soundararajan, Anuradha [Department of Radiology, University of Texas Health Science Center, San Antonio, TX 78229-3900 (United States); Bao Ande [Department of Radiology, University of Texas Health Science Center, San Antonio, TX 78229-3900 (United States); Department of Otolaryngology-Head and Neck Surgery, University of Texas Health Science Center, San Antonio, TX 78229-3900 (United States); Phillips, William T.; Perez, Ricardo [Department of Radiology, University of Texas Health Science Center, San Antonio, TX 78229-3900 (United States); Goins, Beth A. [Department of Radiology, University of Texas Health Science Center, San Antonio, TX 78229-3900 (United States)], E-mail:


    The purpose of this study was to determine the feasibility of radiolabeling liposomal doxorubicin (Doxil) for cancer chemoradionuclide therapy by directly loading the therapeutic radionuclide rhenium-186 ({sup 186}Re) into the liposome interior. The pharmacokinetics, imaging and biodistribution of [{sup 186}Re]Doxil (555 MBq/kg) and control [{sup 186}Re]polyethylene glycol (PEG) liposomes (555 MBq/kg) were determined after intravenous administration in a head and neck cancer xenograft model in nude rats. [{sup 186}Re]Doxil and [{sup 186}Re]PEG liposomes were radiolabeled using [{sup 186}Re]N,N-bis(2-mercaptoethyl)-N',N'-diethylethylenediamine. {sup 186}Re labeling efficiency was 76.1{+-}8.3% with Doxil. The in vitro serum stability of [{sup 186}Re]Doxil at 37{sup o}C was 38.06{+-}12.13% at 24 h. Pharmacokinetic studies revealed that [{sup 186}Re]Doxil had a two-phase blood clearance with half clearance times of 0.8 and 28.2 h. Images acquired over 120 h showed that [{sup 186}Re]Doxil had slow blood clearance, low liver accumulation and increasing spleen accumulation. The biodistribution study at 120 h indicated that the percentage of injected dose (%ID) in the blood and tumor for [{sup 186}Re]Doxil was 20-fold higher than that of [{sup 186}Re]PEG liposomes. The %ID values in the kidney and liver were not significantly different between [{sup 186}Re]Doxil and [{sup 186}Re]PEG liposomes. These results suggest that the long circulation and prolonged bioavailability of [{sup 186}Re]Doxil could potentially deliver high concentrations of both doxorubicin and {sup 186}Re to tumor when encapsulated in the same liposome vehicle.

  7. Pharmacokinetics, absorption, and excretion of radiolabeled revexepride: a Phase I clinical trial using a microtracer and accelerator mass spectrometry-based approach

    Directory of Open Access Journals (Sweden)

    Flach S


    Full Text Available Stephen Flach,1 Marie Croft,2 Jie Ding,1 Ron Budhram,3 Todd Pankratz,2 Mike Pennick,3 Graeme Scarfe,3 Steven Troy,4 Jay Getsy4 1Covance Laboratories Inc., Madison, WI, USA; 2Xceleron Inc., Germantown, MD, USA; 3Shire, Basingstoke, UK; 4Shire, Lexington, MA, USA Purpose: Gastroesophageal reflux disease involves the reflux of gastric and/or duodenal content into the esophagus. Prokinetic therapies, such as the selective 5-hydroxytryptamine receptor 4 agonist revexepride, may aid gastric emptying. This Phase I study evaluated the pharmacokinetics and excretion pathways of [14C]revexepride in healthy individuals using a microtracer approach with accelerator mass spectrometry. Participants and methods: Six healthy men received a single oral dose of 2 mg [14C]revexepride containing ~200 nCi of radioactivity; blood, urine, and fecal samples were collected over a 10-day period. Results: Almost 100% of 14C was recovered: 38.2%±10.3% (mean ± standard deviation was recovered in urine, and 57.3%±0.4% was recovered in feces. Blood cell uptake was low, based on the blood plasma total radioactivity ratio of 0.8. The mean revexepride renal clearance was 8.6 L/h, which was slightly higher than the typical glomerular filtration rate in healthy individuals. Time to reach maximal concentration was 1.75±1.17 hours (mean ± standard deviation. No safety signals were identified. Conclusion: This study demonstrated that revexepride had rapid and moderate-to-good oral absorption. Excretion of radioactivity was completed with significant amounts in feces and urine. Renal clearance slightly exceeded the typical glomerular filtration rate, suggesting the involvement of active transportation in the renal tubules. Keywords: accelerator mass spectrometry, gastroesophageal reflux disease, pharmacokinetics, revexepride, 5-hydroxytryptamine receptor 4 agonist

  8. Population pharmacokinetic modeling of levodopa%左旋多巴中国人群药动学模型的建立

    Institute of Scientific and Technical Information of China (English)

    林玮玮; 王长连; 林翠鸿; 郭仙忠; 黄品芳; 刘亦伟; 吴钢


    目的:建立中国人群左旋多巴/苄丝肼复合制剂中左旋多巴的群体药动学模型.方法:前瞻性收集服用多巴丝肼片的帕金森病(PD)门诊患者稳态谷浓度97例102个血样和健康志愿者13例153个密集血样,高效液相色谱-电化学(HPLC-ECD)法测定左旋多巴(LD)血药浓度.应用NONMEM软件进行群体药动学数据分析.Bootstrap重复抽样用于模型的内部验证.另收集20例PI)患者22个血样点作为验证组进行模型外部验证,计算最简模型和最终模型对验证组的平均预测误差(MPE)和平均绝对误差(MAE)对模型进行外部验证.结果:数据采用—房室模型拟合,年龄(AGE)对LD清除率有显著影响,性别(SEX)、体质量(WT)、给药剂量(TAMT)、合并用药不影响LD的药动学参数.LD的基础模型为:CL(CL/F)(L·h 1)=18.2×EXP[ ETA(1)],V(V/F)(L)=48.4,ka(h-1)=2.13×EXP[ETA(2)];最终模型为:CL(CL/F)(L·h-1)=17.9×(55/AGE)0.59×(EXP[ETA(1)],V(V/F)(L)=47.5,ka(h-1)=2.14×EXP[ETA(2)].CL、V、ka的群体典型值分别为17.9 L·h-1、47.5 L、2.14h-1.Bootstrap重复抽样显示所建立的最终模型稳定、可靠,最终模型对验证组的MPE和MAE较最简模型有显著改善,显示模型有效,且有一定代表性.结论:根据患者的生理用药资料,结合上述模型,可估算个体药动学参数,为临床个体化给药提供参考.%OBJECTIVE To establish a population pharmacokinetic model for levodopa(LD) in levodopa-benserazide compound preparatioa METHODS 102 cases of steady state serum concentration data and 153 dense serum concentration data were collected respectively from 97 PD outpatients and 13 healthy volunteers receiving levodopa-benserazide compound preparation orally. The plasma concentrations of levodopa(LD) was determined by HPLC-ECD method, Population pharmacokinetic data analysis was performed using NONMEM software. The Bootstrap assay was applied for internal validation. 22 blood samples from 20 patients receiving

  9. A Comparative Oncology Study of Iniparib Defines Its Pharmacokinetic Profile and Biological Activity in a Naturally-Occurring Canine Cancer Model.

    Directory of Open Access Journals (Sweden)

    Corey Saba

    Full Text Available Development of iniparib as an anti-cancer agent was hindered in part by lingering questions regarding its mechanism of action, the activity of its metabolites, and their potential accumulation in tumors. Due to strong similarities in metabolism of iniparib between humans and dogs, a veterinary clinical trial in pet dogs with spontaneous cancers was designed to answer specific questions pertaining to pharmacokinetic exposures and tolerability of iniparib. Dogs were treated with iniparib alone and in combination with carboplatin chemotherapy. Iniparib doses ranged between 10-70 mg/kg intravenously (IV. Plasma, tumor and normal tissue samples were collected before and at various time points scheduled after exposure for pharmacokinetic and biologic analysis. The primary endpoints included characterization of dose-limiting toxicities (DLT and determination of the drug exposures that could be achieved in both normal and tumor tissues. Nineteen dogs were treated. DLT included fever, anorexia, diarrhea, neutropenia, and thrombocytopenia; most effects were attributable to carboplatin based on the timing of adverse event onset. The maximum tolerated dose (MTD of iniparib was not identified. Moderate to high variability in plasma exposure was noted for iniparib and all metabolites between animals. When quantifiable, iniparib and metabolite plasma:tumor ratios were < 0.088 and <1.7, respectively. In this study, iniparib was well tolerated as a single agent and in combination with carboplatin over a range of doses. However, clinically relevant concentrations of the parent drug and selected metabolites were not detectable in canine tumor tissues at any studied dose, thus eliminating expectations for clinical responses in dogs or humans. Negative clinical trials in humans, and the uncertainties of its mechanism of action, ultimately led to the decision to stop clinical development of the drug. Nevertheless, the questions that can be asked and answered within

  10. Use of population pharmacokinetic modeling and Monte Carlo simulation to capture individual animal variability in the prediction of flunixin withdrawal times in cattle. (United States)

    Wu, H; Baynes, R E; Leavens, T; Tell, L A; Riviere, J E


    The objective of this study was to develop a population pharmacokinetic (PK) model and predict tissue residues and the withdrawal interval (WDI) of flunixin in cattle. Data were pooled from published PK studies in which flunixin was administered through various dosage regimens to diverse populations of cattle. A set of liver data used to establish the regulatory label withdrawal time (WDT) also were used in this study. Compartmental models with first-order absorption and elimination were fitted to plasma and liver concentrations by a population PK modeling approach. Monte Carlo simulations were performed with the population mean and variabilities of PK parameters to predict liver concentrations of flunixin. The PK of flunixin was described best by a 3-compartment model with an extra liver compartment. The WDI estimated in this study with liver data only was the same as the label WDT. However, a longer WDI was estimated when both plasma and liver data were included in the population PK model. This study questions the use of small groups of healthy animals to determine WDTs for drugs intended for administration to large diverse populations. This may warrant a reevaluation of the current procedure for establishing WDT to prevent violative residues of flunixin.

  11. Optimisation of sampling windows design for population pharmacokinetic experiments. (United States)

    Ogungbenro, Kayode; Aarons, Leon


    This paper describes an approach for optimising sampling windows for population pharmacokinetic experiments. Sampling windows designs are more practical in late phase drug development where patients are enrolled in many centres and in out-patient clinic settings. Collection of samples under the uncontrolled environment at these centres at fixed times may be problematic and can result in uninformative data. Population pharmacokinetic sampling windows design provides an opportunity to control when samples are collected by allowing some flexibility and yet provide satisfactory parameter estimation. This approach uses information obtained from previous experiments about the model and parameter estimates to optimise sampling windows for population pharmacokinetic experiments within a space of admissible sampling windows sequences. The optimisation is based on a continuous design and in addition to sampling windows the structure of the population design in terms of the proportion of subjects in elementary designs, number of elementary designs in the population design and number of sampling windows per elementary design is also optimised. The results obtained showed that optimal sampling windows designs obtained using this approach are very efficient for estimating population PK parameters and provide greater flexibility in terms of when samples are collected. The results obtained also showed that the generalized equivalence theorem holds for this approach.

  12. A systems approach for tumor pharmacokinetics.

    Directory of Open Access Journals (Sweden)

    Greg Michael Thurber

    Full Text Available Recent advances in genome inspired target discovery, small molecule screens, development of biological and nanotechnology have led to the introduction of a myriad of new differently sized agents into the clinic. The differences in small and large molecule delivery are becoming increasingly important in combination therapies as well as the use of drugs that modify the physiology of tumors such as anti-angiogenic treatment. The complexity of targeting has led to the development of mathematical models to facilitate understanding, but unfortunately, these studies are often only applicable to a particular molecule, making pharmacokinetic comparisons difficult. Here we develop and describe a framework for categorizing primary pharmacokinetics of drugs in tumors. For modeling purposes, we define drugs not by their mechanism of action but rather their rate-limiting step of delivery. Our simulations account for variations in perfusion, vascularization, interstitial transport, and non-linear local binding and metabolism. Based on a comparison of the fundamental rates determining uptake, drugs were classified into four categories depending on whether uptake is limited by blood flow, extravasation, interstitial diffusion, or local binding and metabolism. Simulations comparing small molecule versus macromolecular drugs show a sharp difference in distribution, which has implications for multi-drug therapies. The tissue-level distribution differs widely in tumors for small molecules versus macromolecular biologic drugs, and this should be considered in the design of agents and treatments. An example using antibodies in mouse xenografts illustrates the different in vivo behavior. This type of transport analysis can be used to aid in model development, experimental data analysis, and imaging and therapeutic agent design.

  13. Limited-sampling strategy models for estimating the pharmacokinetic parameters of 4-methylaminoantipyrine, an active metabolite of dipyrone

    Directory of Open Access Journals (Sweden)

    Suarez-Kurtz G.


    Full Text Available Bioanalytical data from a bioequivalence study were used to develop limited-sampling strategy (LSS models for estimating the area under the plasma concentration versus time curve (AUC and the peak plasma concentration (Cmax of 4-methylaminoantipyrine (MAA, an active metabolite of dipyrone. Twelve healthy adult male volunteers received single 600 mg oral doses of dipyrone in two formulations at a 7-day interval in a randomized, crossover protocol. Plasma concentrations of MAA (N = 336, measured by HPLC, were used to develop LSS models. Linear regression analysis and a "jack-knife" validation procedure revealed that the AUC0-¥ and the Cmax of MAA can be accurately predicted (R²>0.95, bias 0.85 of the AUC0-¥ or Cmax for the other formulation. LSS models based on three sampling points (1.5, 4 and 24 h, but using different coefficients for AUC0-¥ and Cmax, predicted the individual values of both parameters for the enrolled volunteers (R²>0.88, bias = -0.65 and -0.37%, precision = 4.3 and 7.4% as well as for plasma concentration data sets generated by simulation (R²>0.88, bias = -1.9 and 8.5%, precision = 5.2 and 8.7%. Bioequivalence assessment of the dipyrone formulations based on the 90% confidence interval of log-transformed AUC0-¥ and Cmax provided similar results when either the best-estimated or the LSS-derived metrics were used.

  14. Model Based Definition (United States)

    Rowe, Sidney E.


    In September 2007, the Engineering Directorate at the Marshall Space Flight Center (MSFC) created the Design System Focus Team (DSFT). MSFC was responsible for the in-house design and development of the Ares 1 Upper Stage and the Engineering Directorate was preparing to deploy a new electronic Configuration Management and Data Management System with the Design Data Management System (DDMS) based upon a Commercial Off The Shelf (COTS) Product Data Management (PDM) System. The DSFT was to establish standardized CAD practices and a new data life cycle for design data. Of special interest here, the design teams were to implement Model Based Definition (MBD) in support of the Upper Stage manufacturing contract. It is noted that this MBD does use partially dimensioned drawings for auxiliary information to the model. The design data lifecycle implemented several new release states to be used prior to formal release that allowed the models to move through a flow of progressive maturity. The DSFT identified some 17 Lessons Learned as outcomes of the standards development, pathfinder deployments and initial application to the Upper Stage design completion. Some of the high value examples are reviewed.

  15. Advances and challenges in PBPK modeling--Analysis of factors contributing to the oral absorption of atazanavir, a poorly soluble weak base. (United States)

    Berlin, Mark; Ruff, Aaron; Kesisoglou, Filippos; Xu, Wei; Wang, Michael Hong; Dressman, Jennifer B


    Many active pharmaceutical ingredients (APIs) exhibit a highly variable pharmacokinetic (PK) profile. This behavior may be attributable to pre-absorptive, absorptive and/or post-absorptive factors. Pre-absorptive factors are those related to dosage form disintegration, drug dissolution, supersaturation, precipitation and gastric emptying. Absorptive factors are involved with drug absorption and efflux mechanisms, while drug distribution and clearance are post-absorptive factors. This study aimed to investigate the relative influence of the aforementioned parameters on the pharmacokinetic profile of atazanavir, a poorly soluble weakly basic compound with highly variable pharmacokinetics. The pre-absorptive behavior of the drug was examined by applying biorelevant in vitro tests to reflect upper gastrointestinal behavior in the fasted and fed states. The in vitro results were implemented, along with permeability and post-absorptive data obtained from the literature, into physiologically based pharmacokinetic (PBPK) models. Sensitivity analysis of the resulting plasma profiles revealed that the pharmacokinetic profile of atazanavir is affected by an array of factors rather than one standout factor. According to the in silico model, pre-absorptive and absorptive factors had less impact on atazanavir bioavailability compared to post-absorptive parameters, although active drug efflux and extraction appear to account for the sub-proportional pharmacokinetic response to lower atazanavir doses in the fasted state. From the PBPK models it was concluded that further enhancement of the formulation would bring little improvement in the pharmacokinetic response to atazanavir. This approach may prove useful in assessing the potential benefits of formulation enhancement of other existing drug products on the market.

  16. Population pharmacokinetics of ciprofloxacin in neonates and young infants less than three months of age. (United States)

    Zhao, Wei; Hill, Helen; Le Guellec, Chantal; Neal, Tim; Mahoney, Sarah; Paulus, Stephane; Castellan, Charlotte; Kassai, Behrouz; van den Anker, Johannes N; Kearns, Gregory L; Turner, Mark A; Jacqz-Aigrain, Evelyne


    Ciprofloxacin is used in neonates with suspected or documented Gram-negative serious infections. Currently, its use is off-label partly because of lack of pharmacokinetic studies. Within the FP7 EU project TINN (Treat Infection in NeoNates), our aim was to evaluate the population pharmacokinetics of ciprofloxacin in neonates and young infants <3 months of age and define the appropriate dose in order to optimize ciprofloxacin treatment in this vulnerable population. Blood samples were collected from neonates treated with ciprofloxacin and concentrations were quantified by high-pressure liquid chromatography-mass spectrometry. Population pharmacokinetic analysis was performed using NONMEM software. The data from 60 newborn infants (postmenstrual age [PMA] range, 24.9 to 47.9 weeks) were available for population pharmacokinetic analysis. A two-compartment model with first-order elimination showed the best fit with the data. A covariate analysis identified that gestational age, postnatal age, current weight, serum creatinine concentration, and use of inotropes had a significant impact on ciprofloxacin pharmacokinetics. Monte Carlo simulation demonstrated that 90% of hypothetical newborns with a PMA of <34 weeks treated with 7.5 mg/kg twice daily and 84% of newborns with a PMA ≥34 weeks and young infants receiving 12.5 mg/kg twice daily would reach the AUC/MIC target of 125, using the standard EUCAST MIC susceptibility breakpoint of 0.5 mg/liter. The associated risks of overdose for the proposed dosing regimen were <8%. The population pharmacokinetics of ciprofloxacin was evaluated in neonates and young infants <3 months old, and a dosing regimen was established based on simulation.

  17. Clinical pharmacokinetics of melatonin

    DEFF Research Database (Denmark)

    Harpsøe, Nathja Groth; Andersen, Lars Peter Holst; Gögenur, Ismail


    was performed in PubMed and Embase databases. The pharmacokinetic variables included maximal plasma/serum concentration (Cmax), time to maximal plasma/serum concentration (Tmax), elimination half-life (T1/2), area-under-the-curve plasma/serum concentrations (AUC), clearance (Cl), volume of distribution (VD......) and 1602 L (4 mg, oral). Bioavailability of oral melatonin ranged from 9 to 33%. Pharmacokinetics was affected by age, caffeine, smoking, oral contraceptives, feeding status, and fluvoxamine. Critically ill patients displayed accelerated absorption and compromised elimination. CONCLUSIONS: Despite...

  18. Lecithin and PLGA-based self-assembled nanocomposite, Lecithmer: preparation, characterization, and pharmacokinetic/pharmacodynamic evaluation. (United States)

    Varghese, Seby Elsy; Fariya, Mayur K; Rajawat, Gopal Singh; Steiniger, Frank; Fahr, Alfred; Nagarsenker, Mangal S


    The present study investigates the drug delivery potential of polymer lipid hybrid nanocomposites (Lecithmer®) composed of poly(D,L-lactide-co-glycolide (PLGA) and soya lecithin. Core-shell structure of Lecithmer was evident from cryo-TEM images. Daunorubicin (DNR) and lornoxicam (LNX)-incorporated Lecithmer nanocomposites were evaluated for anticancer and anti-inflammatory activity. DNR- and LNX-loaded Lecithmer had mean particle size of ∼335 and ∼282.7 nm, respectively. Lecithmer formulated with different cationic lipids resulted in lower particle size (∼120 nm) and positive zeta potential. Entrapment efficiency of DNR and LNX was 93.16 and 88.59 %, respectively. In vitro release of DNR from Lecithmer was slower compared to PLGA nanoparticles. DNR release from Lecithmer was significantly higher at pH 5.5 (80.96 %) as compared to pH 7.4 (55.95 %), providing advantage for selective tumor therapy. Similarly, sustained release of LNX (30 % in 10 h) was observed at pH 7.4. DNR in Lecithmer showed superior cytotoxicity on human erythroleukemic K562 cells. Pharmacokinetic study in Wistar rats with i.v. administered DNR-loaded Lecithmer showed higher volume of distribution, lower elimination rate constant, and longer half-life (81.68 L, 0.3535 h(-1), 1.96 h) as compared to DNR solution (57.46 L, 0.4237 h(-1), 1.635 h). Pharmacodynamic evaluation of orally administered LNX-loaded Lecithmer showed superior anti-inflammatory activity with maximum inhibition of 81.2 % vis-à-vis 53.57 % in case of LNX suspension. In light of these results, Lecithmer can be envisaged as a promising nanosystem for parenteral as well as oral drug delivery.

  19. Azithromycin maintenance therapy in patients with cystic fibrosis : A dose advice based on a review of pharmacokinetics, efficacy, and side effects

    NARCIS (Netherlands)

    Wilms, Erik B.; Touw, Daniel J.; Heijerman, Harry G.M.; Van Der Ent, Cornelis K.


    Azithromycin maintenance therapy results in improvement of respiratory function in patients with cystic fibrosis (CF). In azithromycin maintenance therapy, several dosing schemes are applied. In this review, we combine current knowledge about azithromycin pharmacokinetics with the dosing schedules u

  20. Pharmacokinetics of Acetaminophen in Hind Limbs Unloaded Mice: A Model System Simulating the Effects of Low Gravity on Astronauts in Space (United States)

    Peterson, Amanda; Risin, Semyon A.; Ramesh, Govindarajan T.; Dasgupta, Amitava; Risin, Diana


    The pharmacokinetics (PK) of medications administered to astronauts could be altered by the conditions in Space. Low gravity and free floating (and associated hemodynamic changes) could affect the absorption, distribution, metabolism and excretion of the drugs. Knowledge of these alterations is essential for adjusting the dosage and the regimen of drug administration in astronauts. Acquiring of such knowledge has inherent difficulties due to limited opportunities for experimenting in Space. One of the approaches is to use model systems that simulate some of the Space conditions on Earth. In this study we used hind limbs unloaded mice (HLU) to investigate the possible changes in PK of acetaminophen, a widely used analgesic with high probability of use by astronauts. The HLU is recognized as an appropriate model for simulating the effects of low gravity on hemodynamic parameters. Mice were tail suspended (n = 24) for 24-96 hours prior to introduction of acetaminophen (150 - 300 mg/kg). The drug (in aqueous solution containing 10% ethyl alcohol by volume) was given orally by a gavage procedure and after the administration of acetaminophen mice were additionally suspended for 30 min, 1 and 2 hours. Control mice (n = 24) received the same dose of acetaminophen and were kept freely all the time. Blood specimens were obtained either from retroorbital venous sinuses or from heart. Acetaminophen concentration was measured in plasma by the fluorescent polarization immunoassay and the AxSYM analyzer (Abbott Laboratories). In control mice peak acetaminophen concentration was achieved at 30 min. By 1 hour the concentration decreased to less than 50% of the peak level and at 2 hours the drug was almost undetectable in the serum. HLU for 24 hours significantly altered the acetaminophen pharmacokinetic: at 30 min the acetaminophen concentrations were significantly (both statistically and medically significant) lower than in control mice. The concentrations also reduced less

  1. A Population Pharmacokinetic Modeling Approach Shows that Serum Penicillin G Concentrations Are Below Inhibitory Concentrations by Two Weeks after Benzathine Penicillin G Injection in the Majority of Young Adults (United States)


    liter is the suggested minimum protective concentration of penicillin G against group A streptococcus . Note that the majority of measured concen- trations... pneumoniae , Streptococcus pyogenes and Haemophilus influenzae collected from patients across the USA, in 2001-2002, as part of the PROTEKT US study. J...Naval Health Research Center A Population Pharmacokinetic Modeling Approach Shows that Serum Penicillin G Concentrations Are Below Inhibitory

  2. Dermal pharmacokinetics of microemulsion formulations determined by in vivo microdialysis

    DEFF Research Database (Denmark)

    Kreilgaard, Mads


    To investigate the potential of improving dermal drug delivery of hydrophilic and lipophilic substances by formulation in microemulsion vehicles and to establish a reliable pharmacokinetic model to analyze cutaneous microdialysis data....

  3. Prediction and monitoring of the response to chemoradiotherapy in oral squamous cell carcinomas using a pharmacokinetic analysis based on the dynamic contrast-enhanced MR imaging findings

    Energy Technology Data Exchange (ETDEWEB)

    Chikui, Toru; Kawazu, Toshiyuki; Yoshiura, Kazunori [Kyushu University, Department of Oral and Maxillofacial Radiology, Faculty of Dental Science, Fukuoka (Japan); Kawano, Shintaro [Kyushu University, Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Fukuoka (Japan); Hatakenaka, Masamitsu [Kyushu University, Department of Clinical Radiology, Graduate School of Medical Sciences, Fukuoka (Japan); Kyushu University, Radiology Center, Kyushu University Hospital, Fukuoka (Japan); Koga, Syouzou; Ohga, Masahiro [Kyushu University, Radiology Center, Kyushu University Hospital, Fukuoka (Japan); Matsuo, Yoshio; Sunami, Syunya [Kyushu University, Department of Clinical Radiology, Graduate School of Medical Sciences, Fukuoka (Japan); Sugiura, Tsuyoshi [Kyushu University, Department of Maxillofacial Surgery, Kyushu University Hospital, Fukuoka (Japan); Shioyama, Yoshiyuki [Kyushu University, Department of Heavy Particle Therapy and Radiation Oncology, Graduate School of Medical Sciences, Fukuoka (Japan); Obara, Makoto [Philips Electronics Japan, Ltd 2-13-37, Konan Minato-ku, Tokyo (Japan)


    To evaluate whether a pharmacokinetic analysis is useful for both predicting and monitoring the response to chemoradiotherapy (CRT) in oral cancer. Patients with oral squamous cell carcinoma treated with preoperative CRT and surgery were enrolled. They underwent dynamic contrast-enhanced MRI before (n = 23), and after CRT (n = 20). We estimated four parameters: arrival time of contrast medium (TA), exchange rate constant from the extracellular extravascular space (EES) to plasma (k{sub ep}), elimination of contrast medium from the central compartment (k{sub el}) and an amplitude scaling constant (AH) using the Brix model. The histological evaluation of the effects of CRT was performed according to Ohboshi and Shimosato's classification. We analysed the correlation between the parameters and the histological evaluation. The pre-CRT AH between the responders and non-responders was significantly different (P = 0.046), however, the three parameters (TA, K{sub ep}, K{sub el}) were not significantly different among the groups (P = 0.76, P = 0.60, P = 0.09). As AH decreased, the tumour response improved. The change in the AH between the pre- and post-CRT of responders was significantly higher than that of non-responders (P = 0.043). The AH, which is affected by the ratio of the EES, was an important parameter for predicting and monitoring the tumour response to CRT. (orig.)

  4. Cluster Based Text Classification Model

    DEFF Research Database (Denmark)

    Nizamani, Sarwat; Memon, Nasrullah; Wiil, Uffe Kock


    We propose a cluster based classification model for suspicious email detection and other text classification tasks. The text classification tasks comprise many training examples that require a complex classification model. Using clusters for classification makes the model simpler and increases...

  5. Inferring biochemical reaction pathways: the case of the gemcitabine pharmacokinetics

    Directory of Open Access Journals (Sweden)

    Lecca Paola


    Full Text Available Abstract Background The representation of a biochemical system as a network is the precursor of any mathematical model of the processes driving the dynamics of that system. Pharmacokinetics uses mathematical models to describe the interactions between drug, and drug metabolites and targets and through the simulation of these models predicts drug levels and/or dynamic behaviors of drug entities in the body. Therefore, the development of computational techniques for inferring the interaction network of the drug entities and its kinetic parameters from observational data is raising great interest in the scientific community of pharmacologists. In fact, the network inference is a set of mathematical procedures deducing the structure of a model from the experimental data associated to the nodes of the network of interactions. In this paper, we deal with the inference of a pharmacokinetic network from the concentrations of the drug and its metabolites observed at discrete time points. Results The method of network inference presented in this paper is inspired by the theory of time-lagged correlation inference with regard to the deduction of the interaction network, and on a maximum likelihood approach with regard to the estimation of the kinetic parameters of the network. Both network inference and parameter estimation have been designed specifically to identify systems of biotransformations, at the biochemical level, from noisy time-resolved experimental data. We use our inference method to deduce the metabolic pathway of the gemcitabine. The inputs to our inference algorithm are the experimental time series of the concentration of gemcitabine and its metabolites. The output is the set of reactions of the metabolic network of the gemcitabine. Conclusions Time-lagged correlation based inference pairs up to a probabilistic model of parameter inference from metabolites time series allows the identification of the microscopic pharmacokinetics and

  6. Evaluation of pharmacokinetic/pharmacodynamic relationships of PD-0162819, a biotin carboxylase inhibitor representing a new class of antibacterial compounds, using in vitro infection models. (United States)

    Ogden, Adam; Kuhn, Michael; Dority, Michael; Buist, Susan; Mehrens, Shawn; Zhu, Tong; Xiao, Deqing; Miller, J Richard; Hanna, Debra


    The present study investigated the pharmacokinetic/pharmacodynamic (PK/PD) relationships of a prototype biotin carboxylase (BC) inhibitor, PD-0162819, against Haemophilus influenzae 3113 in static concentration time-kill (SCTK) and one-compartment chemostat in vitro infection models. H. influenzae 3113 was exposed to PD-0162819 concentrations of 0.5 to 16× the MIC (MIC = 0.125 μg/ml) and area-under-the-curve (AUC)/MIC ratios of 1 to 1,100 in SCTK and chemostat experiments, respectively. Serial samples were collected over 24 h. For efficacy driver analysis, a sigmoid maximum-effect (E(max)) model was fitted to the relationship between bacterial density changes over 24 h and corresponding PK/PD indices. A semimechanistic PK/PD model describing the time course of bacterial growth and death was developed. The AUC/MIC ratio best explained efficacy (r(2) = 0.95) compared to the peak drug concentration (C(max))/MIC ratio (r(2) = 0.76) and time above the MIC (T>MIC) (r(2) = 0.88). Static effects and 99.9% killing were achieved at AUC/MIC values of 500 and 600, respectively. For time course analysis, the net bacterial growth rate constant, maximum bacterial density, and maximum kill rate constant were similar in SCTK and chemostat studies, but PD-0162819 was more potent in SCTK than in the chemostat (50% effective concentration [EC(50)] = 0.046 versus 0.34 μg/ml). In conclusion, basic PK/PD relationships for PD-0162819 were established using in vitro dynamic systems. Although the bacterial growth parameters and maximum drug effects were similar in SCTK and the chemostat system, PD-0162819 appeared to be more potent in SCTK, illustrating the importance of understanding the differences in preclinical models. Additional studies are needed to determine the in vivo relevance of these results.

  7. Population stochastic modelling (PSM)--an R package for mixed-effects models based on stochastic differential equations. (United States)

    Klim, Søren; Mortensen, Stig Bousgaard; Kristensen, Niels Rode; Overgaard, Rune Viig; Madsen, Henrik


    The extension from ordinary to stochastic differential equations (SDEs) in pharmacokinetic and pharmacodynamic (PK/PD) modelling is an emerging field and has been motivated in a number of articles [N.R. Kristensen, H. Madsen, S.H. Ingwersen, Using stochastic differential equations for PK/PD model development, J. Pharmacokinet. Pharmacodyn. 32 (February(1)) (2005) 109-141; C.W. Tornøe, R.V. Overgaard, H. Agersø, H.A. Nielsen, H. Madsen, E.N. Jonsson, Stochastic differential equations in NONMEM: implementation, application, and comparison with ordinary differential equations, Pharm. Res. 22 (August(8)) (2005) 1247-1258; R.V. Overgaard, N. Jonsson, C.W. Tornøe, H. Madsen, Non-linear mixed-effects models with stochastic differential equations: implementation of an estimation algorithm, J. Pharmacokinet. Pharmacodyn. 32 (February(1)) (2005) 85-107; U. Picchini, S. Ditlevsen, A. De Gaetano, Maximum likelihood estimation of a time-inhomogeneous stochastic differential model of glucose dynamics, Math. Med. Biol. 25 (June(2)) (2008) 141-155]. PK/PD models are traditionally based ordinary differential equations (ODEs) with an observation link that incorporates noise. This state-space formulation only allows for observation noise and not for system noise. Extending to SDEs allows for a Wiener noise component in the system equations. This additional noise component enables handling of autocorrelated residuals originating from natural variation or systematic model error. Autocorrelated residuals are often partly ignored in PK/PD modelling although violating the hypothesis for many standard statistical tests. This article presents a package for the statistical program R that is able to handle SDEs in a mixed-effects setting. The estimation method implemented is the FOCE(1) approximation to the population likelihood which is generated from the individual likelihoods that are approximated using the Extended Kalman Filter's one-step predictions.

  8. Methods for Addressing Uncertainty and Variability to Characterize Potential Health Risk from Trichloroethylene-Contaminated Ground Water at Beale Air Force Base in California:Integration of Uncertainty and Variability in Pharmacokinetics and Dose-Response

    Energy Technology Data Exchange (ETDEWEB)

    Bogen, K T


    Traditional estimates of health risk are typically inflated, particularly if cancer is the dominant endpoint and there is fundamental uncertainty as to mechanism(s) of action. Risk is more realistically characterized if it accounts for joint uncertainty and interindividual variability within a systematic probabilistic framework to integrate the joint effects on risk of distributed parameters of all (linear as well as nonlinear) risk-extrapolation models involved. Such a framework was used to characterize risks to potential future residents posed by trichloroethylene (TCE) in ground water at an inactive landfill site on Beale Air Force Base in California. Variability and uncertainty were addressed in exposure-route-specific estimates of applied dose, in pharmacokinetically based estimates of route-specific metabolized fractions of absorbed TCE, and in corresponding biologically effective doses estimated under a genotoxic/linear (MA{sub G}) vs. a cytotoxic/nonlinear (MA{sub c}) mechanistic assumption for TCE-induced cancer. Increased risk conditional on effective dose was estimated under MA{sub G} based on seven rodent-bioassay data sets, and under MA{sub c} based on mouse hepatotoxicity data. Mean and upper-bound estimates of combined risk calculated by the unified approach were <10{sup -6} and 10{sup -4}, respectively, while corresponding estimates based on traditional deterministic methods were >10{sup -5} and 10{sup -4}, respectively. It was estimated that no TCE-related harm is likely to occur due to any plausible residential exposure scenario involving the site. The systematic probabilistic framework illustrated is particularly suited to characterizing risks that involve uncertain and/or diverse mechanisms of action.

  9. Methods for Addressing Uncertainty and Variability to Characterize Potential Health Risk From Trichloroethylene-Contaminated Ground Water Beale Air Force Base in California: Integration of Uncertainty and Variability in Pharmacokinetics and Dose-Response

    Energy Technology Data Exchange (ETDEWEB)

    Bogen, K.T.


    Traditional estimates of health risk are typically inflated, particularly if cancer is the dominant endpoint and there is fundamental uncertainty as to mechanism(s) of action. Risk is more realistically characterized if it accounts for joint uncertainty and interindividual variability after applying a unified probabilistic approach to the distributed parameters of all (linear as well as nonlinear) risk-extrapolation models involved. Such an approach was applied to characterize risks to potential future residents posed by trichloroethylene (TCE) in ground water at an inactive landfill site on Beale Air Force Base in California. Variability and uncertainty were addressed in exposure-route-specific estimates of applied dose, in pharmacokinetically based estimates of route-specific metabolized fractions of absorbed TCE, and in corresponding biologically effective doses estimated under a genotoxic/linear (MA{sub g}) vs. a cytotoxic/nonlinear (MA{sub c}) mechanistic assumption for TCE-induced cancer. Increased risk conditional on effective dose was estimated under MA{sub G} based on seven rodent-bioassay data sets, and under MA, based on mouse hepatotoxicity data. Mean and upper-bound estimates of combined risk calculated by the unified approach were <10{sup -6} and <10{sup -4}, respectively, while corresponding estimates based on traditional deterministic methods were >10{sup -5} and >10{sup -4}, respectively. It was estimated that no TCE-related harm is likely occur due any plausible residential exposure scenario involving the site. The unified approach illustrated is particularly suited to characterizing risks that involve uncertain and/or diverse mechanisms of action.

  10. Use of a Microsoft Excel based add-in program to calculate plasma sinistrin clearance by a two-compartment model analysis in dogs. (United States)

    Steinbach, Sarah M L; Sturgess, Christopher P; Dunning, Mark D; Neiger, Reto


    Assessment of renal function by means of plasma clearance of a suitable marker has become standard procedure for estimation of glomerular filtration rate (GFR). Sinistrin, a polyfructan solely cleared by the kidney, is often used for this purpose. Pharmacokinetic modeling using adequate software is necessary to calculate disappearance rate and half-life of sinistrin. The purpose of this study was to describe the use of a Microsoft excel based add-in program to calculate plasma sinistrin clearance, as well as additional pharmacokinetic parameters such as transfer rates (k), half-life (t1/2) and volume of distribution (Vss) for sinistrin in dogs with varying degrees of renal function.

  11. Pharmacokinetics of fexofenadine

    DEFF Research Database (Denmark)

    Lappin, Graham; Shishikura, Yoko; Jochemsen, Roeline;


    ). Fexofenadine was administered to 6 healthy male volunteers in a three way cross-over design. A microdose (100microg) of (14)C-drug was administered orally (period 1) and intravenously by 30min infusion (period 2). In period 3 an intravenous tracer dose (100microg) of (14)C-drug was administered simultaneously......A human pharmacokinetic study was performed to assess the ability of a microdose to predict the pharmacokinetics of a therapeutic dose of fexofenadine and to determine its absolute oral bioavailability. Fexofenadine was chosen to represent an unmetabolized transporter substrate (P-gP and OATP...... with an oral unlabelled therapeutic dose (120mg). Plasma was collected from all 3 periods and analysed for both total (14)C content and parent drug by accelerator mass spectrometry (AMS). For period 3, plasma samples were also analysed using HPLC-fluorescence to determine total drug concentration. Urine...

  12. Antifungal pharmacokinetics and pharmacodynamics. (United States)

    Lepak, Alexander J; Andes, David R


    Successful treatment of infectious diseases requires choice of the most suitable antimicrobial agent, comprising consideration of drug pharmacokinetics (PK), including penetration into infection site, pathogen susceptibility, optimal route of drug administration, drug dose, frequency of administration, duration of therapy, and drug toxicity. Antimicrobial pharmacokinetic/pharmacodynamic (PK/PD) studies consider these variables and have been useful in drug development, optimizing dosing regimens, determining susceptibility breakpoints, and limiting toxicity of antifungal therapy. Here the concepts of antifungal PK/PD studies are reviewed, with emphasis on methodology and application. The initial sections of this review focus on principles and methodology. Then the pharmacodynamics of each major antifungal drug class (polyenes, flucytosine, azoles, and echinocandins) is discussed. Finally, the review discusses novel areas of pharmacodynamic investigation in the study and application of combination therapy.

  13. Pharmacokinetics of levodopa. (United States)

    Contin, Manuela; Martinelli, Paolo


    This paper reviews the clinically relevant determinants of levodopa peripheral pharmacokinetics and main observed changes in the levodopa concentration-effect relationship with Parkinson's disease (PD) progression. Available clinically practical strategies to optimise levodopa pharmacokinetics and pharmacodynamics are briefly discussed. Levodopa shows particular pharmacokinetics including an extensive presystemic metabolism, overcome by the combined use of extracerebral inhibitors of the enzyme L: -amino acid decarboxylase and rapid absorption in the proximal small bowel by a saturable facilitated transport system shared with other large neutral amino acids. Drug transport from plasma to the brain is mediated by the same carriers operating in the intestinal mucosa. The main strategies to assure reproducibility of both intestinal absorption and delivery to the brain, and the clinical effect include standardization of levodopa dosing with respect to meal times and a controlled dietary protein intake. Levodopa plasma half-life is very short, resulting in marked plasma drug concentration fluctuations which are matched, as the disease progresses, to swings in the therapeutic response ("wearing-off" phenomena). "Wearing-off" phenomena can also be associated, at the more advanced disease stages, with a "negative", both parkinsonism-exacerbating and dyskinetic effect of levodopa at low, subtherapeutic plasma concentrations. Dyskinesias may also be related to high-levodopa, excessive plasma concentrations. Recognition of the different levodopa toxic response patterns can be difficult on a clinical basis alone and simultaneous monitoring of the levodopa concentration-effect relationship may prove useful to disclose the underlying mechanism and in planning the correct management. Clinically practical strategies to optimise levodopa pharmacokinetics, and possibly its therapeutic response, include liquid drug solutions, controlled release formulations and the use of inhibitors

  14. Pharmacokinetics of rilmenidine

    Energy Technology Data Exchange (ETDEWEB)

    Genissel, P.; Bromet, N. (Biopharmacie Servier, Orleans (France))


    Rilmenidine is a novel antihypertensive agent related to alpha 2-adrenoceptor agonist, used in the treatment of mild or moderate hypertension at the oral dose of 1 mg once a day or 1 mg twice a day. The pharmacokinetic parameters were investigated after single or repeated administration in healthy subjects, using labeled and unlabeled compounds. Rilmenidine was rapidly and extensively absorbed, with an absolute bioavailability close to one and a time to peak plasma concentration of two hours. Rilmenidine was not subjected to presystemic metabolism. Distribution was independent of the free fraction since rilmenidine was weakly bound to plasma proteins (less than 10 percent). The volume of distribution was approximately 5 liters/kg (315 liters). Elimination was rapid, with a total body plasma clearance of approximately 450 ml/minute and an elimination half-life of approximately eight hours. Renal excretion was the major elimination process (two thirds of the total clearance); the parent drug in urine accounted for about 65 percent of the dose administered. Metabolism was very poor; few metabolites were found in urine and no metabolites were detected in plasma. Linear pharmacokinetics was demonstrated for rilmenidine from 0.5 to 2 mg; at 3 mg, a slight deviation from linearity was observed. In repeated administration, the linearity with dose of the pharmacokinetics of rilmenidine was confirmed.

  15. Pharmacokinetic Modeling of Trivalent and Hexavalent Chromium Based on Ingestion and Inhalation of Soluble Chromium Compounds. (United States)


    be largely Cr(III) although some Cr(VI) exposure probably also occurs. Stainless-steel welders are exposed to nickel as well as to chromium compounds...welders are equivocal with respect to involvement of chromium, particularly since nickel in some chemical forms is an established lung carcinogen (Stern...microglobulin (Lindberg and Vesterberg, 1983), retinol-binding protein (Franchini and Mutti , 1988), B-glucuronidase ( Mutti et al., 1979), and kidney brush border

  16. Comparative Kinetics and Distribution to Target Tissues of Organophosphates Using Physiologically - Based Pharmacokinetic Modeling (United States)


    diagnosis . It is now being reported that over 300,000 American troops have been exposed to sub-lethal doses of the gas. Some of the chronic long term...chronic fatigue, muscle weakness and fibromyalgia (Kennedy, 2007). Acute verses chronic The near term effects of high exposure to chemical warfare

  17. Quantitative Evaluation of Dichloroacetic Acid Kinetics in Human -- A Physiologically-Based Pharmacokinetic Modeling Investigation (United States)


    use include mild liver dysfunction, transient central neuropathy , peripheral neuropathy and hypocalcemia. The clinical effects are generally...Naviaux, R.K., McGowan, K.A., Levine, F., Nyhan, W.L., Loupis-Geller, A., Haas, R.H., 2004. Chronic treatment of mitochondrial disease patients with...Momoi, M.Y., 2004. Dichloroacetate treatment for mitochondrial cytopathy: long-term effects in MELAS. Brain Devel. 26, 453-458. Schultz, I.R

  18. Physiologically Based Pharmacokinetic (PBPK) Modeling of Interstrain Variability in Trichloroethylene Metabolism in the Mouse (United States)

    Background: Quantitative estimation of toxicokinetic variability in the human population is a persistent challenge in risk assessment of environmental chemicals. Traditionally, inter-individual differences in the population are accounted for by default assumptions or, in rare cas...

  19. Model Construct Based Enterprise Model Architecture and Its Modeling Approach

    Institute of Scientific and Technical Information of China (English)


    In order to support enterprise integration, a kind of model construct based enterprise model architecture and its modeling approach are studied in this paper. First, the structural makeup and internal relationships of enterprise model architecture are discussed. Then, the concept of reusable model construct (MC) which belongs to the control view and can help to derive other views is proposed. The modeling approach based on model construct consists of three steps, reference model architecture synthesis, enterprise model customization, system design and implementation. According to MC based modeling approach a case study with the background of one-kind-product machinery manufacturing enterprises is illustrated. It is shown that proposal model construct based enterprise model architecture and modeling approach are practical and efficient.

  20. HMM-based Trust Model

    DEFF Research Database (Denmark)

    ElSalamouny, Ehab; Nielsen, Mogens; Sassone, Vladimiro


    with their dynamic behaviour. Using Hidden Markov Models (HMMs) for both modelling and approximating the behaviours of principals, we introduce the HMM-based trust model as a new approach to evaluating trust in systems exhibiting dynamic behaviour. This model avoids the fixed behaviour assumption which is considered...... the major limitation of existing Beta trust model. We show the consistency of the HMM-based trust model and contrast it against the well known Beta trust model with the decay principle in terms of the estimation precision....

  1. Model-based Software Engineering

    DEFF Research Database (Denmark)


    The vision of model-based software engineering is to make models the main focus of software development and to automatically generate software from these models. Part of that idea works already today. But, there are still difficulties when it comes to behaviour. Actually, there is no lack in models...

  2. Model-Based Reasoning (United States)

    Ifenthaler, Dirk; Seel, Norbert M.


    In this paper, there will be a particular focus on mental models and their application to inductive reasoning within the realm of instruction. A basic assumption of this study is the observation that the construction of mental models and related reasoning is a slowly developing capability of cognitive systems that emerges effectively with proper…

  3. 万古霉素群体药动学模型在神经外科重症患者中的应用%Application of a population pharmacokinetic model for vancomycin in patients with severe neurosurgical disease

    Institute of Scientific and Technical Information of China (English)

    王嵘; 朱怀军; 黄玉杰; 罗雪梅; 尹华云; 乔小云


    10 .9 mg/L (range from 1 .6 to 49 .1 mg/L) .The predicted trough level of vancomycin based on the population pharmacokinetic model was significantly correlated to the actual value(r=0 .857 ,P<0 .001) .The mean absolute percentage error was 0 .407 9 . The confidence interval was 9 .36‐14 .07 for the predicted values ,and 8 .92‐14 .32 for the actual values .Conclusions The pharmacokinetic model is valid and useful for planning intravenous dose of vancomycin in patients with severe neurosurgical disease .Large error (about 30% ) was observed in estimation of body weight due to coma .Reduced renal function following contrast agent and/or diuretic drug has an impact on the predicted results . The accuracy of prediction can be increased to nearly 70% after adjusting the covariates .

  4. Principles of models based engineering

    Energy Technology Data Exchange (ETDEWEB)

    Dolin, R.M.; Hefele, J.


    This report describes a Models Based Engineering (MBE) philosophy and implementation strategy that has been developed at Los Alamos National Laboratory`s Center for Advanced Engineering Technology. A major theme in this discussion is that models based engineering is an information management technology enabling the development of information driven engineering. Unlike other information management technologies, models based engineering encompasses the breadth of engineering information, from design intent through product definition to consumer application.

  5. Element-Based Computational Model

    Directory of Open Access Journals (Sweden)

    Conrad Mueller


    Full Text Available A variation on the data-flow model is proposed to use for developing parallel architectures. While the model is a data driven model it has significant differences to the data-flow model. The proposed model has an evaluation cycleof processing elements (encapsulated data that is similar to the instruction cycle of the von Neumann model. The elements contain the information required to process them. The model is inherently parallel. An emulation of the model has been implemented. The objective of this paper is to motivate support for taking the research further. Using matrix multiplication as a case study, the element/data-flow based model is compared with the instruction-based model. This is done using complexity analysis followed by empirical testing to verify this analysis. The positive results are given as motivation for the research to be taken to the next stage - that is, implementing the model using FPGAs.