WorldWideScience

Sample records for bioequivalence recommendations active

  1. 78 FR 52777 - Draft Guidance for Industry on Bioequivalence Recommendations for Risperidone Injection...

    Science.gov (United States)

    2013-08-26

    ... on Bioequivalence Recommendations for Risperidone Injection; Availability AGENCY: Food and Drug... provides specific recommendations on the design of bioequivalence (BE) studies to support abbreviated new... availability of a draft guidance for industry entitled ``Bioequivalence Recommendations for Specific...

  2. 75 FR 33311 - Guidance for Industry on Bioequivalence Recommendations for Specific Products; Availability

    Science.gov (United States)

    2010-06-11

    ... Bioequivalence Recommendations for Specific Products; Availability AGENCY: Food and Drug Administration, HHS... guidance for industry entitled ``Bioequivalence Recommendations for Specific Products.'' This guidance... bioequivalence (BE) studies to support abbreviated new drug applications (ANDAs). Under this process,...

  3. 78 FR 19271 - Draft Guidance for Industry on Bioequivalence Recommendations for Metronidazole Vaginal Gel...

    Science.gov (United States)

    2013-03-29

    ... HUMAN SERVICES Food and Drug Administration Draft Guidance for Industry on Bioequivalence... guidance for industry entitled ``Bioequivalence Recommendations for Metronidazole Vaginal Gel.'' The guidance provides specific recommendations on the design of bioequivalence (BE) studies to...

  4. 77 FR 58399 - Draft Guidance for Industry on Bioequivalence Recommendations for Pentosan Polysulfate Sodium...

    Science.gov (United States)

    2012-09-20

    ... HUMAN SERVICES Food and Drug Administration Draft Guidance for Industry on Bioequivalence... guidance for industry entitled ``Bioequivalence Recommendations for Pentosan Polysulfate Sodium.'' The recommendations provide specific guidance on the design of bioequivalence (BE) studies to support abbreviated...

  5. 78 FR 70953 - Draft Guidance for Industry on Bioequivalence Recommendations for Fluticasone Propionate...

    Science.gov (United States)

    2013-11-27

    ... HUMAN SERVICES Food and Drug Administration Draft Guidance for Industry on Bioequivalence... Industry on Bioequivalence Recommendations for Fluticasone Propionate; Salmeterol Xinafoate'', published in... for Industry on Bioequivalence Recommendations for Fluticasone Propionate; Salmeterol...

  6. 78 FR 46965 - Draft Guidance for Industry on Bioequivalence Recommendations for Mesalamine Rectal Suppositories...

    Science.gov (United States)

    2013-08-02

    ... HUMAN SERVICES Food and Drug Administration Draft Guidance for Industry on Bioequivalence... guidance for industry entitled ``Bioequivalence Recommendations for Mesalamine.'' The recommendations provide specific guidance on the design of bioequivalence (BE) studies to support abbreviated new...

  7. 77 FR 7585 - Draft Guidance for Industry on Bioequivalence Recommendations for Rifaximin Tablets; Availability

    Science.gov (United States)

    2012-02-13

    ... HUMAN SERVICES Food and Drug Administration Draft Guidance for Industry on Bioequivalence... industry entitled ``Bioequivalence Recommendations for Rifaximin,'' one for the 200- milligram (mg... specific guidance on the design of bioequivalence (BE) studies to support abbreviated new drug...

  8. 78 FR 55263 - Draft Guidance for Industry on Bioequivalence Recommendations for Fluticasone Propionate...

    Science.gov (United States)

    2013-09-10

    ... HUMAN SERVICES Food and Drug Administration Draft Guidance for Industry on Bioequivalence... availability of a draft guidance for industry entitled ``Bioequivalence Recommendations for Fluticasone... bioequivalence (BE) studies to support abbreviated new drug applications (ANDAs) for fluticasone...

  9. 77 FR 7586 - Draft Guidance for Industry on Bioequivalence Recommendation for Nitroglycerin Metered Spray...

    Science.gov (United States)

    2012-02-13

    ... HUMAN SERVICES Food and Drug Administration Draft Guidance for Industry on Bioequivalence Recommendation... Administration (FDA) is announcing the availability of two draft guidances for industry entitled ``Bioequivalence... of bioequivalence (BE) studies to support abbreviated new drug applications (ANDAs) for...

  10. 78 FR 73200 - Draft Guidance for Industry on Bioequivalence Recommendations for Paliperidone Palmitate Extended...

    Science.gov (United States)

    2013-12-05

    ... HUMAN SERVICES Food and Drug Administration Draft Guidance for Industry on Bioequivalence... the availability of a revised draft guidance for industry entitled ``Bioequivalence Recommendations... bioequivalence (BE) studies to support abbreviated new drug applications (ANDAs) for paliperidone...

  11. 77 FR 10535 - Final Guidances for Industry Describing Product-Specific Bioequivalence Recommendations...

    Science.gov (United States)

    2012-02-22

    ... Bioequivalence Recommendations; Availability AGENCY: Food and Drug Administration, HHS. ACTION: Notice. SUMMARY... bioequivalence (BE) recommendations. The recommendations provide product-specific guidance on the design of BE... FR 33311), FDA announced the availability of a guidance for industry,...

  12. An Update of the Brazilian Regulatory Bioequivalence Recommendations for Approval of Generic Topical Dermatological Drug Products.

    Science.gov (United States)

    Soares, Kelen Carine Costa; Santos, Gustavo Mendes Lima; Gelfuso, Guilherme M; Gratieri, Tais

    2015-11-01

    This note aims to clarify the Brazilian regulatory bioequivalence recommendations for approval of generic topical dermatological drug products, since the legal framework of the "Brazilian Health Surveillance Agency" (ANVISA) is only available in Portuguese. According to Resolutions RE n. 1170 (December 19th 2006) and RDC n. 37 (August 3rd 2011) in Brazil, only in vitro studies are required for registration of generic topical dermatological drug products. Current Regulatory Agenda of ANVISA, which contains possible future resolutions to be revised over 2015-2016, includes a discussion on biowaiver requirements and on possible in vitro and in vivo comparability tests for these products.

  13. 77 FR 74669 - Draft and Revised Draft Guidances for Industry Describing Product-Specific Bioequivalence...

    Science.gov (United States)

    2012-12-17

    ... Product-Specific Bioequivalence Recommendations; Availability AGENCY: Food and Drug Administration, HHS... additional draft and revised draft product-specific bioequivalence (BE) recommendations. The recommendations... industry entitled ``Bioequivalence Recommendations for Specific Products,'' which explained the...

  14. 78 FR 37230 - Draft and Revised Draft Guidances for Industry Describing Product-Specific Bioequivalence...

    Science.gov (United States)

    2013-06-20

    ... Product-Specific Bioequivalence Recommendations; Availability AGENCY: Food and Drug Administration, HHS... additional draft and revised draft product-specific bioequivalence (BE) recommendations. The recommendations... industry entitled ``Bioequivalence Recommendations for Specific Products,'' which explained the...

  15. 77 FR 3777 - Draft and Revised Draft Guidances for Industry Describing Product-Specific Bioequivalence...

    Science.gov (United States)

    2012-01-25

    ... Product-Specific Bioequivalence Recommendations; Availability AGENCY: Food and Drug Administration, HHS... additional draft and revised draft product-specific bioequivalence (BE) recommendations. The recommendations... guidance for industry entitled ``Bioequivalence Recommendations for Specific Products,'' explaining...

  16. 78 FR 66745 - Draft and Revised Draft Guidances for Industry Describing Product-Specific Bioequivalence...

    Science.gov (United States)

    2013-11-06

    ... Product-Specific Bioequivalence Recommendations; Availability AGENCY: Food and Drug Administration, HHS... additional draft and revised draft product-specific bioequivalence (BE) recommendations. The recommendations... industry entitled ``Bioequivalence Recommendations for Specific Products,'' which explained the...

  17. 77 FR 10536 - Draft and Revised Draft Guidances for Industry Describing Product-Specific Bioequivalence...

    Science.gov (United States)

    2012-02-22

    ... Product-Specific Bioequivalence Recommendations; Availability AGENCY: Food and Drug Administration, HHS... additional draft and revised draft product-specific bioequivalence (BE) recommendations. The recommendations... guidance for industry entitled ``Bioequivalence Recommendations for Specific Products,'' which...

  18. 78 FR 20925 - Draft and Revised Draft Guidances for Industry Describing Product-Specific Bioequivalence...

    Science.gov (United States)

    2013-04-08

    ... Product-Specific Bioequivalence Recommendations; Availability AGENCY: Food and Drug Administration, HHS... additional draft and revised draft product-specific bioequivalence (BE) recommendations. The recommendations... guidance for industry entitled ``Bioequivalence Recommendations for Specific Products,'' which...

  19. 77 FR 35688 - Draft and Revised Draft Guidances for Industry Describing Product-Specific Bioequivalence...

    Science.gov (United States)

    2012-06-14

    ... Product-Specific Bioequivalence Recommendations; Availability AGENCY: Food and Drug Administration, HHS... additional draft and revised draft product-specific bioequivalence (BE) recommendations. The recommendations... guidance for industry entitled ``Bioequivalence Recommendations for Specific Products,'' which...

  20. Clinical, Pharmacokinetic, and In Vitro Studies to Support Bioequivalence of Ophthalmic Drug Products.

    Science.gov (United States)

    Choi, Stephanie H; Lionberger, Robert A

    2016-07-01

    For ophthalmic drug products, the determination of bioequivalence can be challenging, as drug concentrations at the site of action cannot always be measured. The FDA has recommended a variety of studies that can be used to demonstrate bioequivalence for different ophthalmic drug products. Product-specific bioequivalence recommendations for 28 ophthalmic products have been posted on FDA's website as of May 2016, outlining the specific tests which should be performed to demonstrate bioequivalence. The type of study that can be used to demonstrate bioequivalence depends on the drug product's active pharmaceutical ingredient(s), dosage form, indication, site of action, mechanism of action, and scientific understanding of drug release/drug availability and drug product characteristics. This article outlines the FDA's current guidance on studies to demonstrate bioequivalence through clinical endpoint studies, pharmacokinetic studies, and in vitro studies for generic ophthalmic drug products.

  1. 77 FR 18827 - Draft Guidance for Industry on Bioequivalence Recommendations for Iron Sucrose Injection...

    Science.gov (United States)

    2012-03-28

    ... Recommendations for Iron Sucrose Injection; Availability AGENCY: Food and Drug Administration, HHS. ACTION: Notice...) for iron sucrose injection. DATES: Although you can comment on any guidance at any time (see 21 CFR 10... recommendations. This notice announces the availability of draft BE recommendations for iron sucrose......

  2. 78 FR 66743 - Draft Guidance for Industry on Bioequivalence Recommendations for Iron Sucrose; Availability

    Science.gov (United States)

    2013-11-06

    ... iron sucrose injection. The draft guidance is a revised version of a previously issued draft guidance... sucrose injection (Draft Iron Sucrose Injection BE Recommendations of 2013). Venofer (iron sucrose... the Agency's recommendations for BE studies to support ANDAs for iron sucrose injection (Draft......

  3. 77 FR 66621 - Draft Guidance for Industry on Bioequivalence Recommendation for Lenalidomide Capsules; Availability

    Science.gov (United States)

    2012-11-06

    ... availability of revised draft BE recommendations for lenalidomide capsules. Revlimid (lenalidomide capsules.... Revlimid is designated as the reference listed drug, and therefore any ANDAs for generic lenalidomide capsules must demonstrate BE to the Revlimid prior to approval. There are no approved ANDAs for...

  4. Bioequivalence of Two Intravenous Artesunate Products with Its Active Metabolite Following Single and Multiple Injections

    Directory of Open Access Journals (Sweden)

    Qigui Li

    2011-01-01

    Full Text Available In animal species and humans, artesunate (AS undergoes extensive and complex biotransformation to an active metabolite, dihydroartemisinin (DHA. The bioequivalence of two intravenous AS pharmaceutical products with 5% NaHCO3 (China Formulation or 0.3 M PBS (WRAIR Formulation was determined in rats in a two-formulation, two-period, and two-sequence crossover experimental design. Following single and multiple intravenous administrations, a series of blood samples was collected by using an automated blood sampler and drug concentrations were analyzed by LC-MS/MS. The 90% CI of the difference between the two intravenous formulations was contained within 80–125% of the geometric mean of pharmacokinetic parameters for AS and DHA in all animals dosed. Hematological effects were studied on days 1 and 3 after the final dosing, and a rapidly reversible hematological toxicity (significant reductions in reticulocyte levels was seen in the peripheral blood of the rats treated with each formulation. The results showed that bioequivalence with the parent compound and active metabolite was fulfilled in the 82.3–117.7% ranges of all parameters (AUC0–t, Cmax, concentration average and degree of fluctuation in the two-period and two-sequence crossover studies following single and repeated intravenous injections. For the metabolite, the equivalence was satisfied in most pharmacokinetic parameters tested due to the variability in the hydrolysis rate of AS to DHA. The WRAIR formulation of AS was considered to be bioequivalent to the Chinese formulation at steady-state according to the total drug exposure, in terms of both parent drug and active metabolite, rapidly reversal in reticulocyte decline, and extension of single and multiple administrations. Therefore, the parent drug and active metabolites should play similar important roles in the determination of efficacy and safety of the drug.

  5. Mining and representing recommendations in actively evolving recommender systems

    DEFF Research Database (Denmark)

    Assent, Ira

    2010-01-01

    Recommender systems provide an automatic means of filtering out interesting items, usually based on past similarity of user ratings. In previous work, we have suggested a model that allows users to actively build a recommender network. Users express trust, obtain transparency, and grow (anonymous......) recommender connections. In this work, we propose mining such active systems to generate easily understandable representations of the recommender network. Users may review these representations to provide active feedback. This approach further enhances the quality of recommendations, especially as topics...... of interest change over time. Most notably, it extends the amount of control users have over the model that the recommender network builds of their interests....

  6. Bioequivalence and in vitro antimicrobial activity between generic and brand-name levofloxacin.

    Science.gov (United States)

    Sun, Hsin-Yun; Liao, Hsiao-Wei; Sheng, Meng-Huei; Tai, Hui-Min; Kuo, Ching-Hua; Sheng, Wang-Huei

    2016-07-01

    Generic agents play a crucial role in reducing the cost of medical care in many countries. However, the therapeutic equivalence remains a great concern. Our study aims to assess the in vitro antimicrobial activity and bioequivalence between generic and brand-name levofloxacin. Enantiomeric purity test, dissolution test, and in vitro antimicrobial susceptibility against seven clinically important pathogens by the agar dilution method were employed to assess the similarity between four generic products and brand-name levofloxacin (Daiichi Sankyo). All the generic and brand-name levofloxacin passed enantiomeric purity test. The results of dissolution tests were not similar among the generic products and the brand-name levofloxacin. Compared with the generic products, the brand-name levofloxacin had the smallest mean variations (-25% to 13%) with reference standard (United States Pharmacopeia levofloxacin Reference Standards). Variations were observed particularly in dissolution profiles and in vitro activity between generic products and brand-name levofloxacin.

  7. International guidelines for bioequivalence of systemically available orally administered generic drug products: a survey of similarities and differences.

    Science.gov (United States)

    Davit, Barbara; Braddy, April C; Conner, Dale P; Yu, Lawrence X

    2013-10-01

    The objective of this article is to discuss the similarities and differences among bioequivalence approaches used by international regulatory authorities when reviewing applications for marketing new generic drug products which are systemically active and intended for oral administration. We focused on the 13 jurisdictions and organizations participating in the International Generic Drug Regulators Pilot. These are Australia, Brazil, Canada, China, Chinese Taipei, the European Medicines Association, Japan, Mexico, Singapore, South Korea, Switzerland, the USA, and the World Health Organization. We began with a comparison of how the various jurisdictions and organizations define a generic product and its corresponding reference product. We then compared the following bioequivalence approaches: recommended bioequivalence study designs, method of pharmacokinetic calculations and bioequivalence acceptance limits, recommendations for modifying bioequivalence study designs and limits for highly variable drugs and narrow therapeutic index drugs, provisions for waiving bioequivalence study requirements (granting biowaivers), and implementation of the Biopharmaceutics Classification System. We observed that, overall, there are more similarities than differences in bioequivalence approaches among the regulatory authorities surveyed.

  8. Bioequivalence studies for levothyroxine.

    Science.gov (United States)

    Bolton, Sanford

    2005-03-30

    The Food and Drug Administration (FDA) Guidance for Bioavailability and Bioequivalence Studies for Levothyroxine has been challenged by companies that manufacture brand-name products. Their contention is that the current guidance does not adequately address the endogenous background levels of the drug, and that the ratios of the PK parameters, a basis for approval of equivalence, are not assessed correctly. In particular, they conclude that products that have a potency differing by 12.5% cannot be differentiated using the present guideline and criteria for acceptance of bioequivalence. They claim that such a difference can be a public health hazard because of the perception among practitioners that levothyroxine is a narrow therapeutic index drug. This article describes the procedure recommended in the current Guidance for Levothyroxine and demonstrates that the methods recommended are adequate and will accept products that are therapeutically equivalent. To date, no generic product accepted as equivalent using FDA Guidances has been shown to result in a safety and efficacy profile different from its brand counterpart.

  9. PLATELET INHIBITORY ACTIVITY AND PHARAMCOKINETCS OF PRASUGREL A NOVEL THIENOPYRIDINE P2Y12 INHIBITOR: A SINGLE DOSE CROSS OVER BIOEQUIVALENCE STUDY IN HEALTHY HUMAN VOLUNTEERS

    Directory of Open Access Journals (Sweden)

    Sahu Nimain Charan

    2013-08-01

    Full Text Available To compare the bioavailability and bioequivalence of two prasugrel formulations one as a test and the other was the standard. The study was performed according to a randomized, open label, balanced, two-treatment, two-period, two-sequence, single-dose, crossover under fasting period with minimum of seven days wash-out period and was evaluated in 20(+ 2 stand by subjects. To analyse pharmacokinetic properties, the blood samples were drawn taken up to 36 h after dosing. Plasma concentration of prasugrel was determined using liquid chromatography – tandem mass spectrometry method. Pharmacokinetic parameters tmax, Cmax, AUC0-t, AUC0-, t1/2 and λz (Kel were tested for bioequivalence after log-transformation of data and non-parametric evaluation was done for ratios of tmax. The point estimates and 90 % confidence intervals (CI for AUC0-t, AUC0-∞, and Cmax for active metabolite (R-138727 were 95.82-105.18, 96.00-104.69 and 90.80-103.20 respectively. These results indicated that the two formulations of Prasugrel were bioequivalent in case of active metabolite (R-138727, thus may be prescribed interchangeably.

  10. Bioavailability and Bioequivalence in Drug Development.

    Science.gov (United States)

    Chow, Shein-Chung

    2014-01-01

    Bioavailability is referred to as the extent and rate to which the active drug ingredient or active moiety from the drug product is absorbed and becomes available at the site of drug action. The relative bioavailability in terms of the rate and extent of drug absorption is considered predictive of clinical outcomes. In 1984, the United States Food and Drug Administration (FDA) was authorized to approve generic drug products under the Drug Price Competition and Patent Term Restoration Act based on evidence of average bioequivalence in drug absorption through the conduct of bioavailability and bioequivalence studies. This article provides an overview (from an American point of view) of definition of bioavailability and bioequivalence, Fundamental Bioequivalence Assumption, regulatory requirements, and process for bioequivalence assessment of generic drug products. Basic considerations including criteria, study design, power analysis for sample size determination, and the conduct of bioequivalence trial, and statistical methods are provided. Practical issues such as one size-fits-all criterion, drug interchangeability and scaled average criteria for assessment of highly variable drug products are also discussed.

  11. [Applying multilevel models in evaluation of bioequivalence (I)].

    Science.gov (United States)

    Liu, Qiao-lan; Shen, Zhuo-zhi; Chen, Feng; Li, Xiao-song; Yang, Min

    2009-12-01

    This study aims to explore the application value of multilevel models for bioequivalence evaluation. Using a real example of 2 x 4 cross-over experimental design in evaluating bioequivalence of antihypertensive drug, this paper explores complex variance components corresponding to criteria statistics in existing methods recommended by FDA but obtained in multilevel models analysis. Results are compared with those from FDA standard Method of Moments, specifically on the feasibility and applicability of multilevel models in directly assessing the bioequivalence (ABE), the population bioequivalence (PBE) and the individual bioequivalence (IBE). When measuring ln (AUC), results from all variance components of the test and reference groups such as total variance (sigma(TT)(2) and sigma(TR)(2)), between-subject variance (sigma(BT)(2) and sigma(BR)(2)) and within-subject variance (sigma(WT)(2) and sigma(WR)(2)) estimated by simple 2-level models are very close to those that using the FDA Method of Moments. In practice, bioequivalence evaluation can be carried out directly by multilevel models, or by FDA criteria, based on variance components estimated from multilevel models. Both approaches produce consistent results. Multilevel models can be used to evaluate bioequivalence in cross-over test design. Compared to FDA methods, this one is more flexible in decomposing total variance into sub components in order to evaluate the ABE, PBE and IBE. Multilevel model provides a new way into the practice of bioequivalence evaluation.

  12. Interactions between active pharmaceutical ingredients and excipients affecting bioavailability: impact on bioequivalence.

    Science.gov (United States)

    García-Arieta, Alfredo

    2014-12-18

    The aim of the present paper is to illustrate the impact that excipients may have on the bioavailability of drugs and to review existing US-FDA, WHO and EMA regulatory guidelines on this topic. The first examples illustrate that small amounts of sorbitol (7, 50 or 60mg) affect the bioavailability of risperidone, a class I drug, oral solution, in contrast to what is stated in the US-FDA guidance. Another example suggests, in contrast to what is stated in the US-FDA BCS biowaivers guideline, that a small amount of sodium lauryl sulphate (SLS) (3.64mg) affects the bioavailability of risperidone tablets, although the reference product also includes SLS in an amount within the normal range for that type of dosage form. These factors are considered sufficient to ensure that excipients do not affect bioavailability according to the WHO guideline. The alternative criterion, defined in the WHO guideline and used in the FIP BCS biowaivers monographs, that asserts that excipients present in generic products of the ICH countries do not affect bioavailability if used in normal amounts, is shown to be incorrect with an example of alendronate (a class III drug) tablets, where 4mg of SLS increases bioavailability more than 5-fold, although a generic product in the USA contains SLS. Finally, another example illustrates that a 2mg difference in SLS may affect bioavailability of a generic product of a class II drug, even if SLS is contained in the comparator product, and in all cases its amount was within the normal range. Therefore, waivers of in vivo bioequivalence studies (e.g., BCS biowaivers, waivers of certain dosage forms in solution at the time of administration and variations in the excipient composition) should be assessed more cautiously.

  13. Bioavailability & Bioequivalence Studies ? Pharmaceutical Importance

    OpenAIRE

    Pratibha Muntha

    2015-01-01

    Pharmacokinetics has now emerged as an important part of drug development especially in the development of new drugs. The combined studies of Pharmacodynamics and pharmacokinetics present a thorough understanding on how the drug affects the body and how the body affects the drug.Bioavailability is the study of the rate and extent to which the active ingredient is absorbed from a dosage form and it is available at the required action site. Bioequivalence is that the...

  14. Comparative bioequivalence study of meloxicam drugs

    Directory of Open Access Journals (Sweden)

    Ekut Karieva

    2011-03-01

    Full Text Available The governments of many countries strongly support the production and clinical use of generic medicinal products which are “copies” of patented drugs and can be marked at lower cost. At present time bioequivalence testing is regarded as a useful methodology to perform comparisons among different products containing the same active ingredient. This report presents the results of comparative bioequivalence study of three meloxicam formulations: brand-drug “Melbek” with tablets and capsules of meloxicam developed at the Tashkent Pharmaceutical Institute. The results obtained confirm the bioequivalence of the studied drugs, which indicate about scientifically based approach to the selection of excipients and technological process in the development of the above generic drugs.

  15. The bootstrap in bioequivalence studies.

    Science.gov (United States)

    Pigeot, Iris; Hauschke, Dieter; Shao, Jun

    2011-11-01

    In 1997, the U.S. Food and Drug Administration (FDA) suggested in its draft guidance the use of new concepts for assessing the bioequivalence of two drug formulations, namely, the concepts of population and individual bioequivalence. Aggregate moment-based and probability-based measures of bioequivalence were introduced to derive criteria in order to decide whether two formulations should be regarded as bioequivalent or not. The statistical decision may be made via a nonparametric bootstrap percentile interval. In this article, we review the history of population and individual bioequivalence with special focus on the role of the bootstrap in this context.

  16. Complement activation as a bioequivalence issue relevant to the development of generic liposomes and other nanoparticulate drugs

    NARCIS (Netherlands)

    Szebeni, Janos; Storm, G

    2015-01-01

    Liposomes are known to activate the complement (C) system, which can lead in vivo to a hypersensitivity syndrome called C activation-related pseudoallergy (CARPA). CARPA has been getting increasing attention as a safety risk of i.v. therapy with liposomes, whose testing is now recommended in bioequi

  17. Bioequivalence of generic drugs.

    Science.gov (United States)

    Andrade, Chittaranjan

    2015-09-01

    Generic drugs are bioequivalent to the original brand; this is a prerequisite for marketing approval. It is theoretically possible that one generic drug may overestimate the pharmacokinetic (PK) parameters of the original and another generic may underestimate these PK parameters; in consequence, these 2 generics may not be bioequivalent between themselves. The result could be loss of efficacy or development of drug-related adverse effects if these generics are interchanged in stable patients. In a recent study involving 292 indirect comparisons of generic formulations of 9 different drugs, mathematical modeling showed that in most cases (87.0% for maximum concentration, 90.1% for area under the curve, and 80.5% for both) generic drugs are bioequivalent to each other. These reassuring findings notwithstanding, prudence dictates that, in stable patients, generic drugs should be interchanged only if there is a good reason for it. This is because bioequivalent brands of drugs may differ in their excipient content, and this can result in variations in safety profiles.

  18. Highly sensitive and selective high-performance liquid chromatography method for bioequivalence study of cefpodoxime proxetil in rabbit plasma via fluorescence labeling of its active metabolite.

    Science.gov (United States)

    Ahmed, Sameh; Abdel-Wadood, Hanaa M; Mohamed, Niveen A

    2013-09-01

    Cefpodoxime proxetil (CFP), a broad-spectrum third-generation cephalosporin, has been used most widely in the treatment of respiratory and urinary tract infections. For bioequivalence study of CFP in rabbit plasma, it was necessary to develop a highly sensitive and selective high-performance liquid chromatographic (HPLC) method with fluorescence (FL) detection. The pre-column labeling of cefpodoxime acid (CFA) (active metabolite) with an efficient benzofurazan type fluorogenic reagent, 4-N,N-dimethyl aminosulfonyl-7-fluoro-2,1,3-benzoxadiazole (DBD-F) was carried out in the present study in 100mM borate buffer (pH=8.5) at 50°C for 15min. The obtained fluorescent products were separated on C18 column with an isocratic elution of the mobile phase, which consists of 10mM phosphate buffer (pH=3.5)/CH3CN (70:30, v/v). The fluorescent product (DBD-CFA) was detected fluorimetrically at 556nm with an excitation wavelength of 430nm. Cefotaxime sodium was used as internal standard. The method was validated according to the requirements of US-FDA guidelines. The correlation coefficient of 0.999 was obtained in the concentration ranges of 10-1000ngmL(-1). The limits of detection and quantification (S/N=3) were 3 and 10ngmL(-1), respectively. Plasma CFA levels were successfully determined in rabbit with satisfactory precision and accuracy. The proposed HPLC-FL method was successfully applied to study bioequivalence in rabbits for two formulations of different brands contained CFP (prodrug) in a randomized, two-way, single-dose, crossover study and all pharmacokinetic parameters for the two formulations were assessed.

  19. Recommendations

    Science.gov (United States)

    Brazelton, G. Blue; Renn, Kristen A.; Stewart, Dafina-Lazarus

    2015-01-01

    In this chapter, the editors provide a summary of the information shared in this sourcebook about the success of students who have minoritized identities of sexuality or gender and offer recommendations for policy, practice, and further research.

  20. Recommendations of activity restriction in high-risk pregnancy scenarios

    DEFF Research Database (Denmark)

    Bendix, Jane; Hegaard, Hanne Kristine; Bergholt, Thomas;

    2015-01-01

    obstetricians and midwives prescribe activity restriction in most high-risk pregnancies. The degree of activity restriction and the presumed effect vary between clinicians. This may reflect different attitudes and lack of guidelines based on clinical studies of a possible benefit of activity restriction....... to the obstetricians, the midwives also reported that they expected the recommendation to be more effective. Most midwives and obstetricians reported that they thought strict activity restriction was associated with severe or moderate adverse effect, and recommended antithrombotic prophylaxis. Conclusions: Danish......Abstract Aims: To describe specific recommendations of activity restriction, place of care, expected beneficial and adverse effects, and recommended antithrombotic prophylaxis in nine clinical scenarios. Methods: A national survey. All members of the Danish Society of Obstetrics and Gynaecology...

  1. Bioequivalence evaluation of epinephrine autoinjectors with attention to rapid delivery.

    Science.gov (United States)

    Sclar, David Alexander

    2013-01-01

    Timely and proper injection of epinephrine is critical to prevent serious consequences relating to anaphylaxis. In a recent bioavailability study comparing epinephrine delivery from the Auvi-Q™ and EpiPen(®) epinephrine autoinjectors, the Auvi-Q failed to meet the bioequivalence threshold when using partial area under the curve (AUC) analyses based on zero to Tmax recommended for highly variable drugs such as epinephrine. Peak plasma epinephrine concentrations for the EpiPen occurred 10 minutes (median Tmax) after dosing, while peak concentrations for the Auvi-Q occurred 20 minutes after dosing. Though bioequivalence may be concluded for Cmax, AUCinf, and AUC0-t, for fast-acting therapeutics used to treat life-threatening conditions, such as epinephrine, additional pharmacokinetic parameters such as AUC zero to Tmax may be important to evaluate when assessing bioequivalence.

  2. Analysis of foreign physical activity recommendations and guidelines for schools

    Directory of Open Access Journals (Sweden)

    Jan Pavelka

    2014-06-01

    Full Text Available Background:An adequate level of physical activity is an important part of children's lifestyle. The school environment plays a significant role in the area of interventions and strategies aiming to increase the level of physical activity in children. Objectives: The aim of this study is to analyse foreign recommendations leading to an increased level of physical activity in children and young people in Czech schools. Methods: A systematic search of studies published between 1988 and 2012 in the English language was completed in library databases Medline, Sport Discus, ProQuest, PsychInfo, ERIC, Wiley InterScience using the following keywords: physical activity, guidelines, recommendations, school and youth. The studies were then classified based on abstract and full-text analyses. Using a content analysis the expert team formulated the final recommendations to increase the level of physical activity for schools in the Czech Republic (CR. Results: Out of the total number of 91 identified foreign studies, 25 met the predetermined criteria and were used as a basis for formulating the recommendations. These foreign studies included 15 papers published in USA, two in Australia, two in Great Britain, two in Canada, one in the European Union, one in New Zealand and one international paper (an international consensus of experts from 34 countries. Based on the interpretation of the evidence, its justification and final consensus of the expert team, the basic areas for the recommendations to increase the level of physical activity in schools in the CR were identified. Conclusions: An analysis of foreign recommendations to increase the level of physical activity designed for schools and school facilities is one of the possible methods of formulating domestic recommendations. This recommendation could contribute to deeper understanding of the issue of the deteriorating lifestyle of school-aged children in the CR and reflects the efforts for improvement.

  3. Exercise and Physical Activity Recommendations for People with Cerebral Palsy

    Science.gov (United States)

    Peterson, Mark D.; Balemans, Astrid C.J.; Hurvitz, Edward A.

    2016-01-01

    Physical activity (PA) and its promotion, as well as the avoidance of sedentary behaviour play important roles in health promotion and prevention of lifestyle-related diseases. Guidelines for typically developing youth and adults published by the World Health Organization and American College of Sports Medicine are available. However, detailed recommendations for PA and sedentary behaviour have not been established for children, adolescents and adults with cerebral palsy (CP). This paper presents the first CP-specific PA and exercise recommendations. The recommendations are based on (1) a comprehensive review and analysis of the literature, (2) expert opinion and (3) extensive clinical experience. The evidence supporting these recommendations are based on randomized controlled trials and observational studies involving children, adolescents and adults with CP, and buttressed by the previous guidelines for the general population. These recommendations may be used to guide healthcare providers on exercise and daily PA prescription for individuals with CP. PMID:26853808

  4. Open questions on bioequivalence: an updated reappraisal.

    Science.gov (United States)

    Marzo, Antonio

    2007-05-01

    During the last thirteen years, the author has investigated a relevant number of bioequivalence trials, for the approval of generics, which in the Mediterranean area show an increasing business trend. In his activity the author has faced several problems, most of them not considered in operating guidelines, defined "open questions on bioequivalence". They deal with the most appropriate procedures to adopt in case of studies on drugs with long half-lives, of ethics problems, high data dispersion, endogenous substances, presence of active metabolite(s), prevalent metabolites and reversible metabolism, very low plasma concentrations, multiple peak phenomenon, titre differences, polymorphic metabolism, stereogenic atoms. The relevance of a pilot trial, mainly for modified-release formulations, and the problem of frauds are discussed as well. These open questions are discussed in the present review taking into account EU and US FDA guidelines, current literature and personal experience. In most cases suitable approaches are suggested. Appropriate procedures should be planned and defined in the study protocol and extensively discussed in the final report. An appropriate approach to the "open questions" is a requisite to achieve a clearly defined bioequivalence/bioinequi-valence conclusion.

  5. Bioequivalency of ranitidine tablets.

    Science.gov (United States)

    Alkaysi, H N; Salem, M A; Gharaibeh, A M; el-Sayed, Y M; Ali-Gharaibeh, K I; Badwan, A A

    1989-04-01

    The bioavailability of two brands of ranitidine tablets was studied in 10 healthy volunteers. Formulation factors were compared by performing disintegration, dissolution and content uniformity tests. Plasma concentrations of ranitidine were measured using a sensitive and precise high pressure liquid chromatographic (HPLC) procedure. Pharmacokinetic parameters were determined for both formulations and included: Cmax, AUCt, AUC infinity, tmax, t1/2 and the terminal rate of elimination (k). Statistical analysis revealed that differences between the brands were not significant. The two formulations can be considered to be bioequivalent.

  6. PHARMACOKINETIC PARAMETERS TO BE EVALUATED FOR SELECTED LOW MOLECULAR WEIGHT HEPARINs IN BIOEQUIVALENCE STUDIES

    Directory of Open Access Journals (Sweden)

    Chaitanya Gadiko*, Satyanarayana Thota and Sudhakar K. Tippabotla

    2012-11-01

    Full Text Available Bioequivalence needs to be established on healthy human volunteers for Low Molecular Weight Heparins (LMWHs such as Dalteparin, Enoxaparin, Tinzaparin and Fondaparinux using Pharmacodynamic marker(s for generic approval. Anti-Xa and anti-IIa activity are used to determine the activity of LMWHs (Dalteparin, Enoxaparin and Tinzaparin and anti-Xa activity for Fondaparinux in biological samples for the assessment of its bioavailability. These are selected based on the pharmacodynamic activities of LMWHs. LMWHs exhibit their antithrombotic activity preferentially by inhibiting clotting Factor Xa, and to a lesser extent Factor IIa. On the other hand Fondaparinux is a synthetic and specific inhibitor of Factor-Xa and hencebioequivalence needs to be established for only anti-Xa activity. The pharmacodynamic data of anti-IIa activity need to be submitted for regulatory agency as supportive data of comparable therapeutic outcome for all LMWHs except Fondaparinux. In addition to the above, pharmacokinetic data of Heptest (Heparin clotting assay and activated Partial Thromboplastin Time (aPTT may also serve as a supportive evidence for establishing bioequivalence of LMWH formulations as there were no clear recommendations available.

  7. "Assessment of different bioequivalent metrics in Rifampin bioequivalence study "

    OpenAIRE

    "Rouini MR; Tajer Zadeh H; Valad Khani M "

    2002-01-01

    The use of secondary metrics has become special interest in bioequivalency studies. The applicability of partial area method, truncated AUC and Cmax/AUC has been argued by many authors. This study aims to evaluate the possible superiority of these metrics to primary metrics (i.e. AUCinf, Cmax and Tmax). The suitability of truncated AUC for assessment of absorption extent as well as Cmax/AUC and partial AUC for the evaluation of absorption rate in bioequivalency determination was investigated ...

  8. High-throughput LC-MS/MS assay for 6-methoxy-2-naphthylacetic acid, an active metabolite of nabumetone in human plasma and its application to bioequivalence study.

    Science.gov (United States)

    Patel, Bhavin N; Sharma, Naveen; Sanyal, Mallika; Prasad, Arpana; Shrivastav, Pranav S

    2008-11-01

    A simple, precise and accurate assay for the determination of 6-methoxy-2-naphthylacetic acid (6-MNA), an active metabolite of nabumetone in human plasma, was developed and validated using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The analyte (6-MNA) and propranolol (internal standard, IS) were extracted from 200 microL aliquot of human plasma via solid-phase extraction employing HLB Oasis cartridges and separated on a Discovery HS C18 (50 x 4.6 mm, 5 microm) column. Detection of analyte and IS was done by tandem mass spectrometry with a turbo ion spray interface operating in positive ion and multiple reaction monitoring acquisition mode. The total chromatographic runtime was 3.0 min with retention time for 6-MNA and IS at 1.97 and 1.26 min, respectively. The method was validated over a dynamic linear range of 0.20-60.00 microg/mL for 6-MNA with mean correlation coefficient r > or = 0.9986. The intra-batch and inter-batch precision (%CV) across five validation runs (lower limit of quantiation, low-, medium- and high-quality controls and upper limit of quantitation) was less than 7.5%. The accuracy determined at these levels was within -5.8 to +0.2% in terms of percentage bias. The method was successfully applied for a bioequivalence study of 750 mg nabumetone tablet formulation in 12 healthy Indian male subjects under fasted condition.

  9. The Two Main Goals of Bioequivalence Studies.

    Science.gov (United States)

    Endrenyi, Laszlo; Blume, Henning H; Tothfalusi, Laszlo

    2017-02-02

    The principal goal of bioequivalence (BE) investigations has crucial importance and has been the subject of extensive discussions. BE studies are frequently considered to serve as procedures for sensitive discrimination. The BE investigation should be able to provide methods and conditions sensitively identifying relevant differences between drug products if such differences in fact exist. Alternatively, BE studies can be deemed as surrogates of clinical investigations assessing therapeutic equivalence. Bioequivalent drug products will be provided to patients for their benefits. Both points of view are valid since they represent two aspects of product performance. It has been argued that both should be equally sustained and applied. In practice, however, they collide when regulatory conditions and statements are developed. For instance, some regulators prefer to conduct BE studies following single drug administrations since these conditions are considered to provide the highest sensitivity of discrimination between pharmacokinetic profiles and thus, a product's in-vivo performance. Others suggest that, at least for modified-release products, BE investigations should be performed in the steady state since it represents clinical conditions. Preference for one point of view or the other pervades other regulatory statements including suggestions for subjects to be selected in studies and pharmacokinetic measures to be evaluated. An overview is provided on the disturbing inconsistency of statements within and between regulations. It is argued that harmonization would be highly desirable, and relevant recommendations are offered.

  10. Simultaneous analysis of oxybutynin and its active metabolite N-desethyl oxybutynin in human plasma by stable isotope dilution LC-MS/MS to support a bioequivalence study.

    Science.gov (United States)

    Sharma, Primal; Patel, Daxesh P; Sanyal, Mallika; Berawala, Hiren; Guttikar, Swati; Shrivastav, Pranav S

    2013-10-01

    An isotope dilution high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method has been developed for the simultaneous determination of oxybutynin and its pharmacologically active metabolite N-desethyl oxybutynin in human plasma. Extraction of oxybutynin, its metabolite and their deuterated analogs as internal standards (ISs) from 300 μL human plasma was carried out by liquid-liquid extraction with methyl tert-butyl ether-ethyl acetate solvent mixture. Chromatographic separation of analytes was performed on Cosmosil C18 (150 mm × 4.6 mm, 5 μm) column under isocratic conditions with acetonitrile-1.0mM ammonium acetate (90:10, v/v) as the mobile phase. Six endogenous plasma phospholipids (496.3/184.0, 524.3/184.0, 758.5/184.0, 786.5/184.0, 806.5/184.0 and 810.5/184.0) were monitored to determine the extraction efficiency under different extraction conditions. The precursor→product ion transition for both the analytes and ISs were monitored on a triple quadrupole mass spectrometer, operating in the multiple reaction monitoring and positive ionization mode. The method was validated over a concentration range of 0.050-10.0 ng/mL for oxybutynin and 0.500-100 ng/mL for N-desethyl oxybutynin. The mean extraction recovery for analytes (80.4%) and ISs (76.9%) was consistent across five QC levels. Bench top, wet and dry extract, freeze-thaw and long term stability was evaluated for both the analytes. The method was applied to support a bioequivalence study of 5mg tablet formulation in 74 healthy Indian subjects. Assay reproducibility was demonstrated by reanalysis of 344 incurred samples.

  11. [Bioequivalence studies of pharmaceutical preparations].

    Science.gov (United States)

    Vetchý, D; Frýbortová, K; Rabisková, M; Danecková, H

    2007-01-01

    Bioequivalence studies are very important for the development of a pharmaceutical preparation in the pharmaceutical industry. Their rationale is the monitoring of pharmacokinetic and pharmacodynamic parameters after the administration of tested drugs. The target of such study is to evaluate the therapeutic compatibility of tested drugs (pharmaceutical equivalents or pharmaceutical alternatives). The importance of bioequivalence studies is increasing also due to the large growth of the production and consumption of generic products. Generic products represent approximately 50 % of the whole consumption in many European countries and USA. The search output of bioequivalence study is together with the pharmaceutical quality data of medical product one of the main part of the registration file submitted to a national regulatory authorities. The registration of generic products does not demand complicated and expensive clinical study contrary to original product. The comparison of the original and the generic product via bioequivalence study is suggested as sufficient. The aim of this article is to provide to a medical public a summary about the types of bioequivalence studies, their range, rules of their practise and let them gain their own attitude to this question.

  12. Bioequivalence study of 2 orodispersible formulations of zolmitriptan 5 mg in healthy volunteers.

    Science.gov (United States)

    Cánovas, M; Canals, M; Polonio, F; Cabré, F

    2012-10-01

    A bioequivalence study of 2 zolmitriptan (CAS 139264-17-8) orodispersible tablet formulations was carried out in 26 healthy volunteers according to an open label, randomized, 2-period, 2-sequence, crossover, single dose and fasting conditions design. The test and reference formulations were administered in 2 treatment days, separated by a washout period of 7 days. Plasma concentrations of zolmitriptan and its active metabolite (N-desmethyl-zolmitriptan) were obtained by LC/MS/MS method. Log-transformed AUCs and Cmax values were tested for bioequivalence based on the ratios of the geometric means (test/reference). Tmax was analysed nonparametrically. The 90% confidence intervals of the geometric mean values for the test/reference ratios for AUC0-t and Cmax were within the bioequivalence acceptance range of 80-125%. According to the European Guideline 1 it may be therefore concluded that test formulation of zolmitriptan 5 mg orodispersible tablet is bioequivalent to the reference formulation.

  13. SNS Sample Activation Calculator Flux Recommendations and Validation

    Energy Technology Data Exchange (ETDEWEB)

    McClanahan, Tucker C. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Spallation Neutron Source (SNS); Gallmeier, Franz X. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Spallation Neutron Source (SNS); Iverson, Erik B. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Spallation Neutron Source (SNS); Lu, Wei [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Spallation Neutron Source (SNS)

    2015-02-01

    The Spallation Neutron Source (SNS) at Oak Ridge National Laboratory (ORNL) uses the Sample Activation Calculator (SAC) to calculate the activation of a sample after the sample has been exposed to the neutron beam in one of the SNS beamlines. The SAC webpage takes user inputs (choice of beamline, the mass, composition and area of the sample, irradiation time, decay time, etc.) and calculates the activation for the sample. In recent years, the SAC has been incorporated into the user proposal and sample handling process, and instrument teams and users have noticed discrepancies in the predicted activation of their samples. The Neutronics Analysis Team validated SAC by performing measurements on select beamlines and confirmed the discrepancies seen by the instrument teams and users. The conclusions were that the discrepancies were a result of a combination of faulty neutron flux spectra for the instruments, improper inputs supplied by SAC (1.12), and a mishandling of cross section data in the Sample Activation Program for Easy Use (SAPEU) (1.1.2). This report focuses on the conclusion that the SAPEU (1.1.2) beamline neutron flux spectra have errors and are a significant contributor to the activation discrepancies. The results of the analysis of the SAPEU (1.1.2) flux spectra for all beamlines will be discussed in detail. The recommendations for the implementation of improved neutron flux spectra in SAPEU (1.1.3) are also discussed.

  14. Bioequivalence studies: need for the reability of generic drugs

    OpenAIRE

    Laosa, Olga; Centro de Farmacología Clínica, Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid. Madrid, España. Médico especialista en Farmacología Clínica.; Guerra, Pedro; Centro de Farmacología Clínica, Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid. Madrid, España. Médico especialista en Farmacología Clínica.; López-Durán, Jose Luis; Centro de Farmacología Clínica, Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid. Madrid, España. Médico especialista en Farmacología Clínica.; Mosquera, Beatriz; Centro de Farmacología Clínica, Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid. Madrid, España. Licenciada en Ciencias Químicas.; Frías, Jesús; Centro de Farmacología Clínica, Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid. Madrid, España. Servicio de Farmacología Clínica, Hospital Universitario la Paz. Madrid, España. Médico especialista en Farmacología Clínica.

    2009-01-01

    A generic medicine is a pharmaceutical product containing an active ingredient already known and previously developed and invented by others. The cost of these generic or multisource products should be less than their counterparts original. The clinical effects and the risk-benefit balance of a medicine do not depend exclusively on the activity of a pharmacologically active substance. Demonstration of bioequivalence of generic medicine is of great importance. In Europe and the United States g...

  15. Large ethnic variations in recommended physical activity according to activity domains in Amsterdam, the Netherlands

    NARCIS (Netherlands)

    de Munter, J.S.L.; Valkengoed, I.G.M.; Agyemang, C.; Kunst, A.E.; Stronks, K.

    2010-01-01

    ABSTRACT: Purpose: The level of recommended physical activity (PA) is met less frequently by people from some ethnic minorities than others. We explored whether these differences in recommended PA between ethnic minority groups and the general population varied by domain and type of culturally-speci

  16. "Assessment of different bioequivalent metrics in Rifampin bioequivalence study "

    Directory of Open Access Journals (Sweden)

    "Rouini MR

    2002-08-01

    Full Text Available The use of secondary metrics has become special interest in bioequivalency studies. The applicability of partial area method, truncated AUC and Cmax/AUC has been argued by many authors. This study aims to evaluate the possible superiority of these metrics to primary metrics (i.e. AUCinf, Cmax and Tmax. The suitability of truncated AUC for assessment of absorption extent as well as Cmax/AUC and partial AUC for the evaluation of absorption rate in bioequivalency determination was investigated following administration of same product as test and reference to 7 healthy volunteers. Among the pharmacokinetic parameters obtained, Cmax/AUCinf was a better indicator or absorption rate and the AUCinf was more sensitive than truncated AUC in evaluation of absorption extent.

  17. Bioequivalence evaluation of epinephrine autoinjectors with attention to rapid delivery

    Directory of Open Access Journals (Sweden)

    Sclar DA

    2013-04-01

    Full Text Available David Alexander Sclar Department of Pharmacy Practice, College of Pharmacy, Midwestern University, Glendale, AZ, USA Abstract: Timely and proper injection of epinephrine is critical to prevent serious consequences relating to anaphylaxis. In a recent bioavailability study comparing epinephrine delivery from the Auvi-Q™ and EpiPen® epinephrine autoinjectors, the Auvi-Q failed to meet the bioequivalence threshold when using partial area under the curve (AUC analyses based on zero to Tmax recommended for highly variable drugs such as epinephrine. Peak plasma epinephrine concentrations for the EpiPen occurred 10 minutes (median Tmax after dosing, while peak concentrations for the Auvi-Q occurred 20 minutes after dosing. Though bioequivalence may be concluded for Cmax, AUCinf, and AUC0–t, for fast-acting therapeutics used to treat life-threatening conditions, such as epinephrine, additional pharmacokinetic parameters such as AUC zero to Tmax may be important to evaluate when assessing bioequivalence. Keywords: anaphylaxis, therapy, pharmacokinetics, bioavailability, EpiPen, Tmax

  18. 21 CFR 320.63 - Retention of bioequivalence samples.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Retention of bioequivalence samples. 320.63... (CONTINUED) DRUGS FOR HUMAN USE BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS Procedures for Determining the Bioavailability or Bioequivalence of Drug Products § 320.63 Retention of bioequivalence...

  19. Correlation between microstructure and bioequivalence in anti-HIV drug efavirenz.

    Science.gov (United States)

    Fandaruff, Cinira; Segatto Silva, Marcos Antônio; Galindo Bedor, Danilo Cesar; de Santana, Davi Pereira; Rocha, Helvécio Vinícius Antunes; Rebuffi, Luca; Azanza Ricardo, Cristy Leonor; Scardi, Paolo; Cuffini, Silvia Lucia

    2015-04-01

    Polymorphism and particle size distribution can impact the dissolution behaviour and, as a consequence, bioavailability and bioequivalence of poorly soluble drugs, such as Efavirenz (EFV). Nevertheless, these characteristics do not explain some failures occurring in in vitro assays and in in vivo studies. EFV belongs to Class II and the High Activity Antiretroviral Therapy (HAART) is considered the best choice in the treatment of adults and children. EFV is a drug that needs bioequivalence studies for generic compounds. In this work, six raw materials were analyzed and two of them were utilized with human volunteers (in vivo assays or bioequivalence). All the routine pharmaceutical controls of raw materials were approved; however, the reasons for the failure of the bioequivalence assay could not be explained with current knowledge. The aim of this work was to study microstructure, a solid-state property of current interest in the pharmaceutical area, in order to find an explanation for the dissolution and bioequivalence behaviour. The microstructure of EFV raw materials was studied by Whole Powder Pattern Modelling (WPPM) of X-ray powder diffraction data. Results for different EFV batches showed the biorelevance of the crystalline domain size, and a clear correlation with in vitro (dissolution tests) and in vivo assays (bioequivalence).

  20. A rapid LC-ESI-MS/MS method for the quantitation of choline, an active metabolite of citicoline: Application to in vivo pharmacokinetic and bioequivalence study in Indian healthy male volunteers.

    Science.gov (United States)

    Sarkar, Amlan Kanti; Ghosh, Debotri; Haldar, Dhiman; Sarkar, Pradipta; Gupta, Bhaswati; Dastidar, Sujata Ghosh; Pal, Tapan Kumar

    2012-12-01

    A rapid, simple, and sensitive high performance liquid chromatography-tandem mass spectrometry method (LC-ESI-MS/MS) was developed and validated for the determination and pharmacokinetic investigation of choline (CL), active metabolite of citicoline in human plasma using metformin (MF) as IS. The chromatographic separation was performed on a reversed-phase Phenomenx Gemini C18 column with a mobile phase of methanol:water (containing 10mM ammonium formate) (9:1, v/v). The calibration curves were linear over the range of 0.05-5μg/ml. The validated LC-ESI-MS/MS method was successfully applied for the evaluation of pharmacokinetic parameters and bioequivalence study of test and reference control release (CR) tablet preparation of citicoline 1000mg after a single oral administration to all 12 healthy male volunteers.

  1. A note on an individual bioequivalence setting

    OpenAIRE

    Surulescu, Christina; Surulescu, N.

    2005-01-01

    We give a new simpler proof along with a generalization for the inequality of Yao and Iyer \\cite{yao} arising in bioequivalence studies and by using a nonparametric approach we also discuss an extension of the individual bioequivalence setting to the case where the data are not necessarily normally distributed.

  2. "Pharmacodynamically evaluated bioequivalence of two preparations of Enalapril Maleate "

    Directory of Open Access Journals (Sweden)

    "Tajerzadeh H

    2001-07-01

    Full Text Available The bioequivalence of two preparations of enalapril maleate (20 mg tablets manufactured in Iran has been exploited in reference to a standard preparation (Xanef 20 tablets, MSD, Germany in 14 healthy volunteers. Following oral dosing of a single tablet of each of test and standard products, as a randomized crossover design with 10-day washout intervals, the blood samples were collected in predetermined time points and using a synthetic substrate, Hippuryl-Histidy-Leucine (HHL, the release of hippuric acid from the substrate was determined as Angiotensin-Converting-Enzyme (ACE activity of serum fractions. The percent of ACE inhibition in each sample was calculated and plotted against time, from which three pharmacodynamic parameters, i.e. Emax, tmax and AUC0-24 were derived. The results of statistical comparison of these parameters showed that both of the test preparations are bioequivalent with reference standard preparation.

  3. Design Context Aware Activity Recommender System for Iranian Customer Mind Activism in Online Shopping

    Directory of Open Access Journals (Sweden)

    Saber Pahlavan

    2013-11-01

    Full Text Available E-commerce has made life simple and innovative of individuals and groups. Nowadays, social networks are widely used by everyone. So, it is necessary to do appropriate and situation aware activities in these networks to gain benefits, In this research, a context aware recommender system has modeled for using in social networks focus on Iranian customer mind activism in online shopping. This system makes its recommendations for user based on behavior and activities of her friends in the same situation in social network. In other word, this modeled recommender system uses collaborative filtering algorithm. All the connections of user in social network, containing direct and indirect, are considered for recommending by recommender system; but, based on connection type and its distance to user, proportional factor is assigned. On the other, In this research we study the consumer behavior in online shopping of electronics especially in Iran. Primary data was collected through the questionnaire survey and by emails from personal contacts in two major cities of Iran. Price, time saving and convenience were identified as important factors which lead to certain buying behavior in online shopping.

  4. The importance of bioequivalence study: focus on clopidogrel

    Directory of Open Access Journals (Sweden)

    Arini Setiawati

    2011-05-01

    Full Text Available Bioequivalence (BE study is required to show whether a generic copy product can be interchangeable with the brand innovator product. The aim of this article is to provide the rationale for conducting BE studies, the main products requiring BE studies, the design and conduct of BE studies in general, with focus on clopidogrel. All of the clopidogrel generic products in Indonesia have been shown to be BE to the innovator product Plavix® and they contain API (active pharmaceutical ingredient clopidogrel form 1 that complies with USP 30, 1997 requirements: the R-enantiomer content is not more than 1%. A proof that bioequivalence (BE means therapeutic equivalence (TE is also provided for cardiovascular drugs. Clopidogrel has 2 polymorphic forms, form 1 and form 2, which have the same indications. At least one pivotal study of clopidogrel, CAPRIE, used clopidogrel form 1. An atherothrombotic event may be associated with clopidogrel resistance, which occur in about 4 to 30% of patients treated with conventional doses of clopidogrel. (Med J Indones 2011; 20:149-53Keywords: bioequivalent, clopidogrel

  5. Biowaiver: an alternative to in vivo pharmacokinetic bioequivalence studies.

    Science.gov (United States)

    Mishra, V; Gupta, U; Jain, N K

    2010-03-01

    Bioequivalence is a vital concern in drug development even more significant in the case of Narrow Therapeutic Index (NTI) drugs. In clinical development of New Chemical Entities (NCE), bioequivalence studies necessitate to be performed when the formulation of the pharmaceutical dosage form has been changed. In vivo pharmacokinetic data can be used as surrogate parameters for in vivo solubility and permeability data. The Biopharmaceutics Classification System (BCS) has emerged as a helpful tool in product development by alluding to the in vivo performance of the active substance. The bio-relevance of the BCS properties and the in vitro release are best expressed through a correlation between in vitro and in vivo data. Recently BCS has been implemented for waiving bioequivalence studies on the basis of the solubility and gastrointestinal permeability of drug substance and can be strategically deployed to save time and resources during generic drug development. The BCS has been adopted as a very useful tool for in vivo drug design and development worldwide, particularly in terms of regulatory standards. A BCS-based biowaiver has become an important and cost-saving tool in approval of generic drugs.

  6. Adjusted indirect treatment comparisons of bioequivalence studies

    NARCIS (Netherlands)

    Gwaza, L

    2016-01-01

    Generic medicines are approved by regulatory authorities based on demonstration of bioequivalence with the innovator, however, current regulatory systems do not require direct comparison between all available generics of the same innovator to ensure interchangeability. As such, interchangeability be

  7. Carryover negligibility and relevance in bioequivalence studies

    OpenAIRE

    Ocaña i Rebull, Jordi; Sánchez Olavarría, María Pilar; Carrasco Jordan, Josep Lluís

    2015-01-01

    The carryover effect is a recurring issue in the pharmaceutical field. It may strongly influence the final outcome of an average bioequivalence study. Testing a null hypothesis of zero carryover is useless: not rejecting it does not guarantee the non-existence of carryover, and rejecting it is not informative of the true degree of carryover and its influence on the validity of the final outcome of the bioequivalence study. We propose a more consistent approach: even if some carryover is prese...

  8. Intrapersonal, behavioral, and environmental factors associated with meeting recommended physical activity among rural Latino youth.

    Science.gov (United States)

    Perry, Cynthia K; Saelens, Brian E; Thompson, Beti

    2011-11-01

    This study aimed to identify intrapersonal, behavioral, and environmental factors associated with engaging in recommended levels of physical activity among rural Latino middle school youth. Data were from an anonymous survey of 773 Latino youth (51% female) about level of and barriers and motivators to physical activity, risk behaviors, and park use. Logistic regression models identified factors correlated with meeting recommended levels of physical activity (5 days or more 3 60 min/day). Thirty-four percent of girls and 41% of boys reported meeting this physical activity recommendation. Participation in an organized after school activity (p physical education (PE) classes 5 days a week (p physical activity level. Making PE available 5 days a week and creating opportunities for organized after school physical activity programs may increase the number of rural Latino middle school youth who meet recommended physical activity level.

  9. Development of an SPE-LC-MS/MS method for simultaneous quantification of bosentan and its active metabolite hydroxybosentan in human plasma to support a bioequivalence study.

    Science.gov (United States)

    Parekh, Jignesh M; Shah, Dhaval K; Sanyal, Mallika; Yadav, Manish; Shrivastav, Pranav S

    2012-11-01

    A highly sensitive, selective and rapid bioanalytical method has been developed for the simultaneous determination of bosentan and hydroxybosentan in human plasma by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The analytes and their deuterated analogs were quantitatively extracted from 100 μL human plasma by solid phase extraction. The chromatographic separation of analytes was achieved on a Thermo Hypurity C18 (100 mm × 4.6 mm, 5 μ) analytical column with a resolution factor of 2.4 under isocratic conditions. The method was validated over a dynamic concentration range of 0.4-1600 ng/mL for bosentan and 0.2-250 ng/mL for hydroxybosentan. Ion-suppression effects were investigated by post-column infusion of analytes. The precision (%CV) values for the calculated slopes of calibration curves, which would reflect the relative matrix effect, were less than 1.2% for both the analytes. The intra-batch and inter-batch precision (%CV) across quality control levels was ≤4.0% and the mean relative recovery was >94% for both the analytes. The method was successfully applied to a bioequivalence study of 125 mg tablet formulation (test and reference) in 12 healthy Indian male subjects under fasting condition. The ratios of mean log-transformed values of C(max), AUC(0-t) and AUC(0-inf) and their 90% CIs varied from 91.3 to 104.7%. The percentage change for incurred sample reanalysis (ISR) was within ±13.0%.

  10. Recommended level of physical activity and health-related quality of life among Japanese adults

    Directory of Open Access Journals (Sweden)

    Nakamura Yoshio

    2007-11-01

    Full Text Available Abstract Background The benefits of a recommended level of physical activity on physiological health indicators such as morbidity and mortality are well-accepted, but less research has addressed whether or not the association between the recommended level of physical activity and a health-related quality of life (HRQOL exists in the Japanese population. Thus, the present study examined whether the recommended physical activity would be associated with HRQOL in the general Japanese middle-aged population. Methods Data were obtained from 1211 male and female respondents (39.4 ± 10.9 year, mean ± SD from an Internet-based survey of registrants of an Internet research service. Physical activity level was estimated from the short form of the International Physical Activity Questionnaire. HRQOL was assessed with the Medical Outcomes Survey Short Form-8 questionnaire (SF-8. Based on the current national guidelines for exercise in Japan, respondents were divided into a recommended group, an insufficient group, and an inactive group according to their estimated weekly physical activity level. Multivariate analyses of covariance were utilized. Results Across both genders, the recommended group had significantly higher physical functioning (PF scores than the inactive group (p Conclusion Individuals who attained the recommended level of physical activity had better scores on some dimensions of HRQOL than those who did not, suggesting that the recommended level of physical activity may be applicable not only to the physiological objective outcomes but also to some dimensions in both the physical and mental aspects of HRQOL.

  11. International Guidelines for Bioequivalence of Locally Acting Orally Inhaled Drug Products: Similarities and Differences

    OpenAIRE

    Lu, Dongmei; Lee, Sau L.; Lionberger, Robert A.; Choi, Stephanie; Adams, Wallace; Caramenico, Hoainhon N.; Chowdhury, Badrul A.; Conner, Dale P.; Katial, Rohit; Limb, Susan; Peters, John R.; Yu, Lawrence; Seymour, Sally; Li, Bing V.

    2015-01-01

    International regulatory agencies have developed recommendations and guidances for bioequivalence approaches of orally inhaled drug products (OIDPs) for local action. The objective of this article is to discuss the similarities and differences among these approaches used by international regulatory authorities when applications of generic and/or subsequent entry locally acting OIDPs are evaluated. We focused on four jurisdictions that currently have published related guidances for generic and...

  12. Sequential bioequivalence approaches for parallel designs.

    Science.gov (United States)

    Fuglsang, Anders

    2014-05-01

    Regulators in EU, USA and Canada allow the use of two-stage approaches for evaluation of bioequivalence. The purpose of this paper is to evaluate such designs for parallel groups using trial simulations. The methods developed by Diane Potvin and co-workers were adapted to parallel designs. Trials were simulated and evaluated on basis of either equal or unequal variances between treatment groups. Methods B and C of Potvin et al., when adapted for parallel designs, protected well against type I error rate inflation under all of the simulated scenarios. Performance characteristics of the new parallel design methods showed little dependence on the assumption of equality of the test and reference variances. This is the first paper to describe the performance of two-stage approaches for parallel designs used to evaluate bioequivalence. The results may prove useful to sponsors developing formulations where crossover designs for bioequivalence evaluation are undesirable.

  13. Carryover negligibility and relevance in bioequivalence studies.

    Science.gov (United States)

    Ocaña, Jordi; Sanchez O, Maria P; Carrasco, Josep L

    2015-01-01

    The carryover effect is a recurring issue in the pharmaceutical field. It may strongly influence the final outcome of an average bioequivalence study. Testing a null hypothesis of zero carryover is useless: not rejecting it does not guarantee the non-existence of carryover, and rejecting it is not informative of the true degree of carryover and its influence on the validity of the final outcome of the bioequivalence study. We propose a more consistent approach: even if some carryover is present, is it enough to seriously distort the study conclusions or is it negligible? This is the central aim of this paper, which focuses on average bioequivalence studies based on 2 × 2 crossover designs and on the main problem associated with carryover: type I error inflation. We propose an equivalence testing approach to these questions and suggest reasonable negligibility or relevance limits for carryover. Finally, we illustrate this approach on some real datasets.

  14. Comparative bioequivalence studies of tramadol hydrochloride sustained-release 200 mg tablets

    Directory of Open Access Journals (Sweden)

    Suhas S Khandave

    2010-11-01

    Full Text Available Suhas S Khandave1, Satish V Sawant1, Santosh S Joshi1, Yatish K Bansal2, Sonal S Kadam21Accutest Research Laboratories (I Private Limited, Koparkhirne, Navi Mumbai, Maharashtra, India; 2Ipca Laboratories Limited, Kandivli Mumbai, Maharashtra, IndiaBackground: Tramadol hydrochloride is available as 50 mg immediate-release (IR and 100 mg, 200 mg, and 300 mg sustained-release (SR tablets. The recommended dose of tramadol is 50–100 mg IR tablets every 4–6 hours. The tramadol SR 200 mg tablet is a better therapeutic option, with a reduced frequency of dosing, and improved patient compliance and quality of life. The present study evaluated the bioequivalence of a generic tramadol SR 200 mg tablet.Methods: A comparative in vitro dissolution study was performed on the test and reference products, followed by two separate single-dose bioequivalence studies under fasting and fed conditions and one multiple-dose bioequivalence study under fasting conditions. These bioequivalence studies were conducted in healthy human subjects using an open-label, randomized, two-treatment, two-period, two-sequence, crossover design. The oral administration of the test and reference products was done on day 1 for both the single-dose studies and on days 1–5 for the multiple-dose study in each study period as per the randomization code. Serial blood samples were collected at predefined time points in all the studies. Analysis of plasma concentrations of tramadol and O-desmethyltramadol (the M1 metabolite was done by a validated liquid chromatography-mass spectrometry analytical method. The standard acceptance criterion of bioequivalence was applied on log-transformed pharmacokinetic parameters for tramadol and its M1 metabolite.Results: The ratios for geometric least-square means and 90% confidence intervals were within the acceptance range of 80%–125% for log-transformed primary pharmacokinetic parameters for tramadol and its M1 metabolite in all the three studies

  15. Clarithromycin suspension: bioequivalence studies on two different strengths.

    Science.gov (United States)

    Koytchev, Rossen; Ozalp, Yildiz; Erenmemisoglu, Aydin; van der Meer, Mike John; Alpan, Recep Serdar

    2004-09-01

    Two studies were performed in different groups of volunteers, with the aim to prove the bioequivalence of test (Klaromin) and reference clarithromycin (CAS 81103-11-9) suspensions containing in 5 mL either 125 mg (study 1) or 250 mg (study 2) of the drug, administered as an oral dose of 10 mL. Each study was conducted according to an open, randomized, single-dose, two-period cross-over design in healthy volunteers with a wash-out period from 7 to 14 days. Blood samples were taken up to 24 h in both studies, and concentrations of clarithromycin and its principal active 14-hydroxy metabolite were determined by HPLC. In the first study, the 90% confidence interval for intra-individual ratios of AUC0-t and Cmax of clarithromycin were between 0.84 and 1.03 (AUC0-t) and between 0.89 and 1.03 (Cmax). In the second study, i.e. after administration of clarithromycin suspension 250mg/5mL, the 90% confidence interval for intra-individual ratios of AUC0-inf and Cmax of clarithromycin were between 1.01 and 1.17 (AUC0-inf) and between 1.01 and 1.16 (Cmax). All these values were within the acceptance ranges for bioequivalence studies. In both studies, the 90% confidence interval for intra-individual ratios of AUC0-inf and Cmax of 14-hydroxy-clarithromycin were also within the acceptance ranges. In the light of the results of the studies reported here it can be concluded that the clarithromycin test formulations are bioequivalent to the respective reference formulations, i.e. suspensions containing 125 mg/5 mL and 250 mg/5 mL of the drug.

  16. AN ONTOLOGY-BASED TOURISM RECOMMENDER SYSTEM BASED ON SPREADING ACTIVATION MODEL

    Directory of Open Access Journals (Sweden)

    Z. Bahramian

    2015-12-01

    Full Text Available A tourist has time and budget limitations; hence, he needs to select points of interest (POIs optimally. Since the available information about POIs is overloading, it is difficult for a tourist to select the most appreciate ones considering preferences. In this paper, a new travel recommender system is proposed to overcome information overload problem. A recommender system (RS evaluates the overwhelming number of POIs and provides personalized recommendations to users based on their preferences. A content-based recommendation system is proposed, which uses the information about the user’s preferences and POIs and calculates a degree of similarity between them. It selects POIs, which have highest similarity with the user’s preferences. The proposed content-based recommender system is enhanced using the ontological information about tourism domain to represent both the user profile and the recommendable POIs. The proposed ontology-based recommendation process is performed in three steps including: ontology-based content analyzer, ontology-based profile learner, and ontology-based filtering component. User’s feedback adapts the user’s preferences using Spreading Activation (SA strategy. It shows the proposed recommender system is effective and improves the overall performance of the traditional content-based recommender systems.

  17. Investigation of ex vivo stability of fesoterodine in human plasma and its simultaneous determination together with its active metabolite 5-HMT by LC-ESI-MS/MS: Application to a bioequivalence study.

    Science.gov (United States)

    Parekh, Jignesh M; Sanyal, Mallika; Yadav, Manish; Shrivastav, Pranav S

    2013-01-15

    Fesoterodine is a non-selective muscarinic-receptor antagonist, used in the treatment of overactive bladder syndrome. A highly sensitive, selective and rapid method has been developed for the simultaneous determination of fesoterodine and its active metabolite, 5-hydroxymethyl tolterodine (5-HMT) in human plasma by liquid chromatography-tandem mass spectrometry (LC-ESI-MS/MS). Due to rapid conversion of parent drug to 5-HMT, ex vivo stability of fesoterodine in human plasma was extensively studied to optimize the extraction protocol. The analytes and their deuterated analogs were quantitatively extracted from 100μL human plasma by liquid-liquid extraction in methyl tert-butyl ether: n-hexane. The chromatographic separation of analytes was achieved on a Kromasil C18 (100mm×4.6mm, 5μm) column under isocratic conditions. The method was validated over a dynamic concentration range of 0.01-10ng/mL for both the analytes. Ion-suppression effects were investigated by post-column infusion of analytes. The precision (% CV) values for the calculated slopes of calibration curves, which would reflect the relative matrix effect, were less than 1.5% for both the analytes. The intra-batch and inter-batch precision (% CV) across quality control levels varied from 1.82 to 3.73% and the mean extraction recovery was >96% for both the analytes. The method was successfully applied to a bioequivalence study of 8mg fesoterodine tablet formulation (test and reference) in 12 healthy Indian subjects under fasted and fed condition. The assay reproducibility estimated by reanalysis of incurred samples showed a change of ±12.0%.

  18. UPLC-MS/MS assay for the simultaneous quantification of carvedilol and its active metabolite 4'-hydroxyphenyl carvedilol in human plasma to support a bioequivalence study in healthy volunteers.

    Science.gov (United States)

    Patel, Daxesh P; Sharma, Primal; Sanyal, Mallika; Singhal, Puran; Shrivastav, Pranav S

    2013-08-01

    An ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method has been developed for the simultaneous determination of carvedilol and its pharmacologically active metabolite 4'-hydroxyphenyl carvedilol in human plasma using their deuterated internal standards (IS). Samples were prepared by solid-phase extraction using 100 μL human plasma. Chromatographic separation of analytes was achieved on UPLC C18 (50 × 2.1 mm, 1.7 µm) column using acetonitrile-4.0 mM ammonium formate, pH 3.0 adjusted with 0.1% formic acid (78:22, v/v) as the mobile phase. The multiple reaction monitoring transitions for both the analytes and IS were monitored in the positive electrospray ionization mode. The method was validated over a concentration range of 0.05-50 ng/mL for carvedilol and 0.01-10 ng/mL for 4'-hydroxyphenyl carvedilol. Intra- and inter-batch precision (% CV) and accuracy for the analytes varied from 0.74 to 3.88 and 96.4 to 103.3% respectively. Matrix effect was assessed by post-column analyte infusion and by calculation of precision values (coefficient of variation) in the measurement of the slope of calibration curves from eight plasma batches. The assay recovery was within 94-99% for both the analytes and IS. The method was successfully applied to support a bioequivalence study of 12.5 mg carvedilol tablets in 34 healthy subjects.

  19. International Guidelines for Bioequivalence of Locally Acting Orally Inhaled Drug Products: Similarities and Differences.

    Science.gov (United States)

    Lu, Dongmei; Lee, Sau L; Lionberger, Robert A; Choi, Stephanie; Adams, Wallace; Caramenico, Hoainhon N; Chowdhury, Badrul A; Conner, Dale P; Katial, Rohit; Limb, Susan; Peters, John R; Yu, Lawrence; Seymour, Sally; Li, Bing V

    2015-05-01

    International regulatory agencies have developed recommendations and guidances for bioequivalence approaches of orally inhaled drug products (OIDPs) for local action. The objective of this article is to discuss the similarities and differences among these approaches used by international regulatory authorities when applications of generic and/or subsequent entry locally acting OIDPs are evaluated. We focused on four jurisdictions that currently have published related guidances for generic and/or subsequent entry OIDPs. They are Therapeutic Goods Administration (TGA) in Australia, Health Canada (HC) in Canada, European Medicines Association (EMA) of European Union (EU), and the Food and Drug Administration (FDA) in the United States of America (USA). The comparisons of these bioequivalence (BE) recommendations are based on selection of reference products, formulation and inhaler device comparisons, and in vitro tests and in vivo studies, including pharmacokinetic (PK), pharmacodynamics (PD), and clinical studies. For the in vivo studies, the study design, choices of dose, subject inclusion/ exclusion criteria, study period, study endpoint, and equivalence criteria are elaborated in details. The bioequivalence on multiple-strength products and waiver options are also discussed.

  20. Bioequivalence approach for whole effluent toxicity testing

    Energy Technology Data Exchange (ETDEWEB)

    Shukla, R.; Wang, Q.; Fulk, F.; Deng, C.; Denton, D.

    2000-01-01

    Increased use of whole effluent toxicity (WET) tests in the regulatory arena has brought increased concern over the statistical analysis of WET test data and the determination of toxicity. One concern is the issue of statistical power. A number of WET tests may pass the current hypothesis test approach because they lack statistical power to detect relevant toxic effects because of large within-test variability. Additionally, a number of WET tests may fail the current approach because they possess excessive statistical power, as a result of small within-test variability, and detect small differences that may not be biologically relevant. The strengths and limitations of both the traditional hypothesis test approach and the bioequivalence approach for use in the National Pollutant Discharge Elimination System program were evaluated. Data from 5,213 single-concentration, short-term chronic WET tests with Ceriodaphnia dubia provided the database for analysis. Comparison of results between the current approach and the bioequivalence approach indicates that the current approach to WET testing is generally sound but that adopting the proposed bioequivalence approach resolves concerns of statistical power. Specifically, within this data set, applying the bioequivalence approach resulted in failure for tests with relatively large test variability and a pass for tests with relatively small within-test variability.

  1. Pharmacogenetic selection of volunteers increases stringency of bioequivalence studies; the case of clopidogrel

    Directory of Open Access Journals (Sweden)

    J Garcés-Eisele

    2014-01-01

    Full Text Available Clinical response to clopidogrel varies widely due to under-dosing, drug interactions and intrinsic interindividual differences resulting from genetic polymorphisms. Cytochrome P450-2C19 is the principal enzyme involved in the activation of the prodrug and loss-of-function alleles have been described. Upon expiration of the pharmaceutical patent of clopidogrel, generic manufacturers have started to subject interchangeable formulations to bioequivalence studies. The purpose of the current investigation was to study the effect of selection of volunteers homozygous for the CYP2C19FNx011 haplotype on the bioavailability of clopidogrel. A regular 2×2 bioequivalence study between two formulations of clopidogrel was performed in volunteers selected and unselected for relevant CYP2C19 haplotypes for the Mexican population. It was found that selection of volunteers homozygous for the CYP2C19FNx011 haplotype, increased the stringency of bioequivalence statistics and resulted in bioinequivalence of a generic clopidogrel compound that otherwise proved equivalent when tested in an open unselected population. Augmentation of bioequivalence strictness is expected to result from pharmacogenetic selection of volunteers.

  2. Pharmacogenetic selection of volunteers increases stringency of bioequivalence studies; the case of clopidogrel.

    Science.gov (United States)

    Garcés-Eisele, J; Ruiz-Argüelles, A; Estrada-Marín, Larisa; Reyes-Núñez, Virginia; Vázquez-Pérez, R; Guzmán-García, Olga; Coutiño-Medina, R; Acosta-Sandria, Leticia; Cedillo-Carvallo, Beatriz

    2014-07-01

    Clinical response to clopidogrel varies widely due to under-dosing, drug interactions and intrinsic interindividual differences resulting from genetic polymorphisms. Cytochrome P450-2C19 is the principal enzyme involved in the activation of the prodrug and loss-of-function alleles have been described. Upon expiration of the pharmaceutical patent of clopidogrel, generic manufacturers have started to subject interchangeable formulations to bioequivalence studies. The purpose of the current investigation was to study the effect of selection of volunteers homozygous for the CYP2C19*1 haplotype on the bioavailability of clopidogrel. A regular 2×2 bioequivalence study between two formulations of clopidogrel was performed in volunteers selected and unselected for relevant CYP2C19 haplotypes for the Mexican population. It was found that selection of volunteers homozygous for the CYP2C19*1 haplotype, increased the stringency of bioequivalence statistics and resulted in bioinequivalence of a generic clopidogrel compound that otherwise proved equivalent when tested in an open unselected population. Augmentation of bioequivalence strictness is expected to result from pharmacogenetic selection of volunteers.

  3. Activity of the Recommended and Optimized Rates of Pyridate on Chickpea - Mesorhizobium mediterraneum Symbiosis

    Directory of Open Access Journals (Sweden)

    Mehdi PARSA

    2014-03-01

    Full Text Available Crop-rhizobium symbiosis can be influenced by leaching of herbicides which is unavoidable after their application. Due to an adjuvant which might help to develop the low-use-rate of herbicide, an experiment was carried out to compare the impact of the recommended rate (1200 g active ingredient ha-1 and the optimized rate (282.15 g active ingredient ha-1 of pyridate on the biological properties of eight chickpea cultivars inoculated with Mesorhizobium mediterraneum, grown in pots. Based on the required rate of herbicide to give 95% control of common lambsquarters (Chenopodium album L. value, the efficacy of pyridate improved up to 3.87-fold by adding methylated rapeseed oil to spray solution. The ‘Desi’ cultivar had significantly higher nodulation than ‘Kabuli’ cultivar. In general, toxicity of the recommended rate was higher than the optimized rate. With the exception of root dry weight, all of the measured parameters were significantly affected by the recommended rate of pyridate in varying degrees. The symbiotic properties of chickpea cultivars were affected more than 10% at the recommended dose. The reduced nodulation ranged from 29% to 73% among cultivars exposed to pyridate at the recommended dose. The ‘Desi’ cultivar was more sensitive than the ‘Kabuli’ to the recommended rate of pyridate. We may conclude that effective low-use-rate of pyridate via applying of activator adjuvants should be noted.

  4. Significance of metabolites in bioequivalence: losartan potassium as a case study.

    Science.gov (United States)

    Charoo, Naseem Ahmad; Cristofoletti, Rodrigo; Khatri, Aamer Roshanali; Ali, Areeg Anwer

    2014-06-01

    Estimation of metabolite data as a supportive evidence of comparable therapeutic outcome is recommended by various guidance documents. However, a consensus on using it solely to establish bioequivalence (BE) is lacking as parent drug is believed to detect pharmacokinetic differences between test and reference formulations better. Four BE studies of losartan potassium reported in the literature are reviewed. In all the four studies, 90% confidence intervals (CIs) of geometric mean ratios of the test and reference formulations for maximum blood drug concentration (Cmax ) of losartan potassium were outside the acceptable range of 80%-125%, whereas, 90% CIs for its active metabolite, losartan carboxylic acid (LCA), were within the acceptance criteria. Although BE with respect to area under the plasma concentration versus time profile curve was demonstrated in all the cases, BE with respect to Cmax could not be established. However, marketing authorization in all the four cases was granted based on scientific evidence that LCA is 10-40 times more potent than losartan, LCA exhibited higher plasma concentration levels than losartan, pharmacodynamic effects correlate with LCA, and losartan shows wide therapeutic index. Further, widened CI limits for losartan were accepted. Losartan presents an opportunity in the diligence of the principles of quality risk management for selecting moiety on which BE decision must be based.

  5. [GENERIC DRUGS: IS BIOEQUIVALENCE SUFFICIENT TO ENSURE QUALITY, EFFICACY AND SAFETY?].

    Science.gov (United States)

    Carrillo Norte, Juan Antonio; Postigo Mota, Salvador

    2015-05-01

    This article is focusing on the current debate that prescription of generic drugs is producing among patients and healthcare professionals. Following European Medicine Agency (EMA) recommendations, a number of generic medicines have recently been withdrawn from the market in Spain. The authorization for these generic drugs was primarily based on clinical studies conducted at GVK Biosciences in Hyderabad, India. The EMA inspection of GVK revealed data manipulation of electrocardiograms during the development of some studies of generic medicines. These manipulations had taken place over a period of at least five years. The article is also dealing with the consideration that bioavailability and bioequivalence studies receive as a cornerstone to approve generic drugs, and the discrepancies between the national regulatory agencies of medicines to implement guidelines of approval. Likewise, in the last few years, the rapid expansion of clinical trial activity regarding generic medicines and other drugs in emerging markets, is often leading to doubt on the integrity of the way trials were performed and on the reliability of data obtained from these studies.

  6. Resolving the physiological conditions in bioavailability and bioequivalence studies: Comparison of fasted and fed state.

    Science.gov (United States)

    Schneider, Felix; Grimm, Michael; Koziolek, Mirko; Modeß, Christiane; Dokter, Anne; Roustom, Tarek; Siegmund, Werner; Weitschies, Werner

    2016-11-01

    In the present study temperature, pH and pressure profiles of nine healthy human volunteers were investigated after ingestion of the SmartPill® under conditions simulating the fasted state treatment in bioavailability and bioequivalence studies. In a previously published study the same subjects received the SmartPill® under fed conditions as recommended by the FDA. Since large non-digestible objects are mainly emptied during phase III of the interdigestive migrating motor complex, the gastric residence time of the SmartPill® was found to be clearly shorter under fasting conditions. Intragastric pH values during the initial 5min were similar with an identical median value of pH 4.6. Interestingly, the median lowest observed intragastric pH value in fasted state was about one pH unit higher than that under fed conditions. Highest pressure activity was observed within the stomach, in relation to gastric emptying. In fasted state, pressure values upon gastric emptying varied strongly between 30mbar and 304mbar, whereas after fed state ingestion values of at least 240mbar could always be observed. The data showed highly variable gastrointestinal parameters even under fasting conditions which must be considered when evaluating clinical studies and developing biorelevant in vitro test methods especially for large non-disintegrating dosage forms.

  7. On the bioavailability of oral chondroitin sulfate formulations: proposed criteria for bioequivalence studies.

    Science.gov (United States)

    Vergés, Josep; Castañeda-Hernández, Gilberto

    2004-01-01

    Chondroitin sulfate (CS) is a symptomatic slow-acting drug for osteoarthritis (SYSADOA). It should be noted, however, that there is a CS formulation approved as a drug in Europe, with evidenced efficacy and safety demonstrated by clinical trials in osteoarthritic patients. This formulation should therefore be considered as the reference product. This CS is manufactured by Bioibérica (Spain), commercialized in Europe by IBSA (Switzerland) and Bioibérica, and in the United States by Nutramax. Hence, all other CS formulations must demonstrate their bioequivalence with the reference product. Pharmacokinetic studies have shown that oral exogenous CS is absorbed as several metabolites, and the active moiety has not yet been identified. It is thus difficult to establish bioequivalence from plasma concentration against time curves. However, the FDA permits bioequivalence studies comparing the time course of the pharmacological response with two formulations of the same compound. It has been reported that the time course of CS response can be fitted to a modified Hill equation, as follows: E-E0=[(Emax x Ty )/(T50y+Ty)]. Where E is the effect at time T, E0 is the basal effect, Emax is the maximal effect, T50 is the time required to achieve 50% of the maximal effect and y is the sigmoid slope factor. Hence, it is proposed that a generic CS can be compared to the reference product using the Emax, T50, and y values derived by non-linear regression fitting to the modified Hill equation. The reference/test formulation ratio with the 90% confidence intervals (CI) can thus be estimated. If CI for each parameter ratio lies within 0.8-1.2, both CS formulations can be considered as bioequivalent. In the absence of such bioequivalence studies, physicians and patients are advised to use the reference product to obtain the maximal benefit in terms of efficacy and safety.

  8. Physical activity during soccer and its contribution to physical activity recommendations in normal weight and overweight children.

    Science.gov (United States)

    Sacheck, Jennifer M; Nelson, Tara; Ficker, Laura; Kafka, Tamar; Kuder, Julia; Economos, Christina D

    2011-05-01

    Amid the childhood obesity epidemic, understanding how organized sports participation contributes to meeting physical activity recommendations in children is important. Anthropometrics were measured in children (n = 111; 68% female, 9.1 ± 0.8 yr) before one 50-min soccer match. Time spent at different physical activity intensity levels was examined using Actigraph accelerometers. 49% of the match time was spent in sedentary activity (25.4 ± 5.7 min), while 33% of the match (16.9 ± 4.7 min) was spent in moderate-to-vigorous activity (MVPA; p children were overweight/obese and spent more time in sedentary activity (+3.2 ± 1.2 min; p children. These data demonstrate that playing an organized sport such as soccer only meets a portion (~25%) of the 60 min of MVPA recommended and even less of this recommendation is met by overweight/obese children.

  9. An eutomer/distomer ratio near unity does not justify non-enantiospecific assay methods in bioequivalence studies.

    Science.gov (United States)

    García-Arieta, Alfredo; Abad-Santos, Francisco; Rodríguez-Martínez, M Angeles; Varas-Polo, Yolanda; Novalbos, Jesús; Laparidis, Nikos; Gallego-Sandín, Sonia; Orfanidis, Kyriakos; Torrado, Juan

    2005-10-01

    The aim of the present investigation was to compare the pharmacokinetics of two tablet formulations of 600 mg of racemic ibuprofen obtained using enantiospecific and non-enantiospecific assays, in order to explore if chiral assays should be employed in bioequivalence studies of chiral active substances. The stereoselective assay showed that, for both formulations, there was an initial phase where (R)-ibuprofen was the predominant enantiomer followed by a final phase where (S)-ibuprofen was the predominant one. Results from both analytical methods proved that the two formulations were bioequivalent. However, the chiral bioanalytical method detected a larger difference in the eutomer than that showed by the nonchiral bioanalytical method. In conclusion, although the exposure ratios of enantiomers are near unity, the measurement of unresolved ibuprofen alone is not an adequate measure of bioequivalence since it may mask the actual difference in the eutomer exposure among formulations.

  10. Bioequivalence study designs for generic solid oral anticancer drug products: scientific and regulatory considerations.

    Science.gov (United States)

    Kaur, Paramjeet; Chaurasia, Chandra S; Davit, Barbara M; Conner, Dale P

    2013-12-01

    The demonstration of bioequivalence (BE) between the test and reference products is an integral part of generic drug approval process. A sound BE study design is pivotal to the successful demonstration of BE of generic drugs to their corresponding reference listed drug product. Generally, BE of systemically acting oral dosage forms is demonstrated in a crossover, single-dose in vivo study in healthy subjects. The determination of BE of solid oral anticancer drug products is associated with its own unique challenges due to the serious safety risks involved. Unlike typical BE study in healthy subjects, the safety issues often necessitate conducting BE studies in cancer patients. Such BE studies of an anticancer drug should be conducted without disturbing the patients' therapeutic dosing regimen. Attributes such as drug permeability and solubility, pharmacokinetics, dosing regimen, and approved therapeutic indication(s) are considered in the BE study design of solid anticancer drug products. To streamline the drug approval process, the Division of Bioequivalence posts the Bioequivalence Recommendations for Specific Products guidances on the FDA public website. The objective of this article is to illustrate the scientific and regulatory considerations in the design of BE studies for generic solid oral anticancer drug products through examples.

  11. Bioavailability, Bioequivalence and Therapeutic Equivalence: Concepts and Issues for Pharmacy Students.

    Science.gov (United States)

    Edwards, David J.

    1990-01-01

    A lecture given in courses in applied pharmacokinetics at Wayne State University, Michigan, is presented. The definition of bioavailability is reviewed along with methods of calculation, bioequivalence, criteria for establishing bioequivalence of a new product, essentials of a bioequivalence study, and the relationship between bioequivalence and…

  12. Reporting disease activity in clinical trials of patients with rheumatoid arthritis: EULAR/ACR collaborative recommendations.

    NARCIS (Netherlands)

    Aletaha, D.; Landewe, R.B.; Karonitsch, T.; Bathon, J.; Boers, M.; Bombardier, C.; Bombardieri, S.; Choi, H.; Combe, B.; Dougados, M.; Emery, P.; Gomez-Reino, J.; Keystone, E.C.; Koch, G.; Kvien, T.K.; Martin-Mola, E.; Matucci-Cerinic, M.; Michaud, K.; O'Dell, J.; Paulus, H.; Pincus, T.; Richards, P.; Simon, L.; Siegel, J.; Smolen, J.S.; Sokka, T.; Strand, V.; Tugwell, P.; Heijde, D. van der; Riel, P.L.C.M. van; Vlad, S.; Vollenhoven, R. van; Ward, M.; Weinblatt, M.; Wells, G.A.; White, B.; Wolfe, F.; Zhang, B.; Zink, A.; Felson, D.T.

    2008-01-01

    OBJECTIVE: To make recommendations on how to report disease activity in clinical trials of rheumatoid arthritis (RA) endorsed by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). METHODS: The project followed the EULAR standardized operating procedures, w

  13. Reporting disease activity in clinical trials of patients with rheumatoid arthritis: EULAR/ACR collaborative recommendations.

    NARCIS (Netherlands)

    Aletaha, D.; Landewe, R.B.; Karonitsch, T.; Bathon, J.; Boers, M.; Bombardier, C.; Bombardieri, S.; Choi, H.; Combe, B.; Dougados, M.; Emery, P.; Gomez-Reino, J.; Keystone, E.C.; Koch, G.; Kvien, T.K.; Martin-Mola, E.; Matucci-Cerinic, M.; Michaud, K.; O'Dell, J.; Paulus, H.; Pincus, T.; Richards, P.; Simon, L.; Siegel, J.; Smolen, J.S.; Sokka, T.; Strand, V.; Tugwell, P.; Heijde, D. van der; Riel, P.L.C.M. van; Vlad, S.; Vollenhoven, R. van; Ward, M.; Weinblatt, M.; Wells, G.A.; White, B.; Wolfe, F.; Zhang, B.; Zink, A.; Felson, D.T.

    2008-01-01

    OBJECTIVE: To make recommendations on how to report disease activity in clinical trials of rheumatoid arthritis (RA) endorsed by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). METHODS: The project followed the EULAR standardised operating procedures, w

  14. Multiplicity adjustments in testing for bioequivalence.

    Science.gov (United States)

    Hua, Steven Y; Xu, Siyan; D'Agostino, Ralph B

    2015-01-30

    Bioequivalence of two drugs is usually demonstrated by rejecting two one-sided null hypotheses using the two one-sided tests for pharmacokinetic parameters: area under the concentration-time curve (AUC) and maximum concentration (Cmax). By virtue of the intersection-union test, there is no need for multiplicity adjustment in testing the two one-sided null hypotheses within each parameter. However, the decision rule for bioequivalence often requires equivalence to be achieved simultaneously on both parameters that contain four one-sided null hypotheses together; without adjusting for multiplicity, the family wise error rate (FWER) could fail to be controlled at the nominal type-I error rate α. The multiplicity issue for bioequivalence in this regard is scarcely discussed in the literature. To address this issue, we propose two approaches including a closed test procedure that controls FWER for the simultaneous AUC and Cmax bioequivalence and requires no adjustment of the type-I error, and an alpha-adaptive sequential testing (AAST) that controls FWER by pre-specifying the significance level on AUC (α1) and obtaining it for Cmax (α2) adaptively after testing of AUC. While both methods control FWER, the closed test requires testing of eight intersection null hypotheses each at α, and AAST is at times accomplished through a slight deduction in α1 and no deduction in α2 relative to α. The latter considers equivalence reached in AUC a higher importance than that in Cmax. Illustrated with published data, the two approaches, although operate differently, can lead to the same substantive conclusion and are better than a traditional method like Bonferroni adjustment.

  15. Organizational aspects of conducting of bioequivalence study

    Directory of Open Access Journals (Sweden)

    Khokhlov A.L.

    2014-03-01

    Full Text Available Aim: to evaluate the organizational aspects of conducting bioequivalence study in Russia on the example of one of the clinical centers, Yaroslavl. Material and methods. On the basis of the Municipal Autonomous institution of health care of the Yaroslavl region Clinical hospital №2 (CH, clinical base of the Department of clinical pharmacology of YSMA was held 93 bioequivalence studies and pharmacokinetics in the period from 2011 to 2014, of which 15 studies of foreign sponsors and 78 of domestic producers. Result.: The studies involved 48 volunteers of both sexes from the database of clinical center CH №2. There were 698 females (48.6% and 739 males (51.4%. The average age of the volunteers was 26,37 years. In each study there were from 18 to 103 volunteers, depending on the design of the research Protocol. At the same time Russian studies ranged about 18-24 volunteers, about 30-103 volunteers abroad. The number of doubles in domestic studies ranged from 2 to 6 persons, and foreign — from 6 to 12 people. 10-15% from the whole number of subjects were not included into the study. Conclusion. In Russia bioequivalence of medicines for more than ten years is the main requirement of medico-biological control generic drugs. Regardless of the manufacturer to the generic drugs are exactly the same as the original drugs, must meet the following requirements: quality efficiency and safety. In connection with the increase in recent years of bioequivalence studies of medicines, require close monitoring of the quality of these studies on the territory of the Russian Federation.

  16. [Application of multilevel models in the evaluation of bioequivalence (II).].

    Science.gov (United States)

    Liu, Qiao-lan; Shen, Zhuo-zhi; Li, Xiao-song; Chen, Feng; Yang, Min

    2010-03-01

    The main purpose of this paper is to explore the applicability of multivariate multilevel models for bioequivalence evaluation. Using an example of a 4 x 4 cross-over test design in evaluating bioequivalence of homemade and imported rosiglitazone maleate tablets, this paper illustrated the multivariate-model-based method for partitioning total variances of ln(AUC) and ln(C(max)) in the framework of multilevel models. It examined the feasibility of multivariate multilevel models in directly evaluating average bioequivalence (ABE), population bioequivalence (PBE) and individual bioequivalence (IBE). Taking into account the correlation between ln(AUC) and ln(C(max)) of rosiglitazone maleate tablets, the proposed models suggested no statistical difference between the two effect measures in their ABE bioequivalence via joint tests, whilst a contradictive conclusion was derived based on univariate multilevel models. Furthermore, the PBE and IBE for both ln(AUC) and ln(C(max)) of the two types of tablets were assessed with no statistical difference based on estimates of variance components from the proposed models. Multivariate multilevel models could be used to analyze bioequivalence of multiple effect measures simultaneously and they provided a new way of statistical analysis to evaluate bioequivalence.

  17. Comparative study of the recommended methodologies by CLSI and EUCAST for activity evaluation antifungal

    OpenAIRE

    2009-01-01

    The international organizations CLSI and EUCAST developed reference methodologies for activity evaluation antifungal. The aim of this work was to compare the recommended methodologies by the CLSI and EUCAST in the antifungal activity evaluation of crude extracts of Azadirachta indica and green propolis. The results showed that the MIC values determined by the EUCAST methodology were smaller than that determined by the CLSI. Nevertheless, both methodologies were satisfactory to detect and eval...

  18. Recommendations for Promoting Physical Activity for Children and Adolescents in Germany. A Consensus Statement

    Directory of Open Access Journals (Sweden)

    Christine Graf

    2014-05-01

    Full Text Available Increasing physical activity and reduction of sedentary behaviour play important roles in health promotion and prevention of lifestyle-related diseases in children and adolescents. However, the question of how much physical activity is useful for which target group is still a matter of debate. International guidelines (World Health Organization; European Association for the Study of Obesity, which are mainly based on expert opinions, recommend 60 min of physical activity every day. Age- and sex-specific features and regional differences are not taken into account. Therefore, expert consensus recommendations for promoting physical activity of children and adolescents in Germany were developed with special respect to national data, but also with respect to aspects of specific target groups, e.g., children with a lower socio-economic status (SES or with migration background. They propose 90 min/day of physical activity, or at least 12,000 steps daily. Additionally, lifestyle factors, especially restriction of media consumption, were integrated. The recommendations provide orientation for parents and caregivers, for institutions such as schools and kindergartens as well as for communities and stakeholders.

  19. Pharmacogenetic Selection of Volunteers Increases Stringency of Bioequivalence Studies; The Case of Clopidogrel

    OpenAIRE

    Garcés-Eisele, J.; Ruiz-Argüelles, A.; Larisa Estrada-Marín; Virginia Reyes-Núñez; R Vázquez-Pérez; Olga Guzmán-García; R Coutiño-Medina; Leticia Acosta-Sandria; Beatriz Cedillo-Carvallo

    2014-01-01

    Clinical response to clopidogrel varies widely due to under-dosing, drug interactions and intrinsic interindividual differences resulting from genetic polymorphisms. Cytochrome P450-2C19 is the principal enzyme involved in the activation of the prodrug and loss-of-function alleles have been described. Upon expiration of the pharmaceutical patent of clopidogrel, generic manufacturers have started to subject interchangeable formulations to bioequivalence studies. The purpose of the current inve...

  20. Recommending scientific organization by employees as the example of their prosumer activity

    Directory of Open Access Journals (Sweden)

    Agnieszka Izabela Baruk

    2015-09-01

    Full Text Available In the article the problems related to recommending the employer by employees are presented. It is described as the example of employees’ prosumption activity. Transmitting their opinions about the organization as the employer they become the co-creators its image which is one of the key non-material marketing values. The article has theoretical-empirical character. In the theoretical part the essence of prosumption is presented. The special attention is paid to fact that in the literature this appearance is linked with consumption products not with personnel activity. In the empirical part the results of the field researches on recommending employer and its relation determinants are presented. The statistical analysis in the form of correspondence analysis method has been used to these results. It allows to estimate the dependences between analysed variables, to define the power of identified dependences, to show their character, to sort the relation determinants of recommending in the hierarchical system etc. All of the analysed dependences are significant in the statistically meaning. The stronger dependence exists in the case of vertical relation variable in the comparison to the dependence between recommending employer and horizontal relation variable. Of course each of type of organizational relations should be supported by employer because it influences on employees’ identifying with the organization which is the key determinant of the column variable.

  1. Therapy students' recommendations of physical activity for managing persistent low back pain in older adults.

    Science.gov (United States)

    Ryan, Cormac G; Schofield, Patricia; Martin, Denis J

    2013-07-01

    Negative views of older adults can lead to suboptimal care. For older adults with persistent low back pain (LBP), promotion of physical activity by health care professionals is important. Health care professionals' views of older adults are influenced by their training. This study aimed to compare recommendations for physical activity for managing persistent LBP offered by students in physiotherapy and occupational therapy to an older person vs. a younger person. In a cross-sectional online survey, participants (N = 77) randomly received a vignette of either a 40-yr-old or 70-yr-old patient with persistent LBP. Other than age, the vignettes were identical. There was no difference between the younger and older vignettes in the likelihood of participants making overall appropriate physical activity recommendations--63% vs. 59%, OR (95% CI) = 1.19 (0.48-2.99), p = .71--although there was a trend toward age bias on recommendations specific to daily activity. Postqualification education may be where ageist views need to be addressed.

  2. Tourist activated networks: Implications for dynamic bundling and en-route recommendations

    DEFF Research Database (Denmark)

    Zach, Florian; Gretzel, Ulrike

    2011-01-01

    This article discusses tourist-activated networks as a concept to inform technological applications supporting dynamic bundling and en route recommendations. Empirical data were collected from travelers who visited a regional destination in the US and then analyzed with respect to its network...... structure. The results indicate that the tourist-activated network for the destination is rather sparse and that there are clearly differences in core and peripheral nodes. The findings illustrate the structure of a tourist-activated network and provide implications for technology design and tourism...

  3. The benefits of exercise for patients with haemophilia and recommendations for safe and effective physical activity.

    Science.gov (United States)

    Negrier, C; Seuser, A; Forsyth, A; Lobet, S; Llinas, A; Rosas, M; Heijnen, L

    2013-07-01

    Most health care professionals involved in the management of people with haemophilia (PWH) believe that exercise is beneficial and its practice is widely encouraged. This article aims to demonstrate that appropriate exercise (adapted to the special needs of the individual PWH) may be beneficial for all PWH through improved physical, psychosocial and medical status. Based on evidence gathered from the literature, many PWH, particularly those using long-term prophylaxis or exhibiting a mild/moderate bleeding phenotype, are as active as their healthy peers. PWH experience the same benefits of exercise as the general population, being physically healthier than if sedentary and enjoying a higher quality of life (QoL) through social inclusion and higher self-esteem. PWH can also gain physically from increased muscle strength, joint health, balance and flexibility achieved through physiotherapy, physical activity, exercise and sport. Conversely, very little data exist on activity levels of PWH in countries with limited resources. However, regarding specific exercise recommendations in PWH, there is a lack of randomized clinical trials, and consequently formal, evidence-based guidelines have not been produced. Based on published evidence from this review of the literature, together with the clinical experience of the authors, a series of recommendations for the safe participation of PWH in regular physical activities, exercises and sport are now proposed. In summary, we believe that appropriately modified programmes can potentially allow all PWH to experience the physical and psychosocial benefits of being physically active which may ultimately lead to an improved QoL.

  4. [Activating physiotherapy for chronic pain in elderly patients. Recommendations, barriers and resources].

    Science.gov (United States)

    Kuss, K; Laekeman, M

    2015-08-01

    Elderly patients with chronic pain are particularly at risk of functional limitations up to the loss of autonomy and social life. To facilitate autonomy, mobility and quality of life, physiotherapy plays an essential role in pain management. Nevertheless, programs that are specifically geared towards the needs of older patients are still uncommon. This article offers recommendations for structuring physiotherapy programs based on international guideline recommendations. First examples of pain management concepts for older adults demonstrate the positive results of activating therapy. Additionally, this article provides insights into barriers and resources of affected patients and all actors involved. However, physiotherapeutic treatment for aged chronic pain patients in Germany still shows considerable shortcomings but also offers an exciting challenge for the future.

  5. The study of bioavailability and bioequivalence of oseltamivir in Chinese health volunteers

    Institute of Scientific and Technical Information of China (English)

    LI Jing-lai; CUI Meng-cun; WANG Xiao-ying; QIAO Jian-zhong; YUAN Su-lan; ZHANG Zhen-qing; RUAN Jin-xiu; ZHONG Wu; LI Song

    2008-01-01

    Objective To evaluate the bioavailability and bioequivalence of oseltamivir capsule in Chinese health male volunteers. Methods A randomized, two period, two treatment, two sequence crossover bioequivalence trial was designed, 24 Chinese health volunteers were randomly divided into two groups, each group was orally given single dose oseltamivir phosphate (tamifla) or AMMS 607 capsule. The active metabolite oseltamivir carboxylate of oseltamivir in the plasma were determined by liquid chromatographic-tandem mass spectrometric (LC-MS/MS) method. The pharmacokinetics parameters and relative bioavailability were calculated to evaluate the bioequivalence of AMMS 607 and tamifla. Results Cmax of the AMMS 607 and tamifla were 602.07±153.27 ng·mL-1 and 620.09±132.39 ng·mL-1 respectively; tmax were 4.2± 1.1 h and 4.8±1.0 h; t1/2β were 6.60±0.87 h and 6.61±0.83 h;MRT were 10.00±1.77 h and 10.40 ±1.62 h; AUC0-24 were 6285.88±1083.66 ng·h·mL-1 and 6546.01±1199.32 ng·h·mL-1; Compared with the reference of tamifla capsule, the bioavailability F0-tn of AMMS 607 capsule was 99.5±27.7 %. The main pharmacokinetics parameters of AUC0-24, Cmax and Tmax showed no statistically significant difference between the two capsules. Conclusions The AMMS 607 capsule and tamifla capsule are bioequivalent.

  6. BIOEQUIVALENCE STUDY OF TWO ORAL FORMULATIONS OF METAMIZOLE 500 MG IN HEALTHY VOLUNTEERS

    Directory of Open Access Journals (Sweden)

    Dhaneshwar Shep *, Rakesh Ojha , Rajeshwari Rathod , Sweta Patel , Manish Nivsarkar , Sanjay Maroo and Harish Padh

    2012-06-01

    Full Text Available Background: Metamizole (Dipyrone is widely used and has effective analgesic, antipyretic, and antispasmodic properties. After oral or intravenous administration, dipyrone is rapidly hydrolyzed to the active moiety 4-methylaminoantipyrine. Aim: The aim of this study was to assess the bioequivalence of 2 oral formulations of Metamizole 500 mg. Methods: This double blind, randomized, single-dose, 2-period crossover study in healthy Indian adult volunteers was conducted at PERD Centre, Ahmedabad. Subjects received Metamizole 500 mg of either test or reference formulation with a washout period of 7 days. After study drug administration, serial blood samples were collected over a period of 24 hours. Plasma concentration of 4-methylaminoantipyrine was measured by pre-validated LC-MS method. Pharmacokinetic (PK parameters Cmax, Tmax, t1/2, AUC0-t, AUC0-∞, and kel, were determined for test and reference formulations. The formulations were to be considered bioequivalent if the log-transformed ratios of Cmax, AUC0-t, and AUC0-∞ were within the predetermined bioequivalence range of 80% to 125%. Results: A total of 14 subjects were enrolled. No significant differences were found based on analysis of variance, with mean values and 90% confidence intervals of test/reference ratios for these parameters as follows: Cmax, 18.24 versus 18.44 μg/mL (92.68 - 106.61; AUC0-t, 92.97 Versus 91.37 μg.hr/mL (89.49 - 113.09; and AUC0-∞, 96.64 Versus 94.65 μg.hr/mL (92.31 - 111.63. Conclusion: Since the 90% confidence intervals for Cmax, AUC0-t, and AUC0−∞ were within the interval of 80-125%, it was concluded that both formulations were bioequivalent, according to both the rate and extent of absorption.

  7. Bioequivalence of generic drugs: a simple explanation for a US Food and Drug Administration requirement.

    Science.gov (United States)

    Andrade, Chittaranjan

    2015-06-01

    There is a widespread misconception that for a generic drug to be deemed bioequivalent to a branded drug, it must contain 80%-125% of the active ingredient that is present in the branded version. More correctly, bioequivalence is studied in randomized crossover trials that compare the generic drug with the reference agent, and the relevant outcome measures are pharmacokinetic (PK) parameters such as peak drug concentration and area under the curve, which describe the rate and extent of absorption of the drug. The ratio of each PK characteristic of the generic drug to the reference drug is computed; the ideal value of this ratio is 1:1, or just 1.00 (indicating a perfect match, or perfect bioequivalence). Because this ideal is probably unattainable, the US Food and Drug Administration requires that the 90% confidence interval of the PK ratio should lie between 0.80 and 1.25. For the entire 90% confidence interval to meet this requirement, the mean PK value of the generic product should actually lie quite close to that of the reference standard. Therefore, the variation between the generic and the reference is actually small. These concepts are explained in this article with the help of simple, easy-to-understand examples.

  8. Recommendations to improve physical activity among teenagers- A qualitative study with ethnic minority and European teenagers

    Directory of Open Access Journals (Sweden)

    Choudhury Sopna

    2011-05-01

    Full Text Available Abstract Background To understand the key challenges and explore recommendations from teenagers to promote physical activity with a focus on ethnic minority children. Methods Focus groups with teenagers aged 16-18 of Bangladeshi, Somali or Welsh descent attending a participating school in South Wales, UK. There were seventy four participants (18 Somali, 24 Bangladeshi and 32 Welsh children divided into 12 focus groups. Results The boys were more positive about the benefits of exercise than the girls and felt there were not enough facilities or enough opportunity for unsupervised activity. The girls felt there was a lack of support to exercise from their family. All the children felt that attitudes to activity for teenagers needed to change, so that there was more family and community support for girls to be active and for boys to have freedom to do activities they wanted without formal supervision. It was felt that older children from all ethnic backgrounds should be involved more in delivering activities and schools needs to provide more frequent and a wider range of activities. Conclusions This study takes a child-focused approach to explore how interventions should be designed to promote physical activity in youth. Interventions need to improve access to facilities but also counteract attitudes that teenagers should be studying or working and not 'hanging about' playing with friends. Thus, the value of activity for teenagers needs to be promoted not just among the teenagers but with their teachers, parents and members of the community.

  9. [The bioequivalence of two oral propafenone preparations].

    Science.gov (United States)

    Koytchev, R; Alken, R G; Mayer, O; Böhm, R; Ellrich, A; Waldner-Kölblin, R G

    1995-05-01

    The bioequivalence of two oral racemic propafenone (CAS 54063-53-5) preparations was tested in an open, randomised, crossover trial with administration of single doses of 300 mg on two different occasions with a washout period of 7 days. 24 healthy, male volunteers, all proved to be rapid hydroxylators of debrisoquine, were enrolled in the trial. The concentrations of R(+)-, S(-)-propafenone and 5-hydroxypropafenone (5-OH-propafenone) were measured up to 12 h after administration by means of a sensitive and specific HPLC method that allowed the simultaneous quantification of all three substances in plasma. The results of 23 volunteers were evaluated pharmacokinetically. Main target parameters were AUC0-infinity and Cmax of both enantiomers of propafenone. Secondary target parameters were AUC0-infinity and Cmax of 5-OH-propafenone as well as tmax for R(+)- and S(-)-propafenone. The 90% confidence intervals for AUC0-infinity for R(+)-, S(-)-, and 5-OH-propafenone were 0.85-1.07, 0.83-1.10 and 0.84-1.05, respectively. The confidence intervals for Cmax were 0.81-1.12, 0.82-1.17 and 0.87-1.09 for R-, S-, and 5-OH-propafenone, respectively. The concentration maxima of both enantiomers were registered on average 15 min earlier after administration of the test preparation. This difference is of no clinical relevance. Both preparations are bioequivalent according to the criteria of the Committee for Proprietary Medicinal Products (CPMP).

  10. Effect of the Wetting Agent Sodium Lauryl Sulfate on the Pharmacokinetics of Alectinib: Results From a Bioequivalence Study in Healthy Subjects.

    Science.gov (United States)

    Morcos, Peter N; Parrott, Neil; Banken, Ludger; Timpe, Carsten; Lindenberg, Marc; Guerini, Elena; Dall, Georgina; Bogman, Katrijn; Sturm, Carolina; Zeaiter, Ali; Martin-Facklam, Meret; Phipps, Alex

    2016-08-22

    The anaplastic lymphoma kinase (ALK) inhibitor alectinib is an effective treatment for ALK-positive non-small-cell lung cancer. This bioequivalence study evaluated the in vivo performance of test 3 formulations with the reduced wetting agent sodium lauryl sulfate (SLS) content. This randomized, 4-period, 4-sequence, crossover study compared alectinib (600 mg) as 25%, 12.5%, and 3% SLS hard capsule formulations with the reference 50% SLS clinical formulation in healthy subjects under fasted conditions (n = 49), and following a high-fat meal (n = 48). Geometric mean ratios and 90% confidence intervals (CIs) for Cmax , AUC0-last , and AUC0-∞ of alectinib, its major active metabolite, M4, and alectinib plus M4 were determined for the test formulations versus the reference formulation. Bioequivalence was concluded if the 90%CIs were within the 80% to 125% boundaries. The 25% SLS formulation demonstrated bioequivalence to the reference 50% SLS formulation for Cmax , AUC0-last , and AUC0-∞ of alectinib, M4, and alectinib plus M4 under both fasted and fed conditions. Further reductions in SLS content (12.5% and 3% SLS) did not meet the bioequivalence criteria. Cross-group comparisons showed an approximately 3-fold positive food effect. Reducing SLS to 25% resulted in a formulation that is bioequivalent to the current 50% SLS formulation used in alectinib pivotal trials.

  11. Recommended administered activities for {sup 68}Ga-labelled peptides in paediatric nuclear medicine

    Energy Technology Data Exchange (ETDEWEB)

    Machado, J.S.; Beykan, S.; Lassmann, M. [University Hospital Wuerzburg, Department of Nuclear Medicine, Wuerzburg (Germany); Herrmann, K. [University Hospital Wuerzburg, Department of Nuclear Medicine, Wuerzburg (Germany); David Geffen School of Medicine at UCLA, Department of Molecular and Medical Pharmacology, Los Angeles, CA (United States)

    2016-10-15

    The aim of this study was to establish a method for determining administered activities for {sup 68}Ga-labelled peptides. Dose calculations were based on the weight-independent effective dose model proposed by the EANM paediatric dosage card for use in paediatric nuclear medicine. Previously published time-integrated activity coefficients for {sup 68}Ga-DOTATATE, {sup 68}Ga-DOTATOC and {sup 68}Ga-pentixafor were used to calculate age-independent effective doses. Consequently, the corresponding weight-dependent effective dose coefficients were rescaled according to the formalism of the EANM dosage card to determine the radiopharmaceutical class of {sup 68}Ga-labelled peptides (''multiples'') and to calculate the baseline activities based on an upper limit for administered activity (185 MBq) in an adult. All calculated normalization factors suggest that the {sup 68}Ga-labelled peptides are class ''B'' radiopharmaceuticals. The baseline activity for all compounds is 12.8 MBq. In analogy to {sup 18}F-fluoride, we recommend a minimum activity of 14 MBq. For paediatric nuclear medicine applications involving {sup 68}Ga-labelled peptides, we suggest determining administered activities based on the formalism proposed in this work. The corresponding effective doses from these procedures will remain age-independent. (orig.)

  12. Sedentary behaviour and physical activity in South Asian women: time to review current recommendations?

    Directory of Open Access Journals (Sweden)

    Indu Waidyatilaka

    Full Text Available OBJECTIVE: Our aims were to describe activity and sedentary behaviours in urban Asian women, with dysglycaemia (diagnosed at recruitment, and without dysglycaemia and examine the relative contribution of these parameters to their glycaemic status. METHODS: 2800 urban women (30-45 years were selected by random cluster sampling and screened for dysglycaemia for a final sample of 272 newly diagnosed, drug naive dysglycaemic and 345 normoglycaemic women. Physical activity and sedentary behaviours were assessed by the International Physical Activity Questionnaire (IPAQ. Demographic data, diet and anthropometry were recorded. Logistic regression analysis assessed contribution of all parameters to dysglycaemia and exposure attributable fractions were calculated. RESULTS: The mean energy expenditure on walking (2648.5±1023.7 MET-min/week and on moderate and vigorous physical activity (4342.3±1768.1 MET-min/week for normoglycemic women and dysglycaemic women (walking;1046.4±728.4 MET-min/week, moderate and vigorous physical activity; 1086.7±1184.4 MET-min/week was above the recommended amount of physical activity per week. 94.3% of women spent >1000 MET-minutes/week on activity. Mean sitting and TV time for normoglycaemic and dysglycaemic women were 154.3±62.8, 38.4±31.9, 312.6±116.7 and 140.2±56.5 minutes per day respectively. Physical activity and sedentary behaviour contributed to dysglycaemia after adjustment for family history, diet, systolic blood pressure and Body Mass Index. Exposure attributable fractions for dysglycaemia were; lower physical activity: 78%, higher waist circumference: 94%, and TV viewing time: 85%. CONCLUSIONS: Urban South Asian women are at risk of dysglycaemia at lower levels of sedentary behaviour and greater physical activity than western populations, indicating the need for re-visiting current physical activity guidelines for South Asians.

  13. Are marketed topical metronidazole creams bioequivalent? Evaluation by in vivo microdialysis sampling and tape stripping methodology

    DEFF Research Database (Denmark)

    Garcia Ortiz, Patricia Elodia; Hansen, S H; Shah, Surendra P.

    2011-01-01

    To evaluate the bioequivalence of 3 marketed topical metronidazole formulations by simultaneous dermal microdialysis and stratum corneum sampling by the tape stripping methodology, and to compare the techniques as tools for the determination of bioequivalence....

  14. 78 FR 73199 - Draft Guidance for Industry on Bioequivalence Studies With Pharmacokinetic Endpoints for Drugs...

    Science.gov (United States)

    2013-12-05

    ... HUMAN SERVICES Food and Drug Administration Draft Guidance for Industry on Bioequivalence Studies With Pharmacokinetic Endpoints for Drugs Submitted Under an Abbreviated New Drug Application; Availability AGENCY: Food... guidances to industry on ``Bioavailability and Bioequivalence Studies for Orally Administered Drug...

  15. Are marketed topical metronidazole creamas bioequivalent ? Evaluation by in vivo microdialysis sampling and tape stripping methodology

    DEFF Research Database (Denmark)

    Ortiz, P. Garcia; Hansen, Steen Honore'; Shah, V. P.;

    2011-01-01

    To evaluate the bioequivalence of 3 marketed topical metronidazole formulations by simultaneous dermal microdialysis and stratum corneum sampling by the tape stripping methodology, and to compare the techniques as tools for the determination of bioequivalence.......To evaluate the bioequivalence of 3 marketed topical metronidazole formulations by simultaneous dermal microdialysis and stratum corneum sampling by the tape stripping methodology, and to compare the techniques as tools for the determination of bioequivalence....

  16. Study on requirements of bioequivalence for registration of pharmaceutical products in USA, Europe and Canada

    OpenAIRE

    Galgatte, Upendra C.; Jamdade, Vijay R.; Aute, Pravin P.; Chaudhari, Pravin D.

    2013-01-01

    The present study was aimed to study the requirements of bioequivalence for the registration of pharmaceutical products in the USA, Europe and Canada. Before going into bioequivalence studies it is essential for the pharmaceutical industry to study the guidelines of bioequivalence for the respective country where the industry wants to market its products and thus enter into generic market. This study reviews the requirements of bioequivalence with study parameters such as study design, fastin...

  17. Confidence Region Approach for Assessing Bioequivalence and Biosimilarity Accounting for Heterogeneity of Variability

    OpenAIRE

    Jianghao Li; Shein-Chung Chow

    2015-01-01

    For approval of generic drugs, the FDA requires that evidence of bioequivalence in average bioequivalence in terms of drug absorption be provided through the conduct of a bioequivalence study. A test product is said to be average bioequivalent to a reference (innovative) product if the 90% confidence interval of the ratio of means (after log-transformation) is totally within (80%, 125%). This approach is considered a one-parameter approach, which does not account for possible heterogeneity of...

  18. Physical activity levels, duration pattern and adherence to WHO recommendations in German adults

    Science.gov (United States)

    Luzak, Agnes; Heier, Margit; Thorand, Barbara; Laxy, Michael; Nowak, Dennis; Peters, Annette; Schulz, Holger

    2017-01-01

    Background Intensity and duration of physical activity are associated with the achievement of health benefits. Our aim was to characterize physical activity behavior in terms of intensity, duration pattern, and adherence to the WHO physical activity recommendations in a population-based sample of adults from southern Germany. Further, we investigated associations between physical activity and sex, age, and body mass index (BMI), considering also common chronic diseases. Methods We analyzed 475 subjects (47% males, mean age 58 years, range 48–68 years) who wore ActiGraph accelerometers for up to seven days. Measured accelerations per minute obtained from the vertical axis (uniaxial) and the vector magnitude of all three axes (triaxial) were classified as sedentary, light or moderate-to-vigorous physical activity (MVPA) according to predefined acceleration count cut-offs. The average minutes/day spent in each activity level per subject served as outcome. Associations of sex, age, BMI, and seven chronic diseases or health limitations, with the activity levels were analyzed by negative binomial regression. Results Most of the wear time was spent in sedentarism (median 61%/day), whereas the median time spent in MVPA was only 3%, with men achieving more MVPA than women (35 vs. 28 minutes/day, pdiabetes, chronic obstructive pulmonary disease, anxiety/depression, pain or walking difficulties was observed in regression analyses with MVPA as outcome. Conclusions Activity behavior among middle-aged German adults was highly insufficient, indicating a further need for physical activity promotion in order to gain health benefits. PMID:28245253

  19. 21 CFR 320.22 - Criteria for waiver of evidence of in vivo bioavailability or bioequivalence.

    Science.gov (United States)

    2010-04-01

    ... bioavailability or bioequivalence. 320.22 Section 320.22 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS Procedures for Determining the Bioavailability or Bioequivalence of Drug Products §...

  20. 21 CFR 320.21 - Requirements for submission of bioavailability and bioequivalence data.

    Science.gov (United States)

    2010-04-01

    ... bioequivalence data. 320.21 Section 320.21 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS Procedures for Determining the Bioavailability or Bioequivalence of Drug Products § 320.21 Requirements...

  1. 21 CFR 320.24 - Types of evidence to measure bioavailability or establish bioequivalence.

    Science.gov (United States)

    2010-04-01

    ... establish bioequivalence. 320.24 Section 320.24 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS Procedures for Determining the Bioavailability or Bioequivalence of Drug Products § 320.24 Types of...

  2. 21 CFR 320.36 - Requirements for maintenance of records of bioequivalence testing.

    Science.gov (United States)

    2010-04-01

    ... bioequivalence testing. 320.36 Section 320.36 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS Procedures for Determining the Bioavailability or Bioequivalence of Drug Products § 320.36 Requirements...

  3. 21 CFR 320.32 - Procedures for establishing or amending a bioequivalence requirement.

    Science.gov (United States)

    2010-04-01

    ... bioequivalence requirement. 320.32 Section 320.32 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS Procedures for Determining the Bioavailability or Bioequivalence of Drug Products § 320.32 Procedures...

  4. 21 CFR 320.29 - Analytical methods for an in vivo bioavailability or bioequivalence study.

    Science.gov (United States)

    2010-04-01

    ... or bioequivalence study. 320.29 Section 320.29 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS Procedures for Determining the Bioavailability or Bioequivalence of Drug Products §...

  5. 21 CFR 320.23 - Basis for measuring in vivo bioavailability or demonstrating bioequivalence.

    Science.gov (United States)

    2010-04-01

    ... demonstrating bioequivalence. 320.23 Section 320.23 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS Procedures for Determining the Bioavailability or Bioequivalence of Drug Products § 320.23 Basis...

  6. Additional results for 'Sequential design approaches for bioequivalence studies with crossover designs'.

    Science.gov (United States)

    Montague, Timothy H; Potvin, Diane; Diliberti, Charles E; Hauck, Walter W; Parr, Alan F; Schuirmann, Donald J

    2012-01-01

    In 2008, this group published a paper on approaches for two-stage crossover bioequivalence (BE) studies that allowed for the reestimation of the second-stage sample size based on the variance estimated from the first-stage results. The sequential methods considered used an assumed GMR of 0.95 as part of the method for determining power and sample size. This note adds results for an assumed GMR = 0.90. Two of the methods recommended for GMR = 0.95 in the earlier paper have some unacceptable increases in Type I error rate when the GMR is changed to 0.90. If a sponsor wants to assume 0.90 for the GMR, Method D is recommended. Copyright © 2011 John Wiley & Sons, Ltd.

  7. Bioequivalence of three florfenicol preparations in broilers

    Directory of Open Access Journals (Sweden)

    Husamettin Ekici

    2014-12-01

    Full Text Available This study was aimed to determine the bioequivalence of three different preparations of florfenicol using non-drugged broiler chickens. A total of 28 broiler chickens aging 30-day were divided into four equal groups; these were Group I, II, III, and IV. The birds of Group I (for effective substance were given intravenous (i.v. administration of florfenicol dosed at 40 mg/kg body weight (b.wt.. The birds of Group II (for reference drug, Group III (for test-1 drug, and Group IV (for test-2 drug received florfenicol preparations with water (dosed at 40 mg/kg b.wt. through intracrop administration. Blood samples were collected periodically from the birds of all four groups, and blood plasma was separated. Levels of florfenicol and its metabolite (florfenicol amine in the plasma were measured by High Performance Liquid Chromatography (HPLC. In this study, the limit of detection (LOD for florfenicol and florfenicol amine were recorded as 0.017 and 0.78 µg/mL, respectively. On the other hand, the recovery of florfenicol and florfenicol amine were 83.4-84.6 and 82.2-83.8%, respectively. Based on the values of area under the curve (AUC, maximum concentration (Cmax, and time to maximum concentration (Tmax, test-1 drug was found to be acceptable, whereas test-2 drug was remained below the acceptable limits (80-125% of AUC and Cmax. Thus, it was concluded that test-1 drug was bioequivalent as compared to the reference drug.

  8. Bioequivalence assessment of two formulations of ibuprofen

    Directory of Open Access Journals (Sweden)

    Al-Talla ZA

    2011-10-01

    , therefore, Doloraz was considered bioequivalent to Brufen. Keywords: ibuprofen, bioequivalence study, pharmacokinetics

  9. Supporting public health priorities: recommendations for physical education and physical activity promotion in schools.

    Science.gov (United States)

    Hills, Andrew P; Dengel, Donald R; Lubans, David R

    2015-01-01

    Physical activity (PA) provides numerous physiological and psychosocial benefits. However, lifestyle changes, including reduced PA opportunities in multiple settings, have resulted in an escalation of overweight and obesity and related health problems. Poor physical and mental health, including metabolic and cardiovascular problems is seen in progressively younger ages, and the systematic decline in school PA has contributed to this trend. Of note, the crowded school curriculum with an intense focus on academic achievement, lack of school leadership support, funding and resources, plus poor quality teaching are barriers to PA promotion in schools. The school setting and physical educators in particular, must embrace their role in public health by adopting a comprehensive school PA program. We provide an overview of key issues and challenges in the area plus best bets and recommendations for physical education and PA promotion in the school system moving forward.

  10. Evaluation of the highly variable agomelatine pharmacokinetics in Chinese healthy subjects to support bioequivalence study.

    Directory of Open Access Journals (Sweden)

    Qi Pei

    Full Text Available OBJECTIVES: We aim to obtain the intra-subject coefficient of variability of a highly variable antidepressant agomelatine in humans, and propose an adjusted bioequivalence assessment strategy. METHODS: A single-dose, randomized crossover design was conducted in four periods (reference administered thrice, placebo administered once separated by seven days. A validated LC-MS/MS assay was used to measure drug concentrations in serial blood samples. RESULTS: The intra-subject coefficient of variability was calculated using the residual variance of ANOVA analysis, and the results for Cmax and AUC0-t was 78.34% and 43.52%, respectively, in Chinese healthy subjects. The sample size required for standard BE study were 124(192, 340 if the expected deviation between the reference and generic products was set to 0 (5%, 10%. CONCLUSIONS: Agomelatine meets the criteria for highly variable drug in Chinese healthy male subjects, and the traditional BE criteria for agomelatine needs to be adjusted to alleviate the resource and ethical burden of using a large numbers of subjects in clinical trials. Our clinical data on the intra-subject variability of agomelatine PK in Chinese healthy population enables to adjust bioequivalence (BE assessment approach for agomelatine based on the RSABE approaches recommended by regulatory agencies. TRIAL REGISTRATION: ChiCTR.org ChiCTR-TTRCC-13003835.

  11. The role of the upper sample size limit in two-stage bioequivalence designs.

    Science.gov (United States)

    Karalis, Vangelis

    2013-11-01

    Two-stage designs (TSDs) are currently recommended by the regulatory authorities for bioequivalence (BE) assessment. The TSDs presented until now rely on an assumed geometric mean ratio (GMR) value of the BE metric in stage I in order to avoid inflation of type I error. In contrast, this work proposes a more realistic TSD design where sample re-estimation relies not only on the variability of stage I, but also on the observed GMR. In these cases, an upper sample size limit (UL) is introduced in order to prevent inflation of type I error. The aim of this study is to unveil the impact of UL on two TSD bioequivalence approaches which are based entirely on the interim results. Monte Carlo simulations were used to investigate several different scenarios of UL levels, within-subject variability, different starting number of subjects, and GMR. The use of UL leads to no inflation of type I error. As UL values increase, the % probability of declaring BE becomes higher. The starting sample size and the variability of the study affect type I error. Increased UL levels result in higher total sample sizes of the TSD which are more pronounced for highly variable drugs.

  12. International Guidelines for Bioequivalence of Systemically Available Orally Administered Generic Drug Products: A Survey of Similarities and Differences

    OpenAIRE

    Davit, Barbara; Braddy, April C.; Conner, Dale P.; Yu, Lawrence X.

    2013-01-01

    The objective of this article is to discuss the similarities and differences among bioequivalence approaches used by international regulatory authorities when reviewing applications for marketing new generic drug products which are systemically active and intended for oral administration. We focused on the 13 jurisdictions and organizations participating in the International Generic Drug Regulators Pilot. These are Australia, Brazil, Canada, China, Chinese Taipei, the European Medicines Assoc...

  13. Activity of the Recommended and Optimized Rates of Pyridate on Chickpea - Mesorhizobium mediterraneum Symbiosis

    Directory of Open Access Journals (Sweden)

    Mehdi PARSA

    2014-03-01

    Full Text Available Crop-rhizobium symbiosis can be influenced by leaching of herbicides which is unavoidable after their application. Due to an adjuvant which might help to develop the low-use-rate of herbicide, an experiment was carried out to compare the impact of the recommended rate (1200 g active ingredient ha-1 and the optimized rate (282.15 g active ingredient ha-1 of pyridate on the biological properties of eight chickpea cultivars inoculated with Mesorhizobium mediterraneum, grown in pots. Based on the required rate of herbicide to give 95% control of common lambsquarters (Chenopodium album L. value, the efficacy of pyridate improved up to 3.87-fold by adding methylated rapeseed oil to spray solution. The ‘Desi’ cultivar had significantly higher nodulation than ‘Kabuli’ cultivar. In general, toxicity of the recommended rate was higher than the optimized rate. With the exception of root dry weight, all of the measured parameters were significantly affected by the recommended rate of pyridate in varying degrees. The symbiotic properties of chickpea cultivars were affected more than 10% at the recommended dose. The reduced nodulation ranged from 29% to 73% among cultivars exposed to pyridate at the recommended dose. The ‘Desi’ cultivar was more sensitive than the ‘Kabuli’ to the recommended rate of pyridate. We may conclude that effective low-use-rate of pyridate via applying of activator adjuvants should be noted.

  14. A comparative, cross-over, double blind, randomized study for bioequivalence assessment between two formulations of valsartan capsules vs. tablets

    Directory of Open Access Journals (Sweden)

    Milena Pérez

    2006-06-01

    Full Text Available Introduction: Bioequivalence or compared equivalence studies are used to demonstrate claims that the new product, named generic product, will have the same bioavailability as the reference product, named brand product. If two products are bioequivalent it means that they would expect to have the same efficacy and security. Bioequivalence is established by the statistical estimation of significant differences or not in the pharmacokinetics parameters of area under the curve (AUC and maximum concentration (Cmax. In this case, bioequivalence will be evaluated and the bioavailability of Valsartan will be compared. Valsartan is an agent antihypertensive and specific angiotensin II antagonist acting on the AT1 receptor subtype. Objective: The aim of this study was to evaluate the bioequivalence of two pharmaceutical products whose active principle is Valsartan, based on the comparison of the pharmacokinetic measures of rate and extent (in terms of required time in which valsartan reaches the sanguineous circulation after a oral dose to 15 volunteers. Metodology: This was a randomized crossover double blind single-dose study on 15 male healthy volunteers aged between 19 and 28 years. The study was performed in two periods. Each treatment period consisted of a single-dose of 320 mg valsartan, with a wash-out time of 8 days between the first and second period. Plasma concentrations of valsartan were evaluated by HPLC/UV with method of addition of valsartan standard and losartan as internal standard. Results: Valsartan tablets formulation showed this pharmacokinetic parameters: AUC 44,893 µg/mlxh, Cmax 6,430.3 µg/ml and Tmax 2 h. Valsartan capsules formulation showed this pharmacokinetic parameters: AUC 44,963 µg/mlxh, Cmax 5,831.4 µg/ml and Tmax 2.5 h. Conclusion: The study showed no statistically significant differences in the plasma concentration levels after administration of the two formulations of valsartan: 80 mg tablets and 80 mg capsules. So

  15. A comparative, cross-over, double blind, randomized study for bioequivalence assessment between two formulations of valsartan capsules vs. tablets.

    Directory of Open Access Journals (Sweden)

    Milena Pérez

    2009-11-01

    Full Text Available Introduction: Bioequivalence or compared equivalence studies are used to demonstrate claims that the new product, named generic product, will have the same bioavailability as the reference product, named brand product. If two products are bioequivalent it means that they would expect to have the same efficacy and security. Bioequivalence is established by the statistical estimation of significant differences or not in the pharmacokinetics parameters of area under the curve (AUC and maximum concentration (Cmax. In this case, bioequivalence will be evaluated and the bioavailability of valsartan will be compared. Valsartan is an agent antihypertensive and specific angiotensin II antagonist acting on the AT1 receptor subtype. Objective: The aim of this study was to evaluate the bioequivalence of two pharmaceutical products whose active principle is Valsartan, based on the comparison of the pharmacokinetic measures of rate and extent (in terms of required time in which valsartan reaches the sanguineous circulation after a oral dose to 15 volunteers. Metodology: This was a randomized crossover double blind single-dose study on 15 male healthy volunteers aged between 19 and 28 years. The study was performed in two periods. Each treatment period consisted of a single-dose of 320 mg valsartan, with a wash-out time of 8 days between the first and second period. Plasma concentrations of valsartan were evaluated by HPLC/UV with method of addition of valsartan standard and losartan as internal standard. Results: Valsartan tablets formulation showed this pharmacokinetic parameters: AUC 44,893 µg/mlxh, Cmax 6,430.3 µg/ml and Tmax 2 h. Valsartan capsules formulation showed this pharmacokinetic parameters: AUC 44,963 µg/mlxh, Cmax 5,831.4 µg/ml and Tmax 2.5 h. Conclusion: The study showed no statistically significant differences in the plasma concentration levels after administration of the two formulations of valsartan: 80 mg tablets and 80 mg capsules. So

  16. Influence analysis on crossover design experiment in bioequivalence studies.

    Science.gov (United States)

    Huang, Yufen; Ke, Bo-Shiang

    2014-01-01

    Crossover designs are commonly used in bioequivalence studies. However, the results can be affected by some outlying observations, which may lead to the wrong decision on bioequivalence. Therefore, it is essential to investigate the influence of aberrant observations. Chow and Tse in 1990 discussed this issue by considering the methods based on the likelihood distance and estimates distance. Perturbation theory provides a useful tool for the sensitivity analysis on statistical models. Hence, in this paper, we develop the influence functions via the perturbation scheme proposed by Hampel as an alternative approach on the influence analysis for a crossover design experiment. Moreover, the comparisons between the proposed approach and the method proposed by Chow and Tse are investigated. Two real data examples are provided to illustrate the results of these approaches. Our proposed influence functions show excellent performance on the identification of outlier/influential observations and are suitable for use with small sample size crossover designs commonly used in bioequivalence studies.

  17. Impact of food administration on lopinavir-ritonavir bioequivalence studies.

    Science.gov (United States)

    Ibarra, M; Fagiolino, P; Vázquez, M; Ruiz, S; Vega, M; Bellocq, B; Pérez, M; González, B; Goyret, A

    2012-08-15

    A bioequivalence study in 16 Caucasian healthy volunteers (eight male, eight female), comparing plasma drug concentrations after a single oral dose of lopinavir and ritonavir (400 and 100mg, respectively), was carried out following a two-period, two-sequence, two-treatment, randomized crossover design. Formulations were given 15 min after a moderate-fat breakfast in order to diminish both the intrinsic highly-variable performance and the sex differences observed in bioequivalence trials under fasting conditions. Ninety percent confidence intervals for the Test/Reference (T/R) ratio of geometric means for area under concentration-time curve (AUC) and maximum concentration (C(MAX)), either for lopinavir or ritonavir, were within the range of 0.80-1.25. Coprandial administration of formulations not only reduced the number of subjects required for bioequivalence assessment, reducing both ethical and economic cost of the trial, but also the sex differences in the T/R ratio of means.

  18. Two-stage designs for cross-over bioequivalence trials.

    Science.gov (United States)

    Kieser, Meinhard; Rauch, Geraldine

    2015-07-20

    The topic of applying two-stage designs in the field of bioequivalence studies has recently gained attention in the literature and in regulatory guidelines. While there exists some methodological research on the application of group sequential designs in bioequivalence studies, implementation of adaptive approaches has focused up to now on superiority and non-inferiority trials. Especially, no comparison of the features and performance characteristics of these designs has been performed, and therefore, the question of which design to employ in this setting remains open. In this paper, we discuss and compare 'classical' group sequential designs and three types of adaptive designs that offer the option of mid-course sample size recalculation. A comprehensive simulation study demonstrates that group sequential designs can be identified, which show power characteristics that are similar to those of the adaptive designs but require a lower average sample size. The methods are illustrated with a real bioequivalence study example.

  19. RECOMMENDATIONS REGARDING THE INSTITUTIONALIZATION OF MARKETING RESEARCH ACTIVITY IN ROMANIAN MICROCREDIT ORGANIZATIONS

    Directory of Open Access Journals (Sweden)

    Savescu Roxana Florenta

    2012-12-01

    Full Text Available As they mature, microcredit organizations in Romania are becoming aware of the importance of marketing in their current activities. Although marketing interventions should be considered important on all types of markets, the reality is that micro-credit companies in Romania have a limited institutional capacity to develop and implement marketing programs. This implies that marketing efforts should be focused and marketing needs should be prioritized, according to the appropriate level of market development (developing markets, growth markets and mature markets. The paper presents the results of an exploratory marketing research study regarding the marketing activity performed by microfinance institutions in Romania. The purpose of the research was to identify courses of action to institutionalize marketing research in the current activity of the subjects analyzed. It has been our intention to give a very practical dimension to the recommendations regarding the marketing information useful for microcredit organizations and categories of marketing research needing to be conducted regularly, making them applicable within the specific Romanian environment. Given the fact that on a national level scientific concerns about microfinance in Romania, in general or about marketing in the field of microfinance in particular are almost nonexistent, this thesis can be regarded as an innovation. This conclusion comes both from the investigation of existing literature and from the author's interviews with managers of microfinance institutions who have argued that this was the first time when Romanian academic institutions got interested in this sector. Potential beneficiaries of the results of this study are: managers of microcredit organizations interested in the development and sustainability of the institutions they manage; various national and international organizations interested in designing technical assistance programs in the areas identified as being

  20. The activity intensities reached when playing active tennis gaming relative to sedentary gaming, tennis game-play, and current activity recommendations in young adults.

    Science.gov (United States)

    Scanlan, Aaron T; Arkinstall, Hayley; Dalbo, Vincent J; Humphries, Brendan J; Jennings, Cameron T; Kingsley, Michael I C

    2013-09-01

    Although active gaming is popular and can increase energy expenditure in young adults, its efficacy as a prescriptive exercise tool is not well understood. This study aimed to: (a) compare the activity intensities experienced by young adults while playing active tennis gaming with conventional sedentary gaming, tennis game-play, and current activity recommendations for health; and (b) identify changes in activity intensities across playing time. After habitualization, 10 active young adults (age: 20.2 ± 0.4 years; stature: 1.74 ± 0.03 m; body mass: 67.7 ± 3.3 kg) completed 3 experimental trials (sedentary gaming, active tennis gaming, and tennis game-play) on separate days in a randomized order. Heart rate (HR) and metabolic equivalents (METs) were averaged across 5 minutes and 10 minutes intervals, and the entire 20 minutes bout within each condition. Active gaming produced greater intensities across 5-10, 10-15, and 15-20 minutes time intervals compared with sedentary gaming (p Tennis game-play elicited greater HR (67 ± 5% HR(max)) and METs (5.0 ± 0.2) responses than both sedentary (40 ± 2% HR(max), 1.1 ± 0.1 METs) and active gaming (45 ± 2% HR(max), 1.4 ± 0.1 METs) (p tennis game-play produced activity intensities meeting current recommendations for health benefit. Lower HR intensities were reached across 0-5 minutes than during later time intervals during active gaming (6%) and tennis game-play (9%) (p tennis game-play and insufficient to contribute toward promoting and maintaining good health in young adults. These data suggest that active tennis gaming should not be recommended by exercise professionals as a substitute for actual sports participation in young adults.

  1. Bioequivalence Study of Atorvastatin Tablets in Healthy Pakistani Volunteers.

    Science.gov (United States)

    Mohammad, Sohail; Arshad, Usman; Abbass, Nasir; Parvez, Irfan; Abbas, Ghulam; Mahmood, Wajahat

    2015-01-01

    A two way, randomized cross-over bioequivalence study was conducted to analyse the rate and extent of absorption of atorvastatin after a single dose of 80 mg atorvastatin as atorvastatin calcium tablets. The study was carried out using healthy male volunteers (N = 24). A high performance liquid chromatography method was employed to determine the level of drug in human plasma. It was concluded that the test and the reference drug exhibited comparable values of pharmacokinetic parameters. It was also concluded that since there was no significant difference between the rate and extent of absorption of the drug from the test and the reference formulations: these two formulations could thus be declared bioequivalent.

  2. Modifications of sequential designs in bioequivalence trials.

    Science.gov (United States)

    Zheng, Cheng; Zhao, Lihui; Wang, Jixian

    2015-01-01

    Bioequivalence (BE) studies are designed to show that two formulations of one drug are equivalent and they play an important role in drug development. When in a design stage, it is possible that there is a high degree of uncertainty on variability of the formulations and the actual performance of the test versus reference formulation. Therefore, an interim look may be desirable to stop the study if there is no chance of claiming BE at the end (futility), or claim BE if evidence is sufficient (efficacy), or adjust the sample size. Sequential design approaches specially for BE studies have been proposed previously in publications. We applied modification to the existing methods focusing on simplified multiplicity adjustment and futility stopping. We name our method modified sequential design for BE studies (MSDBE). Simulation results demonstrate comparable performance between MSDBE and the original published methods while MSDBE offers more transparency and better applicability. The R package MSDBE is available at https://sites.google.com/site/modsdbe/.

  3. Bioequivalence assessment of two formulations of ibuprofen

    KAUST Repository

    Al-Talla, Zeyad

    2011-10-19

    Background: This study assessed the relative bioavailability of two formulations of ibuprofen. The first formulation was Doloraz , produced by Al-Razi Pharmaceutical Company, Amman, Jordan. The second forumulation was Brufen , manufactured by Boots Company, Nottingham, UK. Methods and results: A prestudy validation of ibuprofen demonstrated long-term stability, freeze-thaw stability, precision, and accuracy. Twenty-four healthy volunteers were enrolled in this study. After overnight fasting, the two formulations (test and reference) of ibuprofen (100 mg ibuprofen/5 mL suspension) were administered as a single dose on two treatment days separated by a one-week washout period. After dosing, serial blood samples were drawn for a period of 14 hours. Serum harvested from the blood samples was analyzed for the presence of ibuprofen by high-pressure liquid chromatography with ultraviolet detection. Pharmacokinetic parameters were determined from serum concentrations for both formulations. The 90% confidence intervals of the ln-transformed test/reference treatment ratios for peak plasma concentration and area under the concentration-time curve (AUC) parameters were found to be within the predetermined acceptable interval of 80%-125% set by the US Food and Drug Administration. Conclusion: Analysis of variance for peak plasma concentrations and AUC parameters showed no significant difference between the two formulations and, therefore, Doloraz was considered bioequivalent to Brufen. 2011 Al-Talla et al, publisher and licensee Dove Medical Press Ltd.

  4. Novel montelukast sodium-loaded stable oral suspension bioequivalent to the commercial granules in rats.

    Science.gov (United States)

    Kim, Dong Wuk; Kim, Young Hun; Yousaf, Abid Mehmood; Kim, Dong Shik; Kwon, Taek Kwan; Park, Jung Hee; Kim, Yong Il; Park, Jae-Hyun; Jin, Sung Giu; Kim, Kyung Soo; Cho, Kwan Hyung; Li, Dong Xun; Kim, Jong Oh; Yong, Chul Soon; Woo, Jong Soo; Choi, Han-Gon

    2016-04-01

    To develop a montelukast sodium-loaded stable oral suspension bioequivalent to the commercial granules in rats, several montelukast sodium-loaded suspensions were prepared with a suspending agent, stabilizers and anti-aggregation agents, and their stabilities were investigated by visually observing the sedimentation phenomenon and determining the concentration of the degradation product. Moreover, dissolution and pharmacokinetic studies of the optimized formulation were examined in rats compared to commercial montelukast sodium-loaded granules. Avicel RC-591 (Avicel), a suspending agent, prevented the sedimentation of these suspensions at >2.496 (w/v) per cent composition. Amongst the stabilizers tested, fumaric acid provided the lowest concentration of montelukast sulphoxide (a degradation product) in these suspensions at 40 °C, demonstrating its excellent stabilizing activity. Furthermore, as an anti-aggregation agent, glycerin gave lower amounts of degradation product than those with poloxamer 407 and Tween 80. In particular, montelukast-loaded oral suspension, an aqueous suspension containing montelukast sodium/Avicel/fumaric acid/glycerin at a concentration of 312/2496/15.6/62.4 (mg/100 ml), and the commercial granules exhibited similar dissolution profiles in 0.5% (w/v) aqueous solution of sodium lauryl sulphate. Moreover, the pharmacokinetics in rats provided by this suspension was comparable to that of the commercial granules, suggesting that they were bioequivalent. In addition, it was physically and chemically stable at 40 °C for at least 6 months. Thus, this montelukast sodium-loaded oral suspension, with bioequivalence to the commercial granules and excellent stability, could be a prospective dosage form for the treatment of asthma.

  5. When is a metric not a metric? Remarks on direct curve comparison in bioequivalence studies.

    Science.gov (United States)

    Jawień, Wojciech

    2009-06-01

    The majority of measures proposed to date for direct curve comparison in bioequivalence studies were investigated. These measures have often been called metrics, but in most cases this was incorrect in the mathematical sense. It was demonstrated, with a set of counter-examples, that the axioms of a metric are fulfilled only for the integral p-metric and some of its transforms. The Rescigno index and two other measures devised by Polli and McLean are the semi-metrics, lacking the triangle inequality, while others also lack symmetry. The use of the p-metric is therefore recommended, and statistical analysis is suggested as a point at which the scaling of differences might be carried out.

  6. Generic products of antiepileptic drugs: a perspective on bioequivalence and interchangeability.

    Science.gov (United States)

    Bialer, Meir; Midha, Kamal K

    2010-06-01

    Most antiepileptic drugs (AEDs) are currently available as generic products, yet neurologists and patients are reluctant to switch to generics. Generic AEDs are regarded as bioequivalent to brand AEDs after meeting the average bioequivalence criteria; consequently, they are considered to be interchangeable with their respective brands without loss of efficacy and safety. According to the U.S. Food and Drug Administration (FDA) the present bioequivalence requirements are already so rigorous and constrained that there is little possibility that generics that meet regulatory bioequivalence criteria could lead to therapeutic problems. So is there a scientific rationale for the concerns about switching patients with epilepsy to bioequivalent generics? Herein we discuss the assessment of bioequivalence and propose a scaled-average bioequivalence approach where scaling of bioequivalence is carried out based on brand lot-to-lot variance as an alternative to the conventional bioequivalence test as a means to determine whether switching patients to generic formulations, or vice versa, is a safe and effective therapeutic option. Meeting the proposed scaled-average bioequivalence requirements will ensure that when an individual patient is switched, he or she has fluctuations in plasma levels similar to those from lot-to-lot of the brand reference levels and thus should make these generic products safely switchable without change in efficacy and safety outcomes.

  7. An Exact Procedure for the Evaluation of Reference-Scaled Average Bioequivalence.

    Science.gov (United States)

    Tothfalusi, Laszlo; Endrenyi, Laszlo

    2016-03-01

    Reference-scaled average bioequivalence (RSABE) has been recommended by Food and Drug Administration (FDA), and in its closely related form by European Medicines Agency (EMA), for the determination of bioequivalence (BE) of highly variable (HV) and narrow therapeutic index (NTI) drug products. FDA suggested that RSABE be evaluated by an approximating procedure. Development of an alternative, numerically exact approach was sought. A new algorithm, called Exact, was derived for the assessment of RSABE. It is based upon the observation that the statistical model of RSABE follows a noncentral t distribution. The parameters of the distribution were derived for crossover and parallel-group study designs. Simulated BE studies of HV and NTI drugs compared the power and consumer risk of the proposed Exact method with those recommended by FDA and EMA. The Exact method had generally slightly higher power than the FDA approach. The consumer risks of the Exact and FDA procedures were generally below the nominal error risk with both methods except for the partial replicate design under certain heteroscedastic conditions. The estimator of RSABE was biased; simulations demonstrated the appropriateness of Hedges' correction. The FDA approach had another, small but meaningful bias. The confidence intervals of RSABE, based on the derived exact, analytical formulas, are uniformly most powerful. Their computation requires in standard cases only a single-line program script. The algorithm assumes that the estimates of the within-subject variances of both formulations are available. With each algorithm, the consumer risk is higher than 5% when the partial replicate design is applied.

  8. Recommendations for Technology Development and Validation Activities in Support of the Origins Program

    Science.gov (United States)

    Capps, Richard W. (Editor)

    1996-01-01

    space optics, OSAT is moving to improve the focus of its sensor, spacecraft, and interferometer/telescope technology programs on the specific additional needs of the OSS Origins Program. To better define Origins mission technology and facilitate its development, OSAT and OSS called for a series of workshops with broad participation from industry, academia and the national laboratory community to address these issues. Responsibility for workshop implementation was assigned jointly to the two NASA field centers with primary Origins mission responsibility, the Goddard Space Flight Center and the Jet Propulsion Laboratory. The Origins Technology Workshop, held at Dana Point, California between June 4 and 6, 1996 was the first in the series of comprehensive workshops aimed at addressing the broad technological needs of the Origins Program. It was attended by 64 individuals selected to provide technical expertise relevant to the technology challenges of the Origins missions. This report summarizes the results of that meeting. A higher level executive summary was considered inappropriate because of the potential loss of important context for the recommendations. Subsequent to the Origins Technology Workshop and prior to publication of this report, NASA Headquarters reorganized the activities of the Of fice of Space Access and Technology. It appears likely that responsibility for the technology programs recommended in this document will move to the Office of Space Science.

  9. Bioequivalence evaluation of two brands of amoxicillin/clavulanic acid 250/125 mg combination tablets in healthy human volunteers: use of replicate design approach.

    Science.gov (United States)

    Idkaidek, Nasir M; Al-Ghazawi, Ahmad; Najib, Naji M

    2004-12-01

    The purpose of this study was to apply a replicate design approach to a bioequivalence study of amoxicillin/clavulanic acid combination following a 250/125 mg oral dose to 23 subjects, and to compare the analysis of individual bioequivalence with average bioequivalence. This was conducted as a 2-treatment 2-sequence 4-period crossover study. Average bioequivalence was shown, while the results from the individual bioequivalence approach had no success in showing bioequivalence. In conclusion, the individual bioequivalence approach is a strong statistical tool to test for intra-subject variances and also subject-by-formulation interaction variance compared with the average bioequivalence approach.

  10. Regulatory Considerations of Bioequivalence Studies for Oral Solid Dosage Forms in Japan.

    Science.gov (United States)

    Kuribayashi, Ryosuke; Takishita, Tomoko; Mikami, Kenichi

    2016-08-01

    Bioequivalence (BE) studies are used to infer the therapeutic equivalence of generic drug products to original drug products throughout the world. In BE studies, bioavailability (BA) should be compared between the original and generic drug products, with BA defined as the rate and extent of absorption of active pharmaceutical ingredients or active metabolites from a product into the systemic circulation. For most of BE studies conducted during generic drug development, BA comparisons are performed in single-dose studies. In Japan, the revised "Guideline for Bioequivalence Studies of Generic Products" was made available in 2012 by the Ministry of Health, Labour, and Welfare, and generic drug development is currently conducted based on this guideline. Similarly, the U.S. Food and Drug Administration and European Medicines Agency have published guidance and guideline on generic drug development. This article introduces the guideline on Japanese BE studies for oral solid dosage forms and the dissolution tests for the similarity and equivalence evaluation between the original and generic drug products. Additionally, we discuss some of the similarities and differences in guideline between Japan, the United States, and the European Union.

  11. Development of a new benazepril hydrochloride chewable tablet and evaluation of its bioequivalence for treatment of heart failure in dogs.

    Science.gov (United States)

    Qian, M; Chen, T; Zhou, D; Zhang, Z; Zhang, Q; Tang, S; Xiao, X

    2016-02-01

    The aim of the study was to develop a new chewable benazepril hydrochloride(BH) tablet, investigate its physical properties, and evaluate its bioequivalence with the branded formulation (Fortekor). A corrective agent was included in the formula to improve its palatability and convenience for administration to dogs. The tablet remained stable in light, heat, and humidity tests, and its physical properties such as hardness, uniformity of content, and dissolution rate were highly consistent with the technical standards. After single and repeated administrations to eight beagles and single dose to 14 mongrel dogs (0.5 mg/kg p.o.), plasma BH and its active metabolite, benazeprilat (BZ), were detected. There was no significant difference in the major pharmacokinetic parameters (Cmax , Tmax, and AUC₀₋₂₄) between the two formulations. The 90% confidence intervals calculated for the ratios of area under the time-concentration curve (AUC₀₋₂₄) were 92.4-116.3% for BH and 89.9-102.3% for BZ, within the accepted range for bioequivalence of 80-125%. The results showed our new chewable tablet is bioequivalent to the commercial product and suitable for addition to the benazepril product family for the treatment of heart failure in dogs.

  12. Pharmacokinetics and bioequivalence of lorazepam tablets in Chinese healthy volunteers

    Institute of Scientific and Technical Information of China (English)

    Xiang-junQIU; Guo-xinHU; Jian-gangWANG; Zong-shunDAI

    2004-01-01

    AIM: To study the pharmacokinetics and bioequivalence of lorazepam tablets in Chinese healthy volunteers. METHODS:Twenty Chinese healthy male volunteers were involved in the study. Each subject received a single dose of 3 mg Lorazepam tested formulation (T, Hubei Zhongtian Airbeck Pharmaceutical Limited Company) or Lorazepam reference formulation (R, Thailand Atlatic Pharmaceutical Limited Company) with a random-

  13. Benefits of achieving vigorous as well as moderate physical activity recommendations: evidence from heart rate complexity and cardiac vagal modulation.

    Science.gov (United States)

    Soares-Miranda, Luisa; Sandercock, Gavin; Vale, Susana; Silva, Pedro; Moreira, Carla; Santos, Rute; Mota, Jorge

    2011-07-01

    The aim of this study was to examine differences in traditional heart rate variability measurements and heart rate complexity (sample entropy) in young adults grouped by objectively measured achievement of either moderate or both moderate and vigorous physical activity recommendations. Of 168 young adults tested (86 females, 82 males; age 20.5 ± 1.2 years), 119 achieved only recommendations for moderate physical activity (moderate group) and 49 achieved recommendations for both moderate and vigorous physical activity (vigorous group). Analysis of covariance controlling for sex, weekly minutes of moderate physical activity, and percentage of body fat was used to assess between-group differences in heart rate variability and heart rate complexity. Logistic regression analysis was used to determine the group characteristics that best predicted high heart rate complexity and vagal indices of heart rate variability. The majority of the autonomic measures were higher (P heart rate complexity and higher heart rate variability. Young adults engaged in regular vigorous physical activity were more than twice as likely to have high heart rate complexity than those involved in predominantly moderate exercise. These findings suggest that vigorous physical activity is more closely associated with high heart rate complexity than moderate physical activity in young adults.

  14. New approach to assess bioequivalence parameters using generalized gamma mixed-effect model (model-based asymptotic bioequivalence test).

    Science.gov (United States)

    Chen, Yuh-Ing; Huang, Chi-Shen

    2014-02-28

    In the pharmacokinetic (PK) study under a 2x2 crossover design that involves both the test and reference drugs, we propose a mixed-effects model for the drug concentration-time profiles obtained from subjects who receive different drugs at different periods. In the proposed model, the drug concentrations repeatedly measured from the same subject at different time points are distributed according to a multivariate generalized gamma distribution, and the drug concentration-time profiles are described by a compartmental PK model with between-subject and within-subject variations. We then suggest a bioequivalence test based on the estimated bioavailability parameters in the proposed mixed-effects model. The results of a Monte Carlo study further show that the proposed model-based bioequivalence test is not only better on maintaining its level but also more powerful for detecting the bioequivalence of the two drugs than the conventional bioequivalence test based on a non-compartmental analysis or the one based on a mixed-effects model with a normal error variable. The application of the proposed model and test is finally illustrated by using data sets in two PK studies.

  15. Quality of Reporting of Bioequivalence Trials Comparing Generic to Brand Name Drugs: A Methodological Systematic Review

    OpenAIRE

    Amélie van der Meersch; Agnès Dechartres; Philippe Ravaud

    2011-01-01

    BACKGROUND: Generic drugs are used by millions of patients for economic reasons, so their evaluation must be highly transparent. OBJECTIVE: To assess the quality of reporting of bioequivalence trials comparing generic to brand-name drugs. METHODOLOGY/PRINCIPAL FINDINGS: PubMed was searched for reports of bioequivalence trials comparing generic to brand-name drugs between January 2005 and December 2008. Articles were included if the aim of the study was to assess the bioequivalency of generic ...

  16. From Bioequivalence to Biosimilarity: The Rise of a Novel Regulatory Framework.

    Science.gov (United States)

    Karalis, V D

    2016-01-01

    One of the most crucial issues in pharmacotherapy is to address the query if a patient can be switched from one product to another of the same active substance. For the conventional small-molecule drugs, there is a consensus on the required bioequivalence criteria. However, proving equivalence in the field of biologicals is an issue with no clear harmony. The aim of this review is to highlight the differences between the biologicals and the conventional chemical drugs, as well as, to present the different regulatory requirements for the placement of biosimilars on the market.Biologicals are substantially larger than chemical compounds, their manufacturing process is very complex, and their protein structure may trigger immune reactions. For this reason, the conventional bioequivalence approach is not adequate, but further emphasis should be placed on the quality of the manufacturing process and the risks of immunogenicity. The assessment procedure of biosimilars should encompass their comparison with the innovator product using all available evidence derived from the development process. The latter includes analytical and animal studies, pharmacokinetic and pharmacodynamic data, as well as, clinical trials focusing on immunogenicity. The US FDA has established a step-wise approach to demonstrate biosimilarity, while the EMA has already issued many guidelines referring either to all biosimilars or to specific products/classes. Overall, a case-by-case assessment procedure is considered by the regulatory authorities. In any case the placement of a biosimilar on the market does not necessarily imply interchangeability with the innovator drug.

  17. Advice for Parents: Recommendations for Home Literacy Activities Based upon Studies of Young Successful Readers.

    Science.gov (United States)

    Rasinski, Timothy V.

    Two research studies hold promise of assisting educators in developing appropriate recommendations for helping parents help their children learn to read and write. Dolores Durkin studied children who entered school already knowing how to read. She followed the students for several years and found that the early readers maintained or extended their…

  18. 76 FR 26307 - Guidance for Industry on the Submission of Summary Bioequivalence Data for Abbreviated New Drug...

    Science.gov (United States)

    2011-05-06

    ... HUMAN SERVICES Food and Drug Administration Guidance for Industry on the Submission of Summary Bioequivalence Data for Abbreviated New Drug Applications; Availability AGENCY: Food and Drug Administration, HHS... guidance for industry entitled ``Submission of Summary Bioequivalence Data for Abbreviated New...

  19. Optimal adaptive sequential designs for crossover bioequivalence studies.

    Science.gov (United States)

    Xu, Jialin; Audet, Charles; DiLiberti, Charles E; Hauck, Walter W; Montague, Timothy H; Parr, Alan F; Potvin, Diane; Schuirmann, Donald J

    2016-01-01

    In prior works, this group demonstrated the feasibility of valid adaptive sequential designs for crossover bioequivalence studies. In this paper, we extend the prior work to optimize adaptive sequential designs over a range of geometric mean test/reference ratios (GMRs) of 70-143% within each of two ranges of intra-subject coefficient of variation (10-30% and 30-55%). These designs also introduce a futility decision for stopping the study after the first stage if there is sufficiently low likelihood of meeting bioequivalence criteria if the second stage were completed, as well as an upper limit on total study size. The optimized designs exhibited substantially improved performance characteristics over our previous adaptive sequential designs. Even though the optimized designs avoided undue inflation of type I error and maintained power at ≥ 80%, their average sample sizes were similar to or less than those of conventional single stage designs.

  20. Levothyroxine: therapeutic use and regulatory issues related to bioequivalence.

    Science.gov (United States)

    Wartofsky, Leonard

    2002-06-01

    Levothyroxine is the overwhelming choice of clinicians for the treatment of hypothyroidism and for the suppression of goitre and thyroid nodules in selected cases. The monitoring of serum levels of thyroid stimulating hormone is necessary for appropriate dosage adjustment of levothyroxine. Levothyroxine has a narrow therapeutic index: both underdosage (subclinical hypothyroidism) and excessive dosage (subclinical hyperthyroidism) are associated with adverse symptoms and pathophysiological effects and are to be avoided. The consequent necessity for careful titration of doses has had an impact on the issue of switchability, or bioequivalence, of the various marketed levothyroxine products. In this article, the basis for concern about currently accepted standards of the FDA for pharmacological bioequivalence are examined in the context of levothyroxine. The history and status of the recent request by the FDA for a new drug application for all levothyroxine products, and its impact on the market leader Synthroid, is also discussed.

  1. Novel bioequivalence approach for narrow therapeutic index drugs.

    Science.gov (United States)

    Yu, L X; Jiang, W; Zhang, X; Lionberger, R; Makhlouf, F; Schuirmann, D J; Muldowney, L; Chen, M-L; Davit, B; Conner, D; Woodcock, J

    2015-03-01

    Narrow therapeutic index drugs are defined as those drugs where small differences in dose or blood concentration may lead to serious therapeutic failures and/or adverse drug reactions that are life-threatening or result in persistent or significant disability or incapacity. The US Food and Drug Administration proposes that the bioequivalence of narrow therapeutic index drugs be determined using a scaling approach with a four-way, fully replicated, crossover design study in healthy subjects that permits the simultaneous equivalence comparison of the mean and within-subject variability of the test and reference products. The proposed bioequivalence limits for narrow therapeutic index drugs of 90.00%-111.11% would be scaled based on the within-subject variability of the reference product. The proposed study design and data analysis should provide greater assurance of therapeutic equivalence of narrow therapeutic index drug products.

  2. Bioequivalence Study of Donepezil Hydrochloride Tablets in Healthy Male Volunteers

    OpenAIRE

    Supanimit Teekachunhatean; Sukit Roongapinun; Nutthiya Hanprasertpong; Siriluk Aunmuang; Noppamas Rojanasthien

    2012-01-01

    The objective of this study was to investigate the bioequivalence of two formulations of 5 mg donepezil HCL tablets: Tonizep as the test and Aricept as the reference. The two products were administered as a single oral dose according to a randomized two-phase crossover with a 3-week washout period in 20 healthy Thai Male volunteers. After drug administration, serial blood samples were collected over a period of 216 hours. Plasma donepezil concentrations were measured by high performance liqui...

  3. DEVELOPMENT AND BIOEQUIVALENCE STUDY OF OLANZAPINE 10mg TABLETS

    Directory of Open Access Journals (Sweden)

    Ravindra Waykar et al

    2012-09-01

    Full Text Available Generic drugs are lower-cost versions of patent-expired original brand-name medications. According to guidelines of regulatory agencies of the Canada, US and European Union, a generic drug must be “identical, or bioequivalent to a brand name drug in dosage form, safety, strength, route of administration, quality, performance characteristics and intended use”. Bioequivalence is decreed when the ratio of the generic to the reference compound for the area-under-the-curve and maximum plasma concentration (Cmax fall within a 0.80–1.25 range. The present study was to develop Olanzapine Tablets and compare pharmacokinetic profile of Zyprexa 10 mg film-coated tablets, Zyprexa Velotabs 10 mg orodispersible tablets and Olanzapine 10mg tablets. Multi media dissolution studies in 0.1N HCl, pH 4.5 acetate buffer and pH 6.8 phosphate buffer were carried out for Reference (Zyprexa Velotab 10 mg and Zyprexa 10 mg and test product (i.e. Olanzapine 10 mg. A single centre, open-label, single-dose, randomised, 3-way crossover bioequivalence study, performed under fasting conditions. Based on the results obtained, it can be concluded that the test olanzapine (Treatment A is bioequivalent to both references Zyprexa Velotab (Treatment B and Zyprexa (Treatment C following a 10 mg dose under fasting conditions. All formulations were well tolerated, with no major side effects and no relevant differences in safety profiles were observed between the preparations, particularly with respect to the number and pattern of adverse event.

  4. Bioequivalence evaluation of epinephrine autoinjectors with attention to rapid delivery

    OpenAIRE

    Sclar DA

    2013-01-01

    David Alexander Sclar Department of Pharmacy Practice, College of Pharmacy, Midwestern University, Glendale, AZ, USA Abstract: Timely and proper injection of epinephrine is critical to prevent serious consequences relating to anaphylaxis. In a recent bioavailability study comparing epinephrine delivery from the Auvi-Q™ and EpiPen® epinephrine autoinjectors, the Auvi-Q failed to meet the bioequivalence threshold when using partial area under the curve (AUC) analyses based on...

  5. Transdermal fentanyl matrix patches Matrifen and Durogesic DTrans are bioequivalent

    DEFF Research Database (Denmark)

    Kress, Hans G; Boss, Hildegard; Delvin, Thomas

    2010-01-01

    least square means of the Test/Reference ratio (90% confidence intervals [CI]) were within the range of 80-125%, demonstrating bioequivalence of Matrifen and Durogesic DTrans: AUC(0-tlast) 92.5 (CI 88.7-96.4), AUC(0-inf) 91.7 (CI 88.0-95.7), and C(max) 98.3 (CI 92.9-104.1). After 72 h application...

  6. Prograf five milligrams versus Tacrolimus medis in healthy volunteers: a bioequivalence study.

    Science.gov (United States)

    Masri, M; Rizk, S; Boujbel, L; Bellahirich, W; Baassoumi, D; Attia, M; Matha, V

    2013-01-01

    For FDA approval, bioequivalence of a generic version of Tacrolimus must be demonstrated in a randomized, two-treatments, two-periods, two-sequences, single-dose crossover study in healthy adult volunteers. Currently there are at least 3 differents generic equivalent for Tacrolimus, that are approved by the EMA and the FDA, with a USA market share of nearly 50%. However, the market share of generic immunosuppressive drugs in the Middle East region is still very low due to the reluctance of the physician to accept Tacrolimus generics, considered to be a narrow therapeutic window drug, that are approved using the standard bioequivalence criteria of 80% to 125%. Herein we present a bioequivalence study of a new Tacrolimus generic, Tacrolimus Medis 5 mg developed by Medis Tunisia batch number 12G3003 compared with Prograf® 5 mg batch number 7202 manufactured by Astellas Toyama Co., Ltd. Japan and HIKMA Pharmaceuticals, Amman-Jordan in healthy adult volunteers using the 90%-111% criteria recommended for drugs with narrow therapeutic window. The study was, balanced, randomized, two-treatments, two-periods, two-sequences, single dose, crossover, comparative oral bioavailability study in healthy adult human volunteers. The study was carried out in accordance with the Basic Principles defined in the U.S. 21 CFR Part 312.20, the principles enunciated in the Declaration of Helsinki (World Medical Association Declaration of Helsinki). Thirty six non-smoking healthy, as determined by medical history, volunteers, 18 years and older, were included. Following randomization using a computer software (pharma solution) the volunteers were given a single oral dose of 5 milligrams following a 12 hour fast with a wash out period of 7 days. Pharmacokinetics profile with blood levels at: 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours were performed following each dose. Tacrolimus plasma level was determined using an HPLC validated method (Transmedical For Life S.A.R.L. Beirut

  7. Regulatory and clinical aspects of psychotropic medicinal products bioequivalence.

    Science.gov (United States)

    Bałkowiec-Iskra, Ewa; Cessak, Grzegorz; Kuzawińska, Olga; Sejbuk-Rozbicka, Katarzyna; Rokita, Konrad; Mirowska-Guzel, Dagmara

    2015-07-01

    Introduction of generic medicinal products to the market has increased access to modern therapies but also enabled significant reduction in their cost, leading to containment of public expenditures on medicinal products reimbursement. The critical assessment of bioequivalence of any reference medicinal product and its counterpart is based on comparison of their rate and extent of absorption. It is assumed that two medicinal products are bioequivalent when their rate and extent of absorption do not show significant differences when administered at the same dose under similar experimental conditions. Bioequivalent medicinal products are declared to be also therapeutically equivalent and can be used interchangeably. However, despite regulatory declaration, switching from reference to generic drugs is often associated with concerns of healthcare providers about decreased treatment effectiveness or occurrence of adverse drug reactions. The aim of this article is to provide a description of rules that guide registration of generic medicinal products in the European Union and to analyze specific examples from the scientific literature concerning therapeutic equivalence of reference and generic antidepressant and antipsychotic medicinal products.

  8. Futility rules in bioequivalence trials with sequential designs.

    Science.gov (United States)

    Fuglsang, Anders

    2014-01-01

    Health Canada, the US Food and Drug Administration, as well as the European Medicines Agency consider sequential designs acceptable for bioequivalence studies as long as the type I error is controlled at 5%. The EU guideline explicitly asks for specification of stopping rules, so the goal of this work is to investigate how stopping rules may affect type I errors and power for recently published sequential bioequivalence trial designs. Using extensive trial simulations, five different futility rules were evaluated for their effect on type I error rates and power in two-stage scenarios. Under some circumstances, notably low sample size in stage 1 and/or high variability power may be very severely affected by the stopping rules, whereas type I error rates appear less affected. Because applicants may initiate sequential studies when the variability is not known in advance, achieving sufficient power and thereby complying with certain guideline requirements may be challenging and application of optimistic futility rules could possibly be unethical. This is the first work to investigate how futility rules affect type I errors and power in sequential bioequivalence trials.

  9. Physical Activity and Pregnancy: Past and Present Evidence and Future Recommendations

    Science.gov (United States)

    Symons Downs, Danielle; Chasan-Taber, Lisa; Evenson, Kelly R.; Leiferman, Jenn; Yeo, SeonAe

    2012-01-01

    Purpose: In this review, we provide researchers and practitioners with an overview of the physical activity and pregnancy literature to promote prenatal physical activity, improve measurement, further elucidate the role of activity in reducing maternal health complications, and inform future research. Method: We examined past and present physical…

  10. 21 CFR 320.30 - Inquiries regarding bioavailability and bioequivalence requirements and review of protocols by...

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Inquiries regarding bioavailability and... FOR HUMAN USE BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS Procedures for Determining the Bioavailability or Bioequivalence of Drug Products § 320.30 Inquiries regarding bioavailability and...

  11. Performance properties of the population bioequivalence approach for in vitro delivered dose for orally inhaled respiratory products.

    Science.gov (United States)

    Morgan, Beth; Strickland, Helen

    2014-01-01

    Regulatory agencies, industry, and academia have acknowledged that in vitro assessments serve a role in establishing bioequivalence for second-entry drug product approvals as well as innovator post-approval drug product changes. For orally inhaled respiratory products (OIPs), the issues of correctly analyzing in vitro data and interpreting the results within the broader context of therapeutic equivalence have garnered significant attention. One of the recommended statistical tests for in vitro data is the population bioequivalence method (PBE). The current literature for assessing the PBE statistical approach for in vitro data assumes a log normal distribution. This paper focuses on an assessment of that assumption for in vitro delivered dose. Concepts in development of a statistical model are presented. The PBE criterion and hypotheses are written for the case when data follows a normal distribution, rather than log normal. Results of a simulation study are reported, characterizing the performance of the PBE approach when data are expected to be normally distributed, rather than log normal. In these cases, decisions using the PBE approach are not consistent for the same absolute mean difference that the test product is from the reference product. A conclusion of inequivalency will occur more often if the test product dose is lower than the reference product for the same deviation from target. These features suggest that more research is needed for statistical equivalency approaches for in vitro data.

  12. Between‐Batch Pharmacokinetic Variability Inflates Type I Error Rate in Conventional Bioequivalence Trials: A Randomized Advair Diskus Clinical Trial

    Science.gov (United States)

    Carroll, KJ; Mielke, J; Benet, LZ; Jones, B

    2016-01-01

    We previously demonstrated pharmacokinetic differences among manufacturing batches of a US Food and Drug Administration (FDA)‐approved dry powder inhalation product (Advair Diskus 100/50) large enough to establish between‐batch bio‐inequivalence. Here, we provide independent confirmation of pharmacokinetic bio‐inequivalence among Advair Diskus 100/50 batches, and quantify residual and between‐batch variance component magnitudes. These variance estimates are used to consider the type I error rate of the FDA's current two‐way crossover design recommendation. When between‐batch pharmacokinetic variability is substantial, the conventional two‐way crossover design cannot accomplish the objectives of FDA's statistical bioequivalence test (i.e., cannot accurately estimate the test/reference ratio and associated confidence interval). The two‐way crossover, which ignores between‐batch pharmacokinetic variability, yields an artificially narrow confidence interval on the product comparison. The unavoidable consequence is type I error rate inflation, to ∼25%, when between‐batch pharmacokinetic variability is nonzero. This risk of a false bioequivalence conclusion is substantially higher than asserted by regulators as acceptable consumer risk (5%). PMID:27727445

  13. Confidence Region Approach for Assessing Bioequivalence and Biosimilarity Accounting for Heterogeneity of Variability

    Directory of Open Access Journals (Sweden)

    Jianghao Li

    2015-01-01

    Full Text Available For approval of generic drugs, the FDA requires that evidence of bioequivalence in average bioequivalence in terms of drug absorption be provided through the conduct of a bioequivalence study. A test product is said to be average bioequivalent to a reference (innovative product if the 90% confidence interval of the ratio of means (after log-transformation is totally within (80%, 125%. This approach is considered a one-parameter approach, which does not account for possible heterogeneity of variability between drug products. In this paper, we study a two-parameter approach (i.e., confidence region approach for assessing bioequivalence, which can also be applied to assessing biosimilarity of biosimilar products. The proposed confidence region approach is compared with the traditional one-parameter approach both theoretically and numerically (i.e., simulation study for finite sample performance.

  14. Variability and impact on design of bioequivalence studies.

    Science.gov (United States)

    Van Peer, Achiel

    2010-03-01

    In 2008, the European Agency for the Evaluation of Medicinal Products released a draft guidance on the investigation of bioequivalence for immediate release dosage forms with systemic action to replace the former guidance of a decade ago. Revisions of the regulatory guidance are based upon many questions over the past years and sometimes continuing scientific discussions on the use of the most suitable statistical analysis methods and study designs, particularly for drugs and drug products with high within-subject variability. Although high within-subject variability is usually associated with a coefficient of variation of 30% or more, new approaches are available in the literature to allow a gradual increase and a levelling off of the bioequivalence limits to some maximum wider values (e.g. 75-133%), dependent on the increase in the within-subject variability. The two-way, cross-over single dose study measuring parent drug is still the design of first choice. A partial replicate design with repeating the reference product and scaling the bioequivalence for the reference variability are proposed for drugs with high within-subject variability. In case of high variability, more regulatory authorities may accept a two-stage or group-sequential bioequivalence design using appropriately adjusted statistical analysis. This review also considers the mechanisms why drugs and drug products may exhibit large variability. The physiological complexity of the gastrointestinal tract and the interaction with the physicochemical properties of drug substances may contribute to the variation in plasma drug concentration-time profiles of drugs and drug products and to variability between and within subjects. A review of submitted bioequivalence studies at the Food and Drug Administration's Office of Generic Drugs over the period 2003-2005 indicated that extensive pre-systemic metabolism of the drug substance was the most important explanation for consistently high variability drugs

  15. Structured Observation of School Administrator Work Activities: Methodological Limitations and Recommendations for Research, Part 1.

    Science.gov (United States)

    Pitner, Nancy J.; Russell, James S.

    1986-01-01

    This paper critically reviews studies of administrator work activities which follow the work of Henry Mintzberg (1973), concentrating on these shortcomings of the method: (1) procedural difficulties in coding; (2) design limitations of classifying activities; (3) inadequate testing of Mintzberg's hypotheses; and (4) failure to explore antecedents…

  16. Distributed smart home activity recommender system using hidden Markov model principles

    DEFF Research Database (Denmark)

    Lynggaard, Per

    2013-01-01

    A smart home is able to propose learned activities to its user and learn new activities by observing the user’s behavioral patterns, that is, the user’s actions. Most of today’s discussed systems use some more or less complex classifier algorithms to predict user activities from contextual...... information provided by sensors. However, an alternative concept using a distributed framework is presented in this paper. It offers the possibility of combining simple low level activity classifiers with a more sophisticated one. The high level classifier has been modeled in Java and tested on a publicly...... available data set that offers approximately seven months of annotated activity including 6468 sensor events produced by a women living in the test home. Using this data set, it has been shown that this system can achieve good performance with a recognition probability of 75%....

  17. Recommendations for Improving the Way University of Jeddah Handles Learning and Training Activities

    Directory of Open Access Journals (Sweden)

    Alhazemi A. Abdulrahman

    2016-11-01

    Full Text Available This Paper analyses the training and learning practices at University of Jeddah and to make recommendations on the basis of good practice in training and learning, as identified through a review of related academic literature. This paper is complemented with the presentation of the summary of responses received from the respondents for the interview questions and analysis of the secondary data to find points in support of the observations made in the primary research. Interviews conducted as part of the data collection process in this research included several questions, which were repeated to each one of the interviewees, and their responses were recorded in a text format in the notebook. It is concluded on the basis of the literature review and primary research at UJ that the leadership style followed by the university management and the lack of coordination between management and administration are major deviations from the best practice framework developed in this research. Primary research and the knowledge acquired through service in the university show that the university uses traditional forms of training and that the dictatorial style of leadership practiced by the management does not create a favorable climate for the staff to learn.

  18. Structured Observation of School Administrator Work Activities: Methodological Limitations and Recommendations for Research, Part II.

    Science.gov (United States)

    Pitner, Nancy J.; Russell, James S.

    1986-01-01

    This paper critically reviews administrator work activity studies which follow the research of Henry Mintzberg. It discusses directions for future research using qualitative and quantitative methods and discourages research that relies solely on Mintzberg's structure. (Author/JAZ)

  19. Current Limitations and Recommendations to Improve Testing for the Environmental Assessment of Endocrine Active Substances

    DEFF Research Database (Denmark)

    Coady, Katherine K; Biever, Ronald C; Denslow, Nancy D

    2016-01-01

    evaluate whether a chemical possesses endocrine activity and whether this activity can result in adverse outcomes either to humans or the environment. Current test systems include in silico, in vitro and in vivo techniques focused on detecting potential endocrine activity, and in vivo tests that collect...... apical data to detect possible adverse effects. These test systems are currently designed to robustly assess endocrine activity and/or adverse effects in the estrogen, androgen, and thyroid hormone signaling pathways; however, there are some limitations of current test systems for evaluating endocrine...... existing test methods are resource intensive in regard to time, cost, and use of animals. However, based on recent experiences, there are opportunities to improve approaches to, and guidance for existing test methods, and reduce uncertainty. For example, in vitro high throughput screening could be used...

  20. Current limitations and recommendations to improve testing for the environmental assessment of endocrine active substances

    Science.gov (United States)

    In this paper existing regulatory frameworks and test systems for assessing potential endocrine-active chemicals are described, and associated challenges discussed, along with proposed approaches to address these challenges. Regulatory frameworks vary somewhat across organizatio...

  1. Testing the Recommendations of the Washington State Nutrition and Physical Activity Plan: The Moses Lake Case Study

    Directory of Open Access Journals (Sweden)

    Donna B. Johnson, PhD, RD

    2006-03-01

    Full Text Available Background The Washington State Nutrition and Physical Activity Plan provides a framework in which policy makers can work together to build and support healthy environments for nutrition and physical activity. The city of Moses Lake, Wash, was chosen to serve as a pilot site to test the conceptual approaches and recommendations of the plan and to develop a model for healthy communities elsewhere in the state. Context Moses Lake is an ethnically diverse, geographically isolated town with a population of about 15,000. Methods An advisory committee used data from an inventory of local policies and environments, along with the recommendations from the state plan, to develop a plan for Healthy Communities Moses Lake. Three initiatives were chosen for the first actions: a connected system of trails and paths, enhanced facilities for breastfeeding in the community, and a community garden. Consequences Records of cumulative actions demonstrated that Healthy Communities Moses Lake continued to be an active and productive project. Initial measures of success were collected by each of the three first action teams. Environmental changes will be monitored by comparison with the initial inventory of local policies. Long-term health outcomes in Moses Lake will be monitored by the Washington State Department of Health.

  2. Food Preference and Foraging Activity of Ants: Recommendations for Field Applications of Low-Toxicity Baits

    OpenAIRE

    Nyamukondiwa, Casper; Addison, Pia

    2014-01-01

    Control of ants using baits of low toxicity cannot be effective without knowledge of bait distribution patterns and bait station densities, which are determined by ants' foraging activities. Furthermore, the success of toxic baits also depends upon attractiveness of bait carriers. Here, we assessed ground and vine foraging activity and food preferences for the three ant species (Linepithema humile (Mayr) (Hymenoptera: Formicidae), Anoplolepis custodiens (F. Smith) and Crematogaster peringueyi...

  3. Evidence-based risk assessment and recommendations for physical activity clearance: Consensus Document 2011.

    Science.gov (United States)

    Warburton, Darren E R; Gledhill, Norman; Jamnik, Veronica K; Bredin, Shannon S D; McKenzie, Don C; Stone, James; Charlesworth, Sarah; Shephard, Roy J

    2011-07-01

    The Physical Activity Readiness Questionnaire (PAR-Q) and the Physical Activity Readiness Medical Evaluation (PARmed-X) are internationally known preparticipation screening tools developed on the basis of expert opinion. The primary purposes of this consensus document were to seek evidence-based support for the PAR-Q and PARmed-X forms, to identify whether further revisions of these instruments are warranted, to determine how people responding positively to questions on the PAR-Q can be safely cleared without medical referral, and to develop exercise clearance procedures appropriate for various clinical conditions across the human lifespan. Seven systematic reviews were conducted, examining physical-activity-related risks and effective risk-stratification procedures for various prevalent chronic conditions. An additional systematic review assessed the risks associated with exercise testing and training of the general population. Two gap areas were identified and evaluated systematically: the role of the qualified exercise professional and the requisite core competencies required by those working with various chronic conditions; and the risks associated with physical activity during pregnancy. The risks associated with being physically inactive are markedly higher than transient risks during and following an acute bout of exercise in both asymptomatic and symptomatic populations across the lifespan. Further refinements of the PAR-Q and the PARmed-X (including online versions of the forms) are required to address the unique limitations imposed by various chronic health conditions, and to allow the inclusion of individuals across their entire lifespan. A probing decision-tree process is proposed to assist in risk stratification and to reduce barriers to physical activity. Qualified exercise professionals will play an essential role in this revised physical activity clearance process.

  4. New recommended schedule for active immunization of normal infants and children.

    Science.gov (United States)

    1986-09-19

    A large, randomized, double-blind trial has made available sufficient data to recommend the simultaneous administration of combined measles-mumps-rubella (MMR), diphtheria and tetanus toxoids and pertussis (DTP), and oral poliovirus (OPV) vaccines to all children 15 months old or older who are eligible to receive these vaccines. In this trial, serologic response and clinical reaction rates following primary immunization with MMR were compared in a test group of 405 children given MMR simultaneously with DTP and OPV and a control group of 410 children given MMR followed by doses of DTP and OPV vaccine 2 months later. Seroconversion rates to each MMR component exceeded 96% in both groups, and the geometric mean titers achieved against the other 6 antigens also were similar in both groups. Rates of most of the common vaccine-associated clinical reactions to DTP and MMR were not augmented by simultaneous administration of these 2 vaccines. Some minor side effects were reported more frequently in the simultaneous-administration group, but these difference were judged to be related to artifacts of the study design rather than to differences in the safety of the 2 vaccine schedules. Data from the Center for Disease Control's Monitoring System for Adverse Events Following Immunization have been reviewed, particularly the information from Idaho, Louisiana, and Tennessee, where policies to administer MMR, DTP, and OPV simultaneously have been in effect for periods ranging from several months to years. The evidence suggests no increased risk of reactions associated with the simulaneous administration of these antigens. The overall implications of simultaneous administartion have not been fully defined, but it is anticipated that implementation of this new schedule will result in at least 3 benefits: a decrease in the number of health care provider visits required for immunization during the 2nd year of life, and accompanying decrease in costs, and an increase in the

  5. Recommended approaches to the scientific evaluation of ecotoxicological hazards and risks of endocrine-active substances

    DEFF Research Database (Denmark)

    Matthiessen, Peter; Ankley, Gerald T.; Biever, Ronald C

    2017-01-01

    A SETAC Pellston Workshop(®) "Environmental Hazard and Risk Assessment Approaches for Endocrine-Active Substances (EHRA)" was held in February 2016 in Pensacola, Florida, USA. The primary objective of the workshop was to provide advice, based on current scientific understanding, to regulators and...

  6. Studies on Bioequivalence of Activity based on "Spectrum-Effect Integrated Fingerprint" and Activity In Vivo%基于谱效整合指纹的体外活性与体内活性的生物等效性研究

    Institute of Scientific and Technical Information of China (English)

    孙莉琼; 丁晓萍; 马生堂; 戚进; 寇俊萍; 余伯阳

    2012-01-01

    This work was aimed to study the bioequivalence of activity based on "spectrum-effect integrated fingerprint" and activity in vivo. The hydrogen peroxide (H2O2) scavenging activity fingerprints of 9 batches of Crataegus leaves collected from different provinces were established through an on-line high-performance liquid chromatography-diode array detector combined with chemiluminescence detection (HPLC-DAD-CL) system. As the positive control, if resveratrol (1 |xg) was presumed as a potency unit, the relative activities of active peaks were calculated as potency unit according to standard potency curves of resveratrol. And the relative total activities of Crataegus leaves should be the sum of potency of all characteristic peaks. A total of 130 mice were randomly divided into 13 groups, the acute ischemic anoxic myocardial injury was induced by subcutaneous injection isoproterenol in mice, the survival time in mice with hypoxic state was recorded and the life extension rate of the treated group was studied. The correlation between the H2O2 scavenging capacity of Crataegus leaves based on HPLC-DAD-CL and the protective effect in mice with myocardial hypoxia was investigated. And the content of total flavonoids was determined to make the results above more authentic. It is found the antioxidant activities in vitro and in vivo both confirm with each other, which means the on-line activity screening method and antioxi-dant-activity integrated fingerprint research platform can be further promoted.%目的:基于谱效整合指纹图谱的药物体外生物活性与体内活性的生物等效性研究.方法:利用高效液相色谱-光电二极管阵列检测器-化学发光检测器(HPLC-DAD-CL)平台,建立9个不同产地山楂叶在线清除过氧化氢( H2O2)的活性整合指纹图谱,结合白藜芦醇清除H2O2的量效关系曲线方程,以1μg白藜芦醇的药效为一个效价单位,计算各指纹峰的效价值,用各指纹峰的效价值之和表示山楂

  7. Merely asking the customer to recommend has an impact on word-of-mouth activity

    DEFF Research Database (Denmark)

    Mattsson, Jan; Söderlund, Magnus

    2015-01-01

    This paper examines if a mere request to a customer – within the frame of a service encounter – to engage in word-of-mouth (WOM) would have an impact on the customer's subsequent WOM activity. Although previous studies have not examined this issue, theoretical arguments do exist. And they point...... in different directions; some suggest a positive impact, while others suggest a negative impact. To explore the issue empirically, we carried out two studies (one survey-based study and one experiment). Both generated the same result: they indicate that merely asking customers to engage in WOM has a positive...... impact on customers' WOM activity. In addition, we found that receiving the request was not negatively associated with the customers' overall evaluations, such as customer satisfaction, which indicates that the potential for negative consequences of making the request seems to be low....

  8. Estimating the differential costs of criminal activity for juvenile drug court participants: challenges and recommendations.

    Science.gov (United States)

    McCollister, Kathryn E; French, Michael T; Sheidow, Ashli J; Henggeler, Scott W; Halliday-Boykins, Colleen A

    2009-01-01

    Juvenile drug court (JDC) programs have expanded rapidly over the past 20 years and are an increasingly popular option for rehabilitating juvenile offenders with substance use problems. Given the high cost of crime to society, an important economic question is whether and to what extent JDC programs reduce criminal activity among juvenile offenders. To address this question, the present study added an economic cost analysis to an ongoing randomized trial of JDC conducted in Charleston, South Carolina. Four treatment conditions were included in the parent study: Family Court with usual community-based treatment (FC, the comparison group), Drug Court with usual community-based treatment (DC), DC with Multisystemic Therapy (DC/MST), and DC/MST enhanced with Contingency Management (DC/MST/CM). The economic study estimated the cost of criminal activity for nine specific crimes at baseline (pretreatment) and 4 and 12 months thereafter. A number of methodological challenges were encountered, suggesting that it may be more difficult to economically quantify frequency and type of criminal activity for adolescents than for adults. The present paper addresses methodological approaches and challenges, and proposes guidelines for future economic evaluations of adolescent substance abuse and crime prevention programs.

  9. Food preference and foraging activity of ants: recommendations for field applications of low-toxicity baits.

    Science.gov (United States)

    Nyamukondiwa, Casper; Addison, Pia

    2014-04-10

    Control of ants using baits of low toxicity cannot be effective without knowledge of bait distribution patterns and bait station densities, which are determined by ants' foraging activities. Furthermore, the success of toxic baits also depends upon attractiveness of bait carriers. Here, we assessed ground and vine foraging activity and food preferences for the three ant species ( Linepithema humile (Mayr) (Hymenoptera: Formicidae), Anoplolepis custodiens (F. Smith) and Crematogaster peringueyi Emery) under field conditions. We found that L. humile's vineyard foraging activity was high and that movement of ant bait by C. peringueyi and A. custodiens in the vineyard was relatively low. Consequently, more bait stations need to be dispensed for more effective control of C. peringueyi and A. custodiens than for L. humile. Different bait densities are discussed for the various ant species. Food preference trials indicated that vineyard foraging ants preferred wet bait attractants over dry ones, making liquids the most ideal carriers for baiting these ants. Linepithema humile was attracted to 25% sugar water, while C. peringueyi was attracted to both 25% sugar water and honey. Anoplolepis custodiens was attracted to tuna but was also attracted to 25% sugar water. Thus, future bait formulations should be tailor made to suit these specific food requirements if baits are to be successful in ant pest management.

  10. Two formulations of venlafaxine are bioequivalent when administered as open capsule mixed with applesauce to healthy subjects

    Directory of Open Access Journals (Sweden)

    Renu T Jain

    2011-01-01

    Full Text Available Venlafaxine is a unique antidepressant approved for treatment of various depressive disorders. A single dose, cross-over bioequivalence study was performed with two different formulations of venlafaxine 150 mg extended-release capsules in which the contents of capsule were mixed with applesauce and administered to healthy subjects under fed condition. A total of 24 healthy adult male subjects participated in this randomized, single-dose, non-blinded, two-way crossover study conducted at a single centre and 23 subjects completed the study as per the study protocol. After an overnight fast of 10 h, a high-fat and high-calorie breakfast was served 30 min before dosing. The subjects then received a single dose of either formulation administered with apple sauce followed by 240 ml of water as per randomized schedule in each period separated by a washout period of 7 days. A series of blood samples were collected upto 72 h for estimation of venlafaxine and its active metabolite, O-desmethylvenlafaxine. The quantification of venlafaxine and O-desmethylvenlafaxine was done by LC-MS/MS method and pharmacokinetic and statistical analysis by WinNonlin® 5.2 and SAS® 9.1.3. The results of the study demonstrated bioequivalence of two formulations as the 90% confidence interval for the intra-individual mean ratio of log-transformed C max , AUC 0-t and AUC 0-inf of the test to the reference formulation were found within the defined bioequivalence range of 80.00%-125.00%. Both the formulations were well tolerated. This alternative mode of administration may provide benefits to patients who have difficulty in swallowing the capsule as a whole.

  11. Pharmacokinetics and bioequivalence of two suxibuzone oral dosage forms in horses.

    Science.gov (United States)

    Jaraiz, V; Rodriguez, C; San Andres, M D; Gonzalez, F; San Andres, M I

    1999-08-01

    A disposition and bioequivalence study with a suxibuzone granulated and a suxibuzone paste oral formulation was performed in horses. Suxibuzone (SBZ) is a nonsteroidal anti-inflammatory drug, which was administered to horses (n = 6) at a dosage of 19 mg/kg bwt by the oral route (p.o.) in a two period cross-over design. Suxibuzone is very rapidly transformed into its main active metabolites, phenylbutazone (PBZ) and oxyphenbutazone (OPBZ). Therefore plasma and synovial fluid concentrations of SBZ, PBZ and OPBZ were simultaneously measured by a sensitive and specific high-performance liquid chromatographic method. The pharmacokinetic parameters were determined by noncompartmental analysis. Suxibuzone could not be detected in any plasma and synovial fluid samples (LOQ) was 608.0 +/- 162.2 micrograms.h/mL and 656.6 +/- 149.7 micrograms.h/mL after granulate and paste administration, respectively. Mean plasma concentration of OPBZ increased to 5-6.7 micrograms/mL, with the maximum concentration (Cmax) appearing between 9 and 12 h after administration of both formulations. The AUCs0-->LOQ for OPBZ were also similar (141.8 +/- 48.3 micrograms.h/mL granulate vs. 171.4 +/- 45.0 micrograms.h/mL paste). It was concluded that the suxibuzone products were bioequivalent with respect to PBZ. For OPBZ, the 95% confidence intervals of the pharmacokinetic parameters were within the acceptable range of 80-125%. The paste formulation provided greater bioavailability of PBZ and OPBZ.

  12. Bioequivalence evaluation of two formulations of pidotimod using a limited sampling strategy.

    Science.gov (United States)

    Huang, Ji-Han; Huang, Xiao-Hui; Wang, Kun; Li, Jian-Chun; Xie, Xue-Feng; Shen, Chen-Lin; Li, Lu-Jin; Zheng, Qing-Shan

    2013-07-01

    The aim of this study was to develop a limited sampling strategy (LSS) to assess the bioequivalence of two formulations of pidotimod. A randomized, two-way, cross-over study was conducted in healthy Chinese volunteers to compare two formulations of pidotimod. A limited sampling model was established using regression models to estimate the pharmacokinetic parameters and assess the bioequivalence of pidotimod. The model was internally validated by the Jack-knife method and graphical methods. The traditional non-compartmental method was also used to analyze the data and compared with LSS method. The results indicate that following oral administration of a single 800 mg dose, the plasma AUC(0-12 h) and C(max) of pidotimod can be predicted accurately using only two to four plasma samples. The bioequivalence assessment based on the LSS models provided results very similar to that obtained using all the observed concentration-time data points and indicate that the two pidotimod formulations were bioequivalent. A LSS method for assessing the bioequivalence of pidotimod formulations was established and proved to be applicable and accurate. This LSS method could be considered appropriate for a pidotimod bioequivalence study, providing an inexpensive cost of sampling acquisition and analysis. And the methodology presented here may also be applicable to bioequivalence evaluation of other medications.

  13. Investigation on the need of multiple dose bioequivalence studies for prolonged-release generic products.

    Science.gov (United States)

    García-Arieta, Alfredo; Morales-Alcelay, Susana; Herranz, Marta; de la Torre-Alvarado, José María; Blázquez-Pérez, Antonio; Suárez-Gea, Ma Luisa; Alvarez, Covadonga

    2012-02-28

    In the European Union multiple dose bioequivalence studies are required for the approval of generic prolonged-release products, but they are not required by the US-FDA. In order to investigate if the multiple dose bioequivalence studies are necessary, the bioequivalence studies assessed in the Spanish Agency for Medicines and Health Care Products in the last 10 years were searched to find all reasons for rejection and identify those cases where the multiple dose study had failed to show bioequivalence and the single dose study had shown bioequivalence. In these latter cases, the plasma concentration at the end of the dosing interval (C(τ)) in the single dose study was assessed to investigate its sensitivity to predict non-bioequivalence in the steady state. The search identified six cases where the non-equivalence in the multiple dose study was not detected by the corresponding single dose study. C(τ) was not able to detect the difference in five cases and in general it was more variable than conventional metrics. In conclusion, the multiple dose bioequivalence study is necessary to ensure therapeutic equivalence and the use of C(τ) would be counterproductive, increasing the sample size of the studies without enough sensitivity to detect differences in the steady state.

  14. Study on requirements of bioequivalence for registration of pharmaceutical products in USA, Europe and Canada.

    Science.gov (United States)

    Galgatte, Upendra C; Jamdade, Vijay R; Aute, Pravin P; Chaudhari, Pravin D

    2014-11-01

    The present study was aimed to study the requirements of bioequivalence for the registration of pharmaceutical products in the USA, Europe and Canada. Before going into bioequivalence studies it is essential for the pharmaceutical industry to study the guidelines of bioequivalence for the respective country where the industry wants to market its products and thus enter into generic market. This study reviews the requirements of bioequivalence with study parameters such as study design, fasting or fed state studies, volunteers recruitment, study dose, sampling points, analytical method validation parameters, moieties to be measured in plasma, pharmacokinetic parameters, criteria for bioequivalence, GCP requirements etc, which are needed for the pharmaceutical industry to carry out bioequivalence studies and to file ANDA. Test products and reference products are needed for this study. Test products are usually manufactured by a sponsor and reference products are provided by the government laboratories of the respective countries. Sampling points also vary with respect to the regulatory guidelines of these countries. All these countries follow ICH GCP guidelines. The criterion of bioequivalence for these countries is 90% CI 80-125% for C max, AUC t , AUC0-∞.

  15. Is physical activity, practiced as recommended for health benefit, a risk factor for osteoarthritis?

    Science.gov (United States)

    Lefèvre-Colau, Marie-Martine; Nguyen, Christelle; Haddad, Rebecca; Delamarche, Paul; Paris, Guillaume; Palazzo, Clémence; Poiraudeau, Serge; Rannou, François; Roren, Alexandra

    2016-06-01

    In this critical narrative review, we examine the role of physical activity (PA), recreational and elite sports in the development of knee/hip osteoarthritis (OA), taking into account the role of injury in this relationship. The process of article selection was unsystematic. Articles were selected on the basis of the authors' expertise, self-knowledge, and reflective practice. In the general adult population, self-reported diagnosis of knee/hip OA was not associated with low, moderate or high levels of PA. For studies using radiographic knee/hip OA as a primary outcome, the incidence of asymptomatic radiographic OA was higher for subjects with the highest quartile of usual PA than the least active subjects. The risk of incident radiographic knee/hip OA features was increased for subjects with a history of regular sports participation (for osteophyte formation but not joint space narrowing). This risk depended on the type of sport (team and power sports but not endurance and running), and certain conditions (high level of practice) were closely related to the risk of injury. The prevalence of radiographic OA was significantly higher, especially the presence of osteophytes, in former elite athletes than controls. The risk of OA was higher with participation in mixed sports, especially soccer or power sports, than endurance sport. However, the prevalence of clinical OA between former elite athletes and controls was similar, with less hip/knee disability in former athletes. Moderate daily recreational or sport activities, whatever the type of sport, are not a consistent risk factor for clinical or radiographic knee/hip OA. Risk of injury in different sports may be the key factor to understanding the risk of OA related to sport.

  16. Model-based analyses of bioequivalence crossover trials using the stochastic approximation expectation maximisation algorithm.

    Science.gov (United States)

    Dubois, Anne; Lavielle, Marc; Gsteiger, Sandro; Pigeolet, Etienne; Mentré, France

    2011-09-20

    In this work, we develop a bioequivalence analysis using nonlinear mixed effects models (NLMEM) that mimics the standard noncompartmental analysis (NCA). We estimate NLMEM parameters, including between-subject and within-subject variability and treatment, period and sequence effects. We explain how to perform a Wald test on a secondary parameter, and we propose an extension of the likelihood ratio test for bioequivalence. We compare these NLMEM-based bioequivalence tests with standard NCA-based tests. We evaluate by simulation the NCA and NLMEM estimates and the type I error of the bioequivalence tests. For NLMEM, we use the stochastic approximation expectation maximisation (SAEM) algorithm implemented in monolix. We simulate crossover trials under H(0) using different numbers of subjects and of samples per subject. We simulate with different settings for between-subject and within-subject variability and for the residual error variance. The simulation study illustrates the accuracy of NLMEM-based geometric means estimated with the SAEM algorithm, whereas the NCA estimates are biased for sparse design. NCA-based bioequivalence tests show good type I error except for high variability. For a rich design, type I errors of NLMEM-based bioequivalence tests (Wald test and likelihood ratio test) do not differ from the nominal level of 5%. Type I errors are inflated for sparse design. We apply the bioequivalence Wald test based on NCA and NLMEM estimates to a three-way crossover trial, showing that Omnitrope®; (Sandoz GmbH, Kundl, Austria) powder and solution are bioequivalent to Genotropin®; (Pfizer Pharma GmbH, Karlsruhe, Germany). NLMEM-based bioequivalence tests are an alternative to standard NCA-based tests. However, caution is needed for small sample size and highly variable drug.

  17. Recommended survey designs for occupancy modelling using motion-activated cameras: insights from empirical wildlife data.

    Science.gov (United States)

    Shannon, Graeme; Lewis, Jesse S; Gerber, Brian D

    2014-01-01

    Motion-activated cameras are a versatile tool that wildlife biologists can use for sampling wild animal populations to estimate species occurrence. Occupancy modelling provides a flexible framework for the analysis of these data; explicitly recognizing that given a species occupies an area the probability of detecting it is often less than one. Despite the number of studies using camera data in an occupancy framework, there is only limited guidance from the scientific literature about survey design trade-offs when using motion-activated cameras. A fuller understanding of these trade-offs will allow researchers to maximise available resources and determine whether the objectives of a monitoring program or research study are achievable. We use an empirical dataset collected from 40 cameras deployed across 160 km(2) of the Western Slope of Colorado, USA to explore how survey effort (number of cameras deployed and the length of sampling period) affects the accuracy and precision (i.e., error) of the occupancy estimate for ten mammal and three virtual species. We do this using a simulation approach where species occupancy and detection parameters were informed by empirical data from motion-activated cameras. A total of 54 survey designs were considered by varying combinations of sites (10-120 cameras) and occasions (20-120 survey days). Our findings demonstrate that increasing total sampling effort generally decreases error associated with the occupancy estimate, but changing the number of sites or sampling duration can have very different results, depending on whether a species is spatially common or rare (occupancy = ψ) and easy or hard to detect when available (detection probability = p). For rare species with a low probability of detection (i.e., raccoon and spotted skunk) the required survey effort includes maximizing the number of sites and the number of survey days, often to a level that may be logistically unrealistic for many studies. For common species with

  18. Physical activity and maternal obesity: cardiovascular adaptations, exercise recommendations, and pregnancy outcomes.

    Science.gov (United States)

    Mottola, Michelle F

    2013-10-01

    Although a healthy lifestyle approach is intuitive for obese pregnant women, no guidelines currently exist to manage these women throughout pregnancy. Women who are medically prescreened for contraindications can engage in a walking program three to four times per week, starting at 25 min per session and adding 2 min per week until reaching 40 min, with sessions continuing until delivery. A target heart rate of 102-124 beats per minute should be promoted for women 20-29 years of age and a rate of 101-120 beats per minute for women 30-39 years of age. A pedometer step count of 10,000 steps per day is suggested as a goal, as this level of activity provides important health benefits. Combining healthy eating with a walking plan prevents excessive weight gain during pregnancy and promotes a healthy fetal environment.

  19. Physical Activity: A Tool for Improving Health (Part 3--Recommended Amounts of Physical Activity for Optimal Health)

    Science.gov (United States)

    Gallaway, Patrick J.; Hongu, Nobuko

    2016-01-01

    By promoting physical activities and incorporating them into their community-based programs, Extension professionals are improving the health of individuals, particularly those with limited resources. This article is the third in a three-part series describing the benefits of physical activity for human health: (1) biological health benefits of…

  20. Effects of Juvenile Idiopathic Arthritis on Kinematics and Kinetics of the Lower Extremities Call for Consequences in Physical Activities Recommendations

    Directory of Open Access Journals (Sweden)

    M. Hartmann

    2010-01-01

    Full Text Available Juvenile idiopathic arthritis (JIA patients (n=36 with symmetrical polyarticular joint involvement of the lower extremities and healthy controls (n=20 were compared concerning differences in kinematic, kinetic, and spatio-temporal parameters with 3D gait analysis. The aims of this study were to quantify the differences in gait between JIA patients and healthy controls and to provide data for more detailed sport activities recommendations. JIA-patients showed reduced walking speed and step length, strongly anterior tilted pelvis, reduced maximum hip extension, reduced knee extension during single support phase and reduced plantar flexion in push off. Additionally the roll-off procedure of the foot was slightly decelerated. The reduced push off motion in the ankle was confirmed by lower peaks in ankle moment and power. The gait of JIA-patients can be explained as a crouch-like gait with hyperflexion in hip and knee joints and less plantar flexion in the ankle. A preventive mobility workout would be recommendable to reduce these restrictions in the future. Advisable are sports with emphasis on extension in hip, knee, and ankle plantar flexion.

  1. Protein turnover, amino acid requirements and recommendations for athletes and active populations

    Energy Technology Data Exchange (ETDEWEB)

    Poortmans, J.R.; Carpentier, A. [Laboratory for Biometry and Sport Nutrition, Faculty of Motor Sciences, Free University of Brussels, Brussels (Belgium); Pereira-Lancha, L.O. [Departamento de Nutrição, Instituto Vita, São Paulo, SP (Brazil); Lancha, A. Jr. [Laboratório de Nutrição Aplicada à Atividade Motora, Escola de Educação Física e Esporte, Universidade de São Paulo, São Paulo, SP (Brazil)

    2012-06-08

    Skeletal muscle is the major deposit of protein molecules. As for any cell or tissue, total muscle protein reflects a dynamic turnover between net protein synthesis and degradation. Noninvasive and invasive techniques have been applied to determine amino acid catabolism and muscle protein building at rest, during exercise and during the recovery period after a single experiment or training sessions. Stable isotopic tracers ({sup 13}C-lysine, {sup 15}N-glycine, {sup 2}H{sub 5}-phenylalanine) and arteriovenous differences have been used in studies of skeletal muscle and collagen tissues under resting and exercise conditions. There are different fractional synthesis rates in skeletal muscle and tendon tissues, but there is no major difference between collagen and myofibrillar protein synthesis. Strenuous exercise provokes increased proteolysis and decreased protein synthesis, the opposite occurring during the recovery period. Individuals who exercise respond differently when resistance and endurance types of contractions are compared. Endurance exercise induces a greater oxidative capacity (enzymes) compared to resistance exercise, which induces fiber hypertrophy (myofibrils). Nitrogen balance (difference between protein intake and protein degradation) for athletes is usually balanced when the intake of protein reaches 1.2 g·kg{sup −1}·day{sup −1} compared to 0.8 g·kg{sup −1}·day{sup −1} in resting individuals. Muscular activities promote a cascade of signals leading to the stimulation of eukaryotic initiation of myofibrillar protein synthesis. As suggested in several publications, a bolus of 15-20 g protein (from skimmed milk or whey proteins) and carbohydrate (± 30 g maltodextrine) drinks is needed immediately after stopping exercise to stimulate muscle protein and tendon collagen turnover within 1 h.

  2. Protein turnover, amino acid requirements and recommendations for athletes and active populations

    Directory of Open Access Journals (Sweden)

    J.R. Poortmans

    2012-10-01

    Full Text Available Skeletal muscle is the major deposit of protein molecules. As for any cell or tissue, total muscle protein reflects a dynamic turnover between net protein synthesis and degradation. Noninvasive and invasive techniques have been applied to determine amino acid catabolism and muscle protein building at rest, during exercise and during the recovery period after a single experiment or training sessions. Stable isotopic tracers (13C-lysine, 15N-glycine, ²H5-phenylalanine and arteriovenous differences have been used in studies of skeletal muscle and collagen tissues under resting and exercise conditions. There are different fractional synthesis rates in skeletal muscle and tendon tissues, but there is no major difference between collagen and myofibrillar protein synthesis. Strenuous exercise provokes increased proteolysis and decreased protein synthesis, the opposite occurring during the recovery period. Individuals who exercise respond differently when resistance and endurance types of contractions are compared. Endurance exercise induces a greater oxidative capacity (enzymes compared to resistance exercise, which induces fiber hypertrophy (myofibrils. Nitrogen balance (difference between protein intake and protein degradation for athletes is usually balanced when the intake of protein reaches 1.2 g·kg-1·day-1 compared to 0.8 g·kg-1·day-1 in resting individuals. Muscular activities promote a cascade of signals leading to the stimulation of eukaryotic initiation of myofibrillar protein synthesis. As suggested in several publications, a bolus of 15-20 g protein (from skimmed milk or whey proteins and carbohydrate (± 30 g maltodextrine drinks is needed immediately after stopping exercise to stimulate muscle protein and tendon collagen turnover within 1 h.

  3. Recommender Systems

    CERN Document Server

    Lü, Linyuan; Yeung, Chi Ho; Zhang, Yi-Cheng; Zhang, Zi-Ke; Zhou, Tao

    2012-01-01

    The ongoing rapid expansion of the Internet greatly increases the necessity of effective recommender systems for filtering the abundant information. Extensive research for recommender systems is conducted by a broad range of communities including social and computer scientists, physicists, and interdisciplinary researchers. Despite substantial theoretical and practical achievements, unification and comparison of different approaches are lacking, which impedes further advances. In this article, we review recent developments in recommender systems and discuss the major challenges. We compare and evaluate available algorithms and examine their roles in the future developments. In addition to algorithms, physical aspects are described to illustrate macroscopic behavior of recommender systems. Potential impacts and future directions are discussed. We emphasize that recommendation has a great scientific depth and combines diverse research fields which makes it of interests for physicists as well as interdisciplinar...

  4. Use of pharmacogenetics in bioequivalence studies to reduce sample size: an example with mirtazapine and CYP2D6.

    Science.gov (United States)

    González-Vacarezza, N; Abad-Santos, F; Carcas-Sansuan, A; Dorado, P; Peñas-Lledó, E; Estévez-Carrizo, F; Llerena, A

    2013-10-01

    In bioequivalence studies, intra-individual variability (CV(w)) is critical in determining sample size. In particular, highly variable drugs may require enrollment of a greater number of subjects. We hypothesize that a strategy to reduce pharmacokinetic CV(w), and hence sample size and costs, would be to include subjects with decreased metabolic enzyme capacity for the drug under study. Therefore, two mirtazapine studies, two-way, two-period crossover design (n=68) were re-analysed to calculate the total CV(w) and the CV(w)s in three different CYP2D6 genotype groups (0, 1 and ≥ 2 active genes). The results showed that a 29.2 or 15.3% sample size reduction would have been possible if the recruitment had been of individuals carrying just 0 or 0 plus 1 CYP2D6 active genes, due to the lower CV(w). This suggests that there may be a role for pharmacogenetics in the design of bioequivalence studies to reduce sample size and costs, thus introducing a new paradigm for the biopharmaceutical evaluation of drug products.

  5. Juvenile Spondyloarthritis Treatment Recommendations

    OpenAIRE

    Tse, Shirley; Burgos-Vargas, Ruben; Colbert, Robert A

    2012-01-01

    No specific recommendations for the treatment of juvenile spondyloarthritis have been established. Important differences exist in how spondyloarthritis begins and progresses in children and adults, supporting the need for pediatric-specific recommendations. Recently published recommendations for the treatment of juvenile arthritis consider children with sacroiliitis in a separate group, and allow for more accelerated institution of a TNF inhibitor depending on disease activity and prognostic ...

  6. Bioequivalence Demonstration for Ω-3 Acid Ethyl Ester Formulations: Rationale for Modification of Current Guidance.

    Science.gov (United States)

    Maki, Kevin C; Johns, Colleen; Harris, William S; Puder, Mark; Freedman, Steven D; Thorsteinsson, Thorsteinn; Daak, Ahmed; Rabinowicz, Adrian L; Sancilio, Frederick D

    2017-02-08

    The US Food and Drug Administration (FDA) draft guidance for establishing bioequivalence (BE) of ω-3 acid ethyl esters (containing both eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA] as ethyl esters), used to treat severe hypertriglyceridemia, recommends the conduct of 2 studies: one with participants in the fasting state and one with participants in the fed state. For the fasting study, the primary measures of BE are baseline-adjusted EPA and DHA levels in total plasma lipids. For the fed study, the primary measures of BE are EPA and DHA ethyl esters in plasma. This guidance differs from that established for icosapent ethyl (EPA ethyl esters) in which the primary measure of BE is baseline-adjusted total EPA in plasma lipids for both the fasting and fed states. The FDA guidance for ω-3 acid ethyl esters is not supported by their physiologic characteristics and triglyceride-lowering mechanisms because EPA and DHA ethyl esters are best characterized as pro-drugs. This article presents an argument for amending the FDA draft guidance for ω-3 acid ethyl esters to use baseline-adjusted EPA and DHA in total plasma lipids as the primary measures of BE for both fasting and fed conditions. This change would harmonize the approaches for demonstration of BE for ω-3 acid ethyl esters and icosapent ethyl (EPA ethyl esters) products for future development programs and is the most physiologically rational approach to BE testing.

  7. Establishing bioequivalence of veterinary premixes (Type A medicated articles).

    Science.gov (United States)

    Hunter, R P; Lees, P; Concordet, D; Toutain, P-L

    2012-04-01

    a) Key issues concerning Premix (Type A medicated articles) Bioequivalence evaluations: 1) This is a complex issue concerning both route of administration and formulation. 2) If the animal is not at the bunk/trough, the animal is not self-administering (eating medicated feed), thus there can be no drug absorption. b) Differing opinions among scientists and regulatory authorities/expert bodies regarding: 1) No harmonization on how to design, conduct, and interpret in vivo studies. 2) Applicability of biowaivers to Type A (premix) products. 3) Why are topdress and complete feed considered differently? Are they different formulations or different routes of administration? 4) Single dose vs. multi-dose studies. 5) What is the final formulation? c) What are the next steps: 1) Harmonize current bioequivalence guidelines through the VICH process. 2) Determine the applicability/non-applicability of the Biopharmaceutical Classification System (BCS). 3) Establish the Total Mixed Ration (i.e. formulation) effects. 4) Define the test subject (individual, pen, etc.).

  8. Therapeutic bioequivalency study of brand name versus generic carbamazepine.

    Science.gov (United States)

    Oles, K S; Penry, J K; Smith, L D; Anderson, R L; Dean, J C; Riela, A R

    1992-06-01

    We performed a randomized double-blind crossover therapeutic bioequivalency study of a generic (Epitol) versus a brand name (Tegretol) carbamazepine product under steady-state conditions in 40 epileptic patients. Each patient received 90-day supplies of Epitol or Tegretol and placebo, which replaced the usual dosage of the alternate product. Group A consisted of 20 seizure-free (from 5 months to 2 years) patients and group B of 20 patients with seizures refractory to drug therapy. In group A, four patients had seizures, two on both Epitol and Tegretol and two on Tegretol. In group B, the average seizure frequencies were 0.25 seizures per day on Epitol and 0.22 seizures per day on Tegretol. Average seizure frequencies were statistically the same (at a 20% difference, p less than 0.05). Areas under the curve were statistically the same (at a 20% difference, p = 0.05). Average peak heights were statistically the same (at a 20% difference, p less than 0.05). Average time to peak was earlier with Epitol. Epitol and Tegretol performed equally well in clinical efficacy and bioequivalency.

  9. Bioequivalence of Progesterone Sustained Release Suppository in Rabbits

    Institute of Scientific and Technical Information of China (English)

    LONG Lihong; HUANG Qun; WU Minghui; HOU Shuxian; DAI Zongshun

    2005-01-01

    To study the bioequivalence of a kind of progesterone sustained release suppository, a randomized cross-over study was conducted in 12 rabbits. A single rectal dose of 2.75 mg/kg progesterone sustained released suppository (tested formulation, T) and progesterone suppository(reference formulation, R) was administered; a multiple dose of 2.75 mg/kg was given up to seven times with an interval of 8 h. Concentrations in serum were determined by a competitive enzyme immunoassay. The main parameters of T were: for single and multiple doses, Cmax was 48.8±11.8ng/mL and 43.5±9.4 ng/mL, Tmax was 0.5±0.3 h and 0.4±0.3 h, AUC(0-24h) was 362.4±143 ng·h·mL-1 and 310.6±70.3ng ·h·mL-1,respectively.The relative bioavailability of T to R were ( 104.2 ±13.4) % and ( 111.4 ± 19. 1 ) %, respectively. Statistical analysis showed that the two formulations were bioequivalent and T had sustained released feature.

  10. A comparison of four different methods for outlier detection in bioequivalence studies.

    Science.gov (United States)

    Ramsay, Timothy; Elkum, Naser

    2005-01-01

    Bioequivalence studies, required by law whenever a new formulation of an existing drug product is introduced to the market, are designed to test whether the bioavailability, defined as the rate and extent to which a substance reaches systemic circulation, is equivalent for each of two or more formulations. Detection and treatment of outlying data in bioequivalence studies are practically important, because inclusion or deletion of potential outlying data may lead to a different conclusion concerning bioequivalence. A review of the literature reveals that four different methods have been proposed for detecting outliers in bioavailability/bioequivalence studies. We present the results of an extensive computer simulation testing the small sample performance of these four testing methods, the results of which indicate that one of these, the estimates distance test, is substantially more powerful than the alternatives.

  11. Does practicing hatha yoga satisfy recommendations for intensity of physical activity which improves and maintains health and cardiovascular fitness?

    Directory of Open Access Journals (Sweden)

    Rundle Andrew

    2007-11-01

    Full Text Available Abstract Background Little is known about the metabolic and heart rate responses to a typical hatha yoga session. The purposes of this study were 1 to determine whether a typical yoga practice using various postures meets the current recommendations for levels of physical activity required to improve and maintain health and cardiovascular fitness; 2 to determine the reliability of metabolic costs of yoga across sessions; 3 to compare the metabolic costs of yoga practice to those of treadmill walking. Methods In this observational study, 20 intermediate-to-advanced level yoga practitioners, age 31.4 ± 8.3 years, performed an exercise routine inside a human respiratory chamber (indirect calorimeter while wearing heart rate monitors. The exercise routine consisted of 30 minutes of sitting, 56 minutes of beginner-level hatha yoga administered by video, and 10 minutes of treadmill walking at 3.2 and 4.8 kph each. Measures were mean oxygen consumption (VO2, heart rate (HR, percentage predicted maximal heart rate (%MHR, metabolic equivalents (METs, and energy expenditure (kcal. Seven subjects repeated the protocol so that measurement reliability could be established. Results Mean values across the entire yoga session for VO2, HR, %MHR, METs, and energy/min were 0.6 L/kg/min; 93.2 beats/min; 49.4%; 2.5; and 3.2 kcal/min; respectively. Results of the ICCs (2,1 for mean values across the entire yoga session for kcal, METs, and %MHR were 0.979 and 0.973, and 0.865, respectively. Conclusion Metabolic costs of yoga averaged across the entire session represent low levels of physical activity, are similar to walking on a treadmill at 3.2 kph, and do not meet recommendations for levels of physical activity for improving or maintaining health or cardiovascular fitness. Yoga practice incorporating sun salutation postures exceeding the minimum bout of 10 minutes may contribute some portion of sufficiently intense physical activity to improve cardio

  12. Recommended Wilderness

    Data.gov (United States)

    National Park Service, Department of the Interior — Recommended wilderness is an Arcview shapefile representing the porposed wilderness areas throughout the park. The boundaries for this data set were digitized by...

  13. Bioequivalence and Bioavailability Clinical Trials: A Status Report from the National Institutes of Health ClinicalTrials.gov Registry

    OpenAIRE

    Stockmann, Chris; Spigarelli, Michael G.; Ampofo, Krow; Sherwin, Catherine MT

    2013-01-01

    Drug development is an expensive process that is marked by a high-failure rate. For this reason early stage bioequivalence and pharmacokinetic studies are essential in determining the fate of new drug products. In this study, we sought to systematically assess the current trends of ongoing and recently completed bioequivalence and bioavailability trials that have been registered within a national clinical trials registry. All bioequivalence and bioavailability studies registered in the United...

  14. Deriving bio-equivalents from in vitro bioassays: assessment of existing uncertainties and strategies to improve accuracy and reporting.

    Science.gov (United States)

    Wagner, Martin; Vermeirssen, Etiënne L M; Buchinger, Sebastian; Behr, Maximilian; Magdeburg, Axel; Oehlmann, Jörg

    2013-08-01

    Bio-equivalents (e.g., 17β-estradiol or dioxin equivalents) are commonly employed to quantify the in vitro effects of complex human or environmental samples. However, there is no generally accepted data analysis strategy for estimating and reporting bio-equivalents. Therefore, the aims of the present study are to 1) identify common mathematical models for the derivation of bio-equivalents from the literature, 2) assess the ability of those models to correctly predict bio-equivalents, and 3) propose measures to reduce uncertainty in their calculation and reporting. We compiled a database of 234 publications that report bio-equivalents. From the database, we extracted 3 data analysis strategies commonly used to estimate bio-equivalents. These models are based on linear or nonlinear interpolation, and the comparison of effect concentrations (ECX ). To assess their accuracy, we employed simulated data sets in different scenarios. The results indicate that all models lead to a considerable misestimation of bio-equivalents if certain mathematical assumptions (e.g., goodness of fit, parallelism of dose-response curves) are violated. However, nonlinear interpolation is most suitable to predict bio-equivalents from single-point estimates. Regardless of the model, subsequent linear extrapolation of bio-equivalents generates additional inaccuracy if the prerequisite of parallel dose-response curves is not met. When all these factors are taken into consideration, it becomes clear that data analysis introduces considerable uncertainty in the derived bio-equivalents. To improve accuracy and transparency of bio-equivalents, we propose a novel data analysis strategy and a checklist for reporting Minimum Information about Bio-equivalent ESTimates (MIBEST).

  15. Recommender systems

    CERN Document Server

    Kembellec, Gérald; Saleh, Imad

    2014-01-01

    Acclaimed by various content platforms (books, music, movies) and auction sites online, recommendation systems are key elements of digital strategies. If development was originally intended for the performance of information systems, the issues are now massively moved on logical optimization of the customer relationship, with the main objective to maximize potential sales. On the transdisciplinary approach, engines and recommender systems brings together contributions linking information science and communications, marketing, sociology, mathematics and computing. It deals with the understan

  16. Bioequivalence of Sandoz methylphenidate osmotic-controlled release tablet with Concerta® (Janssen-Cilag)

    OpenAIRE

    Schapperer, Elisabeth; Daumann, Heike; Lamouche, Stéphane; Thyroff-Friesinger, Ursula; Viel, François; Weitschies, Werner

    2015-01-01

    The aim was to assess the bioequivalence of Sandoz methylphenidate osmotic-controlled release (OCR) tablets (Sandoz [Methylphenidate[ MPH OCR) with Concerta®, a methylphenidate formulation indicated for the treatment of attention deficit/hyperactivity disorder (ADHD). Four open-label, randomized, single-dose, two-way crossover bioequivalence studies were conducted in healthy subjects: three fasting studies with 54-, 36- and 18-mg doses of methylphenidate, and one fed study with the 54-mg dose...

  17. Somatic characteristics in relation to meeting recommended physical activity in overweight and obese women aged 30-60 years

    Directory of Open Access Journals (Sweden)

    Tereza Sofková

    2015-09-01

    Full Text Available Background: Physical activity (PA can provide health benefits and thus reduce the risk of complications from obesity and improve mental well-being. We consider body composition as an acceptable indicator of the functional condition of the body. Aims: Our research objective was to analyse selected body composition fractions in relation to meeting recommended PA in overweight and obese women. Methods: 221 women participated in our study, divided in two age groups: 30 to 44.9 years (Maturus I, n = 118 and 45 to 60 years (Maturus II, n = 103. Each age group was further differentiated by sub-groups (adequate and inadequate PA according to the achieved PA level (medium PA: 3 to 6 MET; ≥ 150 min/week. To determine the PA parameters within one week the ActiGraph GT1M accelerometer was used. The InBody 720 body composition analyser was used to determine body composition parameters. Descriptive characteristics and data analysis were carried out using Statistica 10.0. Differences were compared by the Student's t-test. Statistical significance level was set at α < .05. Results: Younger women who achieved adequate PA reached lower average values of body fat mass and visceral fat area than women with inadequate PA. Higher average values of the fat-free mass, body cell mass and skeletal muscle mass were found in older women with adequate PA in comparison with women with inadequate PA. Conclusions: The research study verified a positive relationship between meeting the recommended PA level and its impact on body composition health risk indicators. A positive approach to the PA may lead to a decrease in health problems associated with excess weight and obesity.

  18. Bioavailability and Bioequivalence in Drug Development

    OpenAIRE

    Chow, Shein-Chung

    2014-01-01

    Bioavailability is referred to as the extent and rate to which the active drug ingredient or active moiety from the drug product is absorbed and becomes available at the site of drug action. The relative bioavailability in terms of the rate and extent of drug absorption is considered predictive of clinical outcomes. In 1984, the United States Food and Drug Administration (FDA) was authorized to approve generic drug products under the Drug Price Competition and Patent Term Restoration Act base...

  19. Impact of truncated area under the curve on failed bioequivalence studies: a computer simulation analysis.

    Science.gov (United States)

    Mahmood, Iftekhar

    2004-01-01

    The common measures used in a bioequivalence study are area under the curve (AUC) and the maximum plasma concentration. Estimation of AUC requires frequent blood samples. For long half-life drugs, sampling for long periods of time may become cumbersome. To resolve this issue some investigators have suggested the use of truncated AUC in bioequivalence studies for long half-life drugs. The suggested length of time for the truncated AUC is 72 hours. Many studies have been conducted to show that truncated AUC till 72 hours is a suitable approach. However, the suitability of truncated AUC for failed bioequivalence study has not been demonstrated. This report of simulated plasma concentration versus time data evaluates the suitability of truncated AUC for failed bioequivalence study of two hypothetical drugs. The results of the study indicate that the truncated approach for the estimation of the AUC for long half-life drugs in bioequivalence studies may be useful but it also increases the probability of accepting drugs as being bioequivalent when they are not.

  20. Recommender Systems for Learning

    CERN Document Server

    Manouselis, Nikos; Verbert, Katrien; Duval, Erik

    2013-01-01

    Technology enhanced learning (TEL) aims to design, develop and test sociotechnical innovations that will support and enhance learning practices of both individuals and organisations. It is therefore an application domain that generally covers technologies that support all forms of teaching and learning activities. Since information retrieval (in terms of searching for relevant learning resources to support teachers or learners) is a pivotal activity in TEL, the deployment of recommender systems has attracted increased interest. This brief attempts to provide an introduction to recommender systems for TEL settings, as well as to highlight their particularities compared to recommender systems for other application domains.

  1. Bioequivalence study of two losartan formulations administered orally in healthy male volunteers.

    Science.gov (United States)

    Bienert, Agnieszka; Brzezińiski, Rafał; Szałek, Edyta; Dubai, Vitali; Grześkowiak, Edmund; Dyderski, Stanisław; Drobnik, Leon; Wolc, Anna; Olejniczak-Rabinek, Magdalena

    2006-01-01

    The bioavailability of a new losartan preparation (2-butyl-4-chloro-1-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]imidazole-5-methanol monopotassium salt, CAS 114798-26-4) was compared with the reference preparation of the drug in 24 healthy male volunteers, aged between 19 and 32. The open, randomized, single-blind two-sequence, two-period crossover study design was performed. Under fasting conditions, each subject received a single oral dose of 100 mg losartan as a test or reference formulation. The plasma concentrations of losartan and its active metabolite were analyzed by a rapid and sensitive HPLC method with UV detection. The pharmacokinetic parameters included AUC0-36h, AUC0-infinity, Cmax, t1/2, and Ke. Values of AUC0-infinity demonstrate nearly identical bioavailability of losartan from the examined formulations. The AUC0-infinity of losartan was 2019.92+/-1002.90 and 2028.58+/-837.45 ng x h/ml for the test and reference formulation, respectively. The AUC0-infinity of the metabolite was 10851.52+/-4438.66 and 11041.18 +/-5015.81 ng x h/ml for test and reference formulation, respectively. The maximum plasma concentration (Cmax) of losartan was 745.94+/-419.75 ng/ml for the test and 745.74+/-329.99 ng/ml for the reference product and the Cmax of the metabolite was 1805.77+/-765.39 and 1606.22 +/-977.22 ng/ml for the test and reference product, respectively. No statistical differences were observed for Cmax and the area under the plasma concentration-time curve for both losartan and its active metabolite. 90 % confidence limits calculated for Cmax and AUC from zero to infinity (AUC0-infinity) of losartan and its metabolite were included in the bioequivalence range (0.8-1.25 for AUC). This study shows that the test formulation is bioequivalent to the reference formulation for losartan and its main active metabolite.

  2. Early Site Permit Demonstration Program: Recommendations for communication activities and public participation in the Early Site Permit Demonstration Program

    Energy Technology Data Exchange (ETDEWEB)

    1993-01-27

    On October 24, 1992, President Bush signed into law the National Energy Policy Act of 1992. The bill is a sweeping, comprehensive overhaul of the Nation`s energy laws, the first in more than a decade. Among other provisions, the National Energy Policy Act reforms the licensing process for new nuclear power plants by adopting a new approach developed by the US Nuclear Regulatory Commission (NRC) in 1989, and upheld in court in 1992. The NRC 10 CFR Part 52 rule is a three-step process that guarantees public participation at each step. The steps are: early site permit approval; standard design certifications; and, combined construction/operating licenses for nuclear power reactors. Licensing reform increases an organization`s ability to respond to future baseload electricity generation needs with less financial risk for ratepayers and the organization. Costly delays can be avoided because design, safety and siting issues will be resolved before a company starts to build a plant. Specifically, early site permit approval allows for site suitability and acceptability issues to be addressed prior to an organization`s commitment to build a plant. Responsibility for site-specific activities, including communications and public participation, rests with those organizations selected to try out early site approval. This plan has been prepared to assist those companies (referred to as sponsoring organizations) in planning their communications and public involvement programs. It provides research findings, information and recommendations to be used by organizations as a resource and starting point in developing their own plans.

  3. [Bioequivalence and bioavailability after single administration of effervescent ranitidine tablets].

    Science.gov (United States)

    Hartmann, B; Schmieder, G; Tetzloff, W; Töberich, H

    1992-08-01

    An open two-way cross-over study in 12 healthy male volunteers was performed in order to determine the relative bioavailability of a 150 mg ranitidine (Zantic, CAS 66357-35-5) effervescent tablet sweetened with saccharine in comparison to the 150 mg standard ranitidine dispersible tablet (Trinkette). On two occasions separated by a wash-out period of 1 week volunteers received a single oral dose of both formulations. On each administration day blood samples were collected at predetermined time points in order to investigate the pharmacokinetic parameters. Single oral doses of ranitidine were very well tolerated by healthy male volunteers. The non-parametric 95% confidence intervals for AUC and Cmax were 87 to 116% and 84 to 107%, respectively. The relative bioavailability of the ranitidine effervescent tablet was 99% compared to the dispersible tablet. The mean of the Cmax ratio was 95%. The ranitidine effervescent tablet could thus be claimed to be bioequivalent to the dispersible tablet.

  4. Scientific considerations concerning the EMA change in the definition of "dose" of the BCS-based biowaiver guideline and implications for bioequivalence.

    Science.gov (United States)

    Daousani, Chrysa; Macheras, Panos

    2015-01-30

    This work discusses the scientific aspects of the definition of dose as the 'highest single oral IR dose' recommended for administration in the SmPC (summary of product characteristics) in the current European Medicines Agency (EMA) 2010 Guideline, for the purpose of biopharmaceutics classification system (BCS)-based biowaiver decision making. Analysis of theoretical and experimental data dealing with drug dissolution and biopharmaceutic drug classification reveals that the drug dose is an important parameter for both drug dissolution and biopharmaceutic classification. The relevant implications for the dose considerations in bioequivalence studies are also discussed briefly. It is suggested that the concept of "the highest single dose oral IR dose recommended for administration in the SmPC" of the EMA 2010 Guideline be abolished. It is advisable, each dose strength be considered separately i.e., whether or not it meets the solubility-dissolution regulatory criteria.

  5. Comparative bioequivalence study of leflunomide tablets in Indian healthy volunteers.

    Science.gov (United States)

    Agarwal, S; Das, A; Ghosh, D; Sarkar, A K; Chattaraj, T K; Pal, T K

    2012-03-01

    The pharmacokinetics of teriflunomide [CAS No. 163451-81-8], the metabolite of leflunomide [CAS No. 75706-12-6] has been evaluated in adult human volunteers after oral administration of tablet formulation. However, no published data is available regarding the bioavailability of this in the Indian population. In light of the above, a study was designed to carry out a bioequivalence study of 2 preparations of leflunomide 20 mg in healthy Indian male volunteers.24 healthy male volunteers (age, 25±4.1 years; weight, 57.58±7.01 kg) were enrolled in this study. Each subject received a test and reference formulation in a single dose, fasting 2 period, 2 way crossover study with a wash out period of 4 weeks. Analysis of teriflunomide from plasma samples was done by a simple and sensitive HPLC method using UV detection developed in our laboratory. An analysis of variance was performed on the pharmacokinetic parameters Cmax, AUC0-t, AUC0-∞ using GLM procedures in which sources of variation were subject, formulation, and period.The results indicated that there are no statistically significant differences between the 2 products in either the mean concentration-time profiles or in the obtained pharmacokinetic parameters. 90% confidence limits for the log transformed data of Cmax, AUC0-t, AUC0-∞. were within the acceptable range of 0.80-1.25.The results indicate that the 2 products are bioequivalent in terms of rate and extent of drug absorption. Both the preparations were well tolerated with no adverse reactions throughout the study.

  6. [Generics: similarities, bioequivalence but no conformity].

    Science.gov (United States)

    Even-Adin, D; De Muylder, J A; Sternon, J

    2002-01-01

    The using of generic forms (GF) is presented as a potential source of budgetary "saving of money" in the field of pharmaceutical expenses. Not frequently prescribed in Belgium, they win a new interest thanks to the recent making use of the "reference repayment". Sale's authorization of GF is controlled by european rules, but some questions about their identity to original medications remain. Do similarities based only upon qualitative and quantitative composition in active molecules, pharmaceutical forms and biodisponibility give us all requested guaranties? Several cases of discordances can appear; the major elements of non conformity are the nature of excipients, notice's contents and the value of biodisponibility studies. However, in term of economy, in the drug market, development of GF appears to constitute an unavoidable phenomenon.

  7. Physical activity of female children and adolescents based on step counts: meeting the recommendation and relation to BMI

    Directory of Open Access Journals (Sweden)

    Kantanista Adam

    2015-06-01

    Full Text Available Study aim: the aim of this study was to assess the step counts of children and adolescents with different BMIs and to present the results in relation to the step count recommendation.

  8. A Multi-centric Bioequivalence Trial in Ph+ Chronic Myeloid Leukemia Patients to Assess Bioequivalence and Safety Evaluation of Generic Imatinib Mesylate 400 mg Tablets

    Science.gov (United States)

    Arora, Rachna; Sharma, Manju; Monif, Tausif; Iyer, Sunil

    2016-01-01

    Purpose This study was designed to characterize the pharmacokinetic profile and to assess bioequivalence of the sponsor’s test formulation (imatinib mesylate 400 mg tablets) with an innovator product (Gleevec 400 mg tablets, Novartis Pharmaceuticals) under fed conditions, in adult patients of Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) stabilized on imatinib mesylate 400 mg. In addition, the aim of this study was to monitor the safety profile of investigational medicinal products (IMPs). Materials and Methods A multicenter, randomized, open label, two-period, crossover, single dose bioequivalence study was designed for conduct under fed conditions in 42 adult Ph+ CML patients already stabilized on imatinib 400 mg tablets. Pharmacokinetic parameters Tmax, Cmax, and AUC0-24 were calculated using a non-compartmental model on validated WinNonlin software. Validated SAS software was used for statistical evaluation of data. The safety profile of investigational products was monitored during the course of study by applying a clinical process for recording observed untoward effects postadministration of investigational products. Results The 90% confidence intervals for the test/reference mean ratios of the ln-transformed PK variables Cmax (99.0%) and AUC0-24 (99.2%) were within an acceptable range of 80%-125%, as per bioequivalence assumptions. Both formulations were well tolerated after oral administration of IMPs. Conclusion The test product was found to be bioequivalent and safe, and thus can be used interchangeably in clinical practice. PMID:26875198

  9. Trend study electricity 2022. Meta studies analysis and activity recommendations. dena report; Trendstudie Strom 2022. Metastudienanalyse und Handlungsempfehlungen. dena-Berichtsteil

    Energy Technology Data Exchange (ETDEWEB)

    Peters, Sebastian; Teichmann, Mario; Voelker, Jakob; Weber, Andreas

    2013-03-07

    The dena report concerning the trend study electricity 2022 covers the following issues: (I) aim of the project - methodology; (II) qualitative analysis of studies on the development of the energy system in Germany (meta analysis); (III) comparison of results and activity recommendations: energy demand and energy efficiency, renewable energies, conventional energies, grids, energy storage, electricity market design, European aspects; roadmap.

  10. Recommendations for participation in leisure-time physical activity and competitive sports in patients with arrhythmias and potentially arrhythmogenic conditions Part I: Supraventricular arrhythmias and pacemakers.

    NARCIS (Netherlands)

    Heidbuchel, H.; Panhuyzen-Goedkoop, N.M.; Corrado, D.; Hoffmann, E.; Biffi, A.; Delise, P.; Blomstrom-Lundqvist, C.; Hees, L. van; Ivarhoff, P.; Dorwarth, U.; Pelliccia, A.

    2006-01-01

    This document by the Study Group on Sports Cardiology of the European Society of Cardiology extends on previous recommendations for sports participation for competitive athletes by also incorporating guidelines for those who want to perform recreational physical activity. For different supraventricu

  11. Bioequivalence study of two oral formulations of irbesartan 300 mg in healthy volunteers.

    Science.gov (United States)

    Cánovas, M; Cabré, F; Polonio, F

    2014-01-01

    A bioequivalence study of 2 irbesartan (CAS 138402-11-6) film-coated tablet formulations was carried out in 40 healthy volunteers according to an open label, randomized, 2-period, 2-sequence, crossover, single dose and fasting conditions design. The test and reference formulations were administered in 2 treatment days, separated by a washout period of 7 days. Blood samples were drawn up to 96 h following drug administration. Plasma concentrations of irbesartan were obtained by a validated HPLC method using MS/MS detection. Log-transformed AUC0-t and Cmax values were tested for bioequivalence based on the ratios of the geometric LSmeans (test/reference). tmax was analysed nonparametrically. The 90% confidence intervals of the geometric LSmean values for the test/reference ratios for AUC0-t (98.06-109.48%, point estimator 103.61%) and Cmax (88.93-100.87%, point estimator 94.72%) were within the bioequivalence acceptance range of 80-125%. According to the European Guideline on the Investigation of Bioequivalence it may be therefore concluded that test formulation of irbesartan 300 mg film-coated tablet is bioequivalent to the reference formulation. Overall, it was judged that the study was conducted with a good tolerance of the subjects to both study drugs.

  12. Bioequivalence Study of Two Orodispersible Rizatriptan Formulations of 10 mg in Healthy Volunteers.

    Science.gov (United States)

    Cánovas, Mercè; Polonio, Francisco; Cabré, Francesc

    2016-06-13

    The aim of the study was to assess the bioequivalence and tolerability of two different oral formulations of rizatriptan. A bioequivalence study was carried out in 40 healthy volunteers according to an open label, randomized, two-period, two-sequence, crossover, single dose, and fasting conditions design. The test and reference formulations were administered in two treatment days, separated by a washout period of seven days. Plasma concentrations of rizatriptan were obtained by the LC/MS/MS (Liquid chromatography tandem-mass spectrometry) method. Log-transformed AUC0-t (area under the plasma concentration-time curve from zero to the last measurable concentration) and Cmax (maximum plasma concentration) values were tested for bioequivalence based on the ratios of the geometric means (test/reference). The tmax (time to reach maximum plasma concentration) was analysed nonparametrically. The 90% confidence intervals of the geometric mean values for the test/reference ratios for AUC0-t and Cmax were within the bioequivalence acceptance range of 80%-125%. According to the European Guideline, it may therefore be concluded that the test formulation of rizatriptan 10 mg orodispersible tablet is bioequivalent to the reference formulation (Maxalt(®) Max 10 mg oral lyophilisate). The safety profile of both formulations was consistent with the summary of the product characteristics.

  13. Bioequivalence Study of Two Orodispersible Rizatriptan Formulations of 10 mg in Healthy Volunteers

    Science.gov (United States)

    Cánovas, Mercè; Polonio, Francisco; Cabré, Francesc

    2016-01-01

    The aim of the study was to assess the bioequivalence and tolerability of two different oral formulations of rizatriptan. A bioequivalence study was carried out in 40 healthy volunteers according to an open label, randomized, two-period, two-sequence, crossover, single dose, and fasting conditions design. The test and reference formulations were administered in two treatment days, separated by a washout period of seven days. Plasma concentrations of rizatriptan were obtained by the LC/MS/MS (Liquid chromatography tandem-mass spectrometry) method. Log-transformed AUC0-t (area under the plasma concentration-time curve from zero to the last measurable concentration) and Cmax (maximum plasma concentration) values were tested for bioequivalence based on the ratios of the geometric means (test/reference). The tmax (time to reach maximum plasma concentration) was analysed nonparametrically. The 90% confidence intervals of the geometric mean values for the test/reference ratios for AUC0-t and Cmax were within the bioequivalence acceptance range of 80%–125%. According to the European Guideline, it may therefore be concluded that the test formulation of rizatriptan 10 mg orodispersible tablet is bioequivalent to the reference formulation (Maxalt® Max 10 mg oral lyophilisate). The safety profile of both formulations was consistent with the summary of the product characteristics.

  14. [Dissolution testing combined with computer simulation technology to evaluate the bioequivalence of domestic amoxicillin capsule].

    Science.gov (United States)

    Pan, Rui-Xue; Gao, Yuan; Chen, Wan-Li; Li, Yu-Lan; Hu, Chang-Qin

    2014-08-01

    Re-evaluation of bioequivalence of generic drugs is one of the key research focus currently. As a means to ensure consistency of the therapeutic effectiveness of drug products, clinical bioequivalence has been widely accepted as a gold standard test. In vitro dissolution testing based on the theory of the BCS is the best alternative to in vivo bioequivalence study. In this article, the conventional dissolution method and flow-through cell method were used to investigate the dissolution profiles of domestic amoxicillin capsules in different dissolution media, and the absorption behavior of the drugs with different release rates (t85% = 15-180 min) in the gastrointestinal tract was predicted by Gastro Plus. The flow-through cell method was thought better to reflect the release characteristics in vivo, and amoxicillin capsules with regard to the release rates up to 45 min (t85% = 45 min) were having a satisfied bioequivalence with the oral solution according to the C(max) and AUC. Although two different dissolution profiles of domestic amoxicillin capsules were found by flow-through cell methods, prediction results revealed that domestic capsules were probably bioequivalent to each other.

  15. Update on the safety and bioequivalence of biosimilars – focus on enoxaparin

    Directory of Open Access Journals (Sweden)

    Jeske W

    2013-06-01

    Full Text Available Walter Jeske,1 Jeanine M Walenga,1 Debra Hoppensteadt,2 Jawed Fareed2 1Cardiovascular Institute; 2Department of Pathology, Loyola University Chicago, Maywood, IL, USA Abstract: Generic forms of chemically-derived drugs must exhibit chemical identity and be bioequivalent in healthy human subjects. The use of generic drugs results in a considerable savings of healthcare expenditures. Biologic drugs are produced in living systems or are derived from biologic material and extend beyond proteins to include antibodies, polysaccharides, polynucleotides, and live viral material. Such drugs pose a challenge to characterize as they tend to be larger in size than chemically-derived drugs, can exhibit a variety of post-translational modifications, and can have activities that are dependent on specific conformations. Biosimilars are not true generics, but rather, exhibit a high degree of similarity to the reference product and are considered to be biologically and clinically comparable to the innovator product. Therefore, the development process for biosimilars is more complex than for a true generic. Guidance is now available from the US Food and Drug Administration and from the European Medicines Agency for the development of biosimilar drugs. Biosimilar drugs are expected to have a major impact in the management of various diseases in coming years. Keywords: generic, biosimilar, low molecular weight heparin

  16. Presentation of the intrasubject coefficient of variation for sample size planning in bioequivalence studies.

    Science.gov (United States)

    Hauschke, D; Steinijans, W V; Diletti, E; Schall, R; Luus, H G; Elze, M; Blume, H

    1994-07-01

    Bioequivalence studies are generally performed as crossover studies and, therefore, information on the intrasubject coefficient of variation is needed for sample size planning. Unfortunately, this information is usually not presented in publications on bioequivalence studies, and only the pooled inter- and intrasubject coefficient of variation for either test or reference formulation is reported. Thus, the essential information for sample size planning of future studies is not made available to other researchers. In order to overcome such shortcomings, the presentation of results from bioequivalence studies should routinely include the intrasubject coefficient of variation. For the relevant coefficients of variation, theoretical background together with modes of calculation and presentation are given in this communication with particular emphasis on the multiplicative model.

  17. Bioequivalence of Sandoz methylphenidate osmotic-controlled release tablet with Concerta® (Janssen-Cilag).

    Science.gov (United States)

    Schapperer, Elisabeth; Daumann, Heike; Lamouche, Stéphane; Thyroff-Friesinger, Ursula; Viel, François; Weitschies, Werner

    2015-02-01

    The aim was to assess the bioequivalence of Sandoz methylphenidate osmotic-controlled release (OCR) tablets (Sandoz [Methylphenidate[ MPH OCR) with Concerta®, a methylphenidate formulation indicated for the treatment of attention deficit/hyperactivity disorder (ADHD). Four open-label, randomized, single-dose, two-way crossover bioequivalence studies were conducted in healthy subjects: three fasting studies with 54-, 36- and 18-mg doses of methylphenidate, and one fed study with the 54-mg dose. The d- and l-threo-methylphenidate plasma levels were quantified using liquid chromatographic methods with tandem mass spectrometry (LC MS/MS). Bioequivalence of the formulations was accepted if the 90% geometric confidence intervals of the ratio of least-squares means of Sandoz MPH OCR to Concerta® of ln-transformed area under the curve (AUC0-t ) and C max were within the acceptance range of 80-125%. All studies met the bioequivalence criteria, and 90% geometric confidence intervals for AUC0-t and C max were within the predefined range. All plasma concentration time curves for Sandoz MPH OCR under fasting conditions showed a biphasic profile comparable with Concerta®, confirmed by bioequivalence of the partial metrics AUC0-2h, AUC2-24 h, C max(0-2 h) and C max(2-24 h). Both products were well tolerated and no relevant differences in the safety profiles were observed. It was concluded that Sandoz MPH OCR is bioequivalent to Concerta® in terms of rate and extent of absorption when administered as a single dose of one extended-release tablet of 54, 36, or 18 mg under fasting conditions and at a dose of 54 mg under fed conditions.

  18. Sex-by-formulation interaction assessed through a bioequivalence study of efavirenz tablets.

    Science.gov (United States)

    Ibarra, Manuel; Magallanes, Laura; Lorier, Marianela; Vázquez, Marta; Fagiolino, Pietro

    2016-03-31

    Although sex-related differences in gastrointestinal physiology have been vastly reported, its impact on drug oral bioavailability and bioequivalence (product discrimination) is often ignored. On this work results from an average bioequivalence study between tablets containing 600mg of the antiretroviral efavirenz (EFV), carried out with 14 healthy subjects (8 female and 6 men) in a randomized 2-period, 2-treatment crossover design, are analyzed from a sex-based approach. Sequences were balanced within each sex group. Considering all subjects, no differences were observed on EFV absorbed amount, as shown by the estimated 90CI of the AUC96 Test/Reference bioequivalence ratio (T/R): 0.950-1.05. However, results were not conclusive due to the 90CI for CMAX T/R was 0.743-1.07. Over this parameter, a significant sex-by-formulation interaction was detected: 90CI CMAX T/R was 0.838-1.36 in women and 0.540-0.920 in men; with a 52% relative difference between point estimates. Formulation differences were therefore evidenced only by male subjects. In vitro dissolution and disintegration tests for both products were carried out in two aqueous media: A) SLS 0.25% and B) HCl/KCl pH1.2. T/R results for dissolution efficiency and tablet disintegration times of formulations in both A and B media were highly correlated with CMAX T/R bioequivalence results observed in women and men respectively, showing that a dissimilar gastrointestinal environment between sexes affected EFV oral absorption. This work shows how sex-by-formulation interaction can affect bioequivalence conclusions. Sex effect on product discrimination should be specially disclosed in bioequivalence studies, mainly for drugs aimed to be given to both sexes.

  19. HPLC-UV determination of metformin in human plasma for application in pharmacokinetics and bioequivalence studies.

    Science.gov (United States)

    Porta, Valentina; Schramm, Simone Grigoleto; Kano, Eunice Kazue; Koono, Eunice Emiko; Armando, Yara Popst; Fukuda, Kazuo; Serra, Cristina Helena Dos Reis

    2008-01-07

    In this study, a simple, rapid and sensitive HPLC method with UV detection is described for determination of metformin in plasma samples from bioequivalence assays. Sample preparation was accomplished through protein precipitation with acetonitrile and chromatographic separation was performed on a reversed-phase phenyl column at 40 degrees C. Mobile phase consisted of a mixture of phosphate buffer and acetonitrile at flow rate of 1.0 ml/min. Wavelength was set at 236 nm. The method was applied to a bioequivalence study of two drug products containing metformin, and allowed determination of metformin at low concentrations with a higher throughput than previously described methods.

  20. Evaluation of Bioequivalency and Toxicological Effects of Three Sources of Arachidonic Acid (ARA) in Domestic Piglets

    OpenAIRE

    2011-01-01

    Arachidonic acid (ARA) and docosahexaenoic acid (DHA) are routinely added to infant formula to support growth and development. We evaluated the bioequivalence and safety of three ARA-rich oils for potential use in infant formula using the neonatal pig model. The primary outcome for bioequivalence was brain accretion of ARA and DHA. Days 3 to 22 of age, domestic pigs fed one of three formulas, each containing ARA at ~0.64% and DHA at ~0.34% total fatty acids (FA). Control diet ARA was provided...

  1. Reference tables for the intrasubject coefficient of variation in bioequivalence studies.

    Science.gov (United States)

    Steinijans, V W; Sauter, R; Hauschke, D; Diletti, E; Schall, R; Luus, H G; Elze, M; Blume, H; Hoffmann, C; Franke, G

    1995-08-01

    Bioequivalence studies are usually performed as crossover studies and, therefore, information on the intrasubject coefficient of variation is needed for sample size planning. However, this information is usually not accessible in publications on bioequivalence studies, and only the pooled inter- and intrasubject coefficient of variation for either test or reference formulation is reported. It is the purpose of the present communication to provide reference values of the intrasubject coefficient of variation for various previously investigated drugs. The presentation includes pertinent pharmacokinetic characteristics for immediate- and extended-release formulations in single- and multiple-dose crossover studies.

  2. Sequential design approaches for bioequivalence studies with crossover designs.

    Science.gov (United States)

    Potvin, Diane; DiLiberti, Charles E; Hauck, Walter W; Parr, Alan F; Schuirmann, Donald J; Smith, Robert A

    2008-01-01

    The planning of bioequivalence (BE) studies, as for any clinical trial, requires a priori specification of an effect size for the determination of power and an assumption about the variance. The specified effect size may be overly optimistic, leading to an underpowered study. The assumed variance can be either too small or too large, leading, respectively, to studies that are underpowered or overly large. There has been much work in the clinical trials field on various types of sequential designs that include sample size reestimation after the trial is started, but these have seen only little use in BE studies. The purpose of this work was to validate at least one such method for crossover design BE studies. Specifically, we considered sample size reestimation for a two-stage trial based on the variance estimated from the first stage. We identified two methods based on Pocock's method for group sequential trials that met our requirement for at most negligible increase in type I error rate.

  3. Bioequivalence studies of drugs prescribed mainly for women.

    Science.gov (United States)

    McGilveray, Iain J

    2011-01-01

    The basic components of pharmacokinetics are absorption, distribution, metabolism, and excretion. During pregnancy there may be changes in one or many of these components. Early drug studies did not include a representative proportion of women, however, researchers as well as regulators agree that studies on the sex differences in the disposition of drugs are important, but at what stage in the clinical trial process? Except for drugs used only in women, such as those for estrogen-dependent breast cancer, caution prevails and the differences are usually studied at phase 3. Studies in pregnant women are much rarer but some do get done, e.g., with antivirals and antimalarials, where the positive risk-benefit of these agents is the likelihood that fetal transfer of these drugs might help protect the fetus. Women are being included in pharmacokinetic studies for new drug applications in accordance with the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), U.S. Food and Drug Administration (FDA), and Health Canada (HC) guidances. A new look at bioequivalence studies, to compare results in men and women, would help determine if interactions of formulation and gender are a problem.

  4. Assessment of Bioequivalence of Weak Base Formulations Under Various Dosing Conditions Using Physiologically Based Pharmacokinetic Simulations in Virtual Populations. Case Examples: Ketoconazole and Posaconazole.

    Science.gov (United States)

    Cristofoletti, Rodrigo; Patel, Nikunjkumar; Dressman, Jennifer B

    2017-02-01

    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.

  5. The Irish Working Group on Information Literacy (WGIL) - Part II: Report of Cross-Sector Activity 2006 - 2008 and Recommendations for Action

    OpenAIRE

    2009-01-01

    In 2006, the Library Association of Ireland (LAI) Working Group on Information Literacy (WGIL) was established with an agreed role to ‘recommend strategies for the development of information skills education at both theoretical and practical level in the library and information services sector in Ireland’. A two-year review of current information literacy activity in the Republic of Ireland by WGIL culminated in the completion of a cross-sectoral report which provides a snapshot of informatio...

  6. Pilot and Repeat Trials as Development Tools Associated with Demonstration of Bioequivalence.

    Science.gov (United States)

    Fuglsang, Anders

    2015-05-01

    The purpose of this work is to use simulated trials to study how pilot trials can be implemented in relation to bioequivalence testing, and how the use of the information obtained at the pilot stage can influence the overall chance of showing bioequivalence (power) or the chance of approving a truly bioinequivalent product (type I error). The work also covers the use of repeat pivotal trials since the difference between a pilot trial followed by a pivotal trial and a pivotal trial followed by a repeat trial is mainly a question of whether a conclusion of bioequivalence can be allowed after the first trial. Repeating a pivotal trial after a failed trial involves dual or serial testing of the bioequivalence null hypothesis, and the paper illustrates how this may inflate the type I error up to almost 10%. Hence, it is questioned if such practice is in the interest of patients. Tables for power, type I error, and sample sizes are provided for a total of six different decision trees which allow the developer to use either the observed geometric mean ratio (GMR) from the first or trial or to assume that the GMR is 0.95. In cases when the true GMR can be controlled so as not to deviate more from unity than 0.95, sequential design methods ad modum Potvin may be superior to pilot trials. The tables provide a quantitative basis for choosing between sequential designs and pivotal trials preceded by pilot trials.

  7. Pharmacokinetics-Based Approaches for Bioequivalence Evaluation of Topical Dermatological Drug Products.

    Science.gov (United States)

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

    2015-11-01

    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.

  8. Applying multilevel models in evaluation of bioequivalence(Ⅰ)%多水平模型在生物等效性评价中的应用(Ⅰ)

    Institute of Scientific and Technical Information of China (English)

    刘巧兰; 沈卓之; 陈峰; 李晓松; 杨珉

    2009-01-01

    探讨多水平模型在生物等效性评价中的应用价值.以2×4试验设计的抗高血压药生物等效性评价为研究实例,研究多水平模型对效应指标值的变异即方差的分解方式,并与FDA推荐的矩法所获得的方差分量进行比较.对比传统FDA推荐的生物等效性评价标准,研究利用多水平模型直接进行平均等效性、群体等效性和个体等效性评价的可行性.对于2×4试验设计的单变量两水平模型获得ln(AUC)指标的方差分量如试验药T的总方差σ_(TT)~2、个体间方差σ_(BT)~2和个体内方差σ_(WT)~2以及参比药R的总方差σ_(TR)~2、个体间方差σ_(BR)~2和个体内方差σ_(WR)~2,与FDA推荐的矩法所获得的结果非常接近.实际应用中,根据FDA提出的生物等效性评价的标准和程序进行评价,直接用多水平模型的估计值进行平均、群体和个体等效性评价,两者结果一致.多水平模型适合于交叉设计的生物等效性评价,相对于FDA推荐的方法,多水平模型对于复杂的有影响因素的交叉试验设计更容易估计方差分量,进而可以评价平均、群体和个体等效性,实际应用上更具有灵活性,为生物等效性评价提供了新的思路和方法.%This study aims to explore the application value of multilevel models for bioequivalence evaluation.Using a real example of 2×4 cross-over experimental design in evaluating bioequivalence of antihypertensive drug,this paper explores complex variance components corresponding to criteria statistics in existing methods recommended by FDA but obtaines in multilevel models analysis.Results are compared with those from FDA standard Method of Moments,specifically on the feasibility and applicability of multilevel models in directly assessing the bioequivalence(ABE),the population bioequivalence(PBE)and the individual bioequivalence (IBE).When measuring ln(AUC),results from all variance components of the test and reference groups such

  9. 78 FR 19491 - Walking as a Way for Americans To Get the Recommended Amount of Physical Activity for Health

    Science.gov (United States)

    2013-04-01

    ... attention of Joan Dorn, Ph.D., Chief, Physical Activity and Health Branch, Division of Nutrition, Physical... INFORMATION CONTACT: Joan Dorn, Ph.D., Chief, Physical Activity and Health Branch, Division of Nutrition... adults' participation in physical activity: Review and update, 1996-2001. Med Sci Sports Exerc. 2002...

  10. Importance of characteristics and modalities of physical activity and exercise in defining the benefits to cardiovascular health within the general population: recommendations from the EACPR (Part I).

    Science.gov (United States)

    Vanhees, L; De Sutter, J; GeladaS, N; Doyle, F; Prescott, E; Cornelissen, V; Kouidi, E; Dugmore, D; Vanuzzo, D; Börjesson, M; Doherty, P

    2012-08-01

    Over the last decades, more and more evidence is accumulated that physical activity (PA) and exercise interventions are essential components in primary and secondary prevention for cardiovascular disease. However, it is less clear whether and which type of PA and exercise intervention (aerobic exercise, dynamic resistive exercise, or both) or characteristic of exercise (frequency, intensity, time or duration, and volume) would yield more benefit in achieving cardiovascular health. The present paper, as the first of a series of three, will make specific recommendations on the importance of these characteristics for cardiovascular health in the population at large. The guidance offered in this series of papers is aimed at medical doctors, health practitioners, kinesiologists, physiotherapists and exercise physiologists, politicians, public health policy makers, and the individual member of the public. Based on previous and the current literature, recommendations from the European Association on Cardiovascular Prevention and Rehabilitation are formulated regarding type, volume, and intensity of PA and exercise.

  11. Recommendations for simulations to predict environmental concentrations of active substances of plant protection products and their metabolites in groundwater (PECgw) in the national assessment for authorisation in Germany

    Energy Technology Data Exchange (ETDEWEB)

    Holdt, Gabriele; Gallien, Peter; Nehls, Angelika [Umweltbundesamt Dessau (DE)] (and others)

    2011-09-15

    In the national assessment for authorisation in Germany the leaching behaviour of a plant protection product is determined in a stepwise procedure in accordance with FOCUS groundwater report (2009). The recommendations given in this paper here are related to tier 1 and tier 2, only. A further publication is planned for the tier 3 and tier 4 assessments in accordance with the principles provided by FOCUS. The tier 1 leaching assessment in the EU evaluation process is based on the nine FOCUS (2009) standard groundwater scenarios. In the member state evaluation for Germany, a sub-set of the standard scenarios with climatic and soil conditions found to be relevant for Ger-many are taken into account (Hamburg and Kremsmuenster). The soils of the two scenarios cover the pH-range of agricultural soils and allow the pH-dependent behaviour of compounds to be addressed. For the parameterisation of the degradation behaviour of an active substance and its metabolites in soil the recommendations of FOCUS should be followed. Normalised degradation rates may be taken from either laboratory or from field dissipation studies. For the parameterisation of the sorption behaviour of an active substance and its metabolites in soil the recommendations of FOCUS should be considered. With respect to the correlation of degradation and/or sorption behaviour to soil properties (pH, OC) further detailed recommendations are provided to facilitate the selection of conservative sorption parameters for leaching assessment. Proposals and detailed schemes for the handling of the DT50 and Kfoc values (including their variability) are given. Further recommendations are given in this paper on how to use other modelling parameters e.g. crop rotation, plant uptake factor, formation of metabolites, correlations / multi-correlations of substance parameters to soil properties, and application of statistical methods. Tier 2 of the leaching assessment consists of more refined modelling approaches. This

  12. The new European Medicines Agency guideline on the investigation of bioequivalence.

    Science.gov (United States)

    Morais, José Augusto Guimarães; Lobato, Maria do Rosário

    2010-03-01

    In this MiniReview, the main modifications made during the revision of the current Note for Guidance on the Investigation of Bioavailability and Bioequivalence are reviewed and justified. Several new features have been added to this guideline, as well as changes aimed at improving the clarity of the guidance provided. The first issue to be addressed was to limit the scope of the guideline to bioequivalence studies for immediate release dosage forms with systemic action. Therefore, the guideline refers to bioequivalence alone. Moreover, the new definition of Generic Medicinal Product has been incorporated. Clearer guidance covering more specific cases is now given on sections such as: fed/fasting conditions, use of metabolite data, enantiomers and strength to be used in the bioequivalence study. Steady-state design is now restricted and other designs, such as parallel group design, replicate design and two-stage design, are now incorporated in a more explicit form. New practical guidance on Highly Variable Drug Products and Narrow Therapeutic Index Drugs has been incorporated. The possibility for a biowaiver based on the Biopharmaceutics Classification System is now more explicit for Class I drugs and can be extended to Class III drugs under restricted conditions. We are aware that the initial goal of providing a very specific and clear guidance on these issues has not been entirely achieved, mainly because it is almost impossible to cover all individual cases and predict every possible situation that may arise. Demonstration of bioequivalence will still require in many instances a case by case approach.

  13. Study of the trial subjects’ protection aspects in Phase I clinical trials and bioequivalence studies

    Directory of Open Access Journals (Sweden)

    K. O. Zupanets

    2016-03-01

    Full Text Available Protection of rights, health and well-being of persons who are taking the drug during the trial (trial subjects is one of the basic principles of clinical trials (CT management. Aim. In order to study key aspects of volunteer protection, determine factors that influence these indicators and estimate the importance of ensuring their proper implementation on the clinical site (CS three survey of 135 trial subjects were carried out to evaluate the importance of assessing the impact of factors such as the procedure of signing the informed consent (IC at the CS and testing procedures for HIV / AIDS, hepatitis and others. Assessment of the quality of life of trial subjects as indirect indicator of the quality of clinical trials that ensures the proper protection of their life was the subject of the third survey. Methods and results. The general model of the relationship between the key aspects of the trial subjects protection and the factors which are providing them during the clinical trials of drugs management was substantiated, which included the main aspects of the trial subjects’ protection, protective factors and basic CT management procedures, the impact of the above factors on the possibility of providing protection aspects depends on their implementation quality. It was found that trial subjects’ protection improvement can be achieved during the IC signing process. It is necessary to ensure a higher level of volunteers understanding of the terms that could be used in the IC form. Regarding the procedure of compulsory testing for HIV/AIDS in the course of screening, we can conclude that the majority of the trial subjects believe that this procedure is an additional factor in their health protection and do not consider it as an excessive psychological pressure on them. Conclusion. Assessing the quality of life during the bioequivalence study at the CS makes possible to reach a conclusion on general well-being and satisfaction with those

  14. Presentation of coefficient of variation for bioequivalence sample-size calculation
.

    Science.gov (United States)

    Lee, Yi Lin; Mak, Wen Yao; Looi, Irene; Wong, Jia Woei; Yuen, Kah Hay

    2017-03-03

    The current study aimed to further contribute information on intrasubject coefficient of variation (CV) from 43 bioequivalence studies conducted by our center. Consistent with Yuen et al. (2001), current work also attempted to evaluate the effect of different parameters (AUC0-t, AUC0-∞, and Cmax) used in the estimation of the study power. Furthermore, we have estimated the number of subjects required for each study by looking at the values of intrasubject CV of AUC0-∞ and have also taken into consideration the minimum sample-size requirement set by the US FDA. A total of 37 immediate-release and 6 extended-release formulations from 28 different active pharmaceutical ingredients (APIs) were evaluated. Out of the total number of studies conducted, 10 studies did not achieve satisfactory statistical power on two or more parameters; 4 studies consistently scored poorly across all three parameters. In general, intrasubject CV values calculated from Cmax were more variable compared to either AUC0-t and AUC0-∞. 20 out of 43 studies did not achieve more than 80% power when the value was calculated from Cmax value, compared to only 11 (AUC0-∞) and 8 (AUC0-t) studies. This finding is consistent with Steinijans et al. (1995) [2] and Yuen et al. (2001) [3]. In conclusion, the CV values obtained from AUC0-t and AUC0-∞ were similar, while those derived from Cmax were consistently more variable. Hence, CV derived from AUC instead of Cmax should be used in sample-size calculation to achieve a sufficient, yet practical, test power.
.

  15. Predictors of Meeting Physical Activity and Fruit and Vegetable Recommendations in 9-11-Year-Old Children

    Science.gov (United States)

    Beck, Jimikaye; De Witt, Peter; McNally, Janise; Siegfried, Scott; Hill, James O; Stroebele-Benschop, Nanette

    2015-01-01

    Objective: Childhood obesity represents a significant public health problem. This study examined physical activity and nutrition behaviours and attitudes of 9-11-year-olds, and factors influencing these behaviours. Design: Study participants recorded pedometer steps for 7 days and completed physical activity enjoyment, food attitudes and food…

  16. Demonstrating Bioequivalence of Locally Acting Orally Inhaled Drug Products (OIPs): Workshop Summary Report.

    Science.gov (United States)

    Adams, Wallace P; Ahrens, Richard C; Chen, Mei-Ling; Christopher, David; Chowdhury, Badrul A; Conner, Dale P; Dalby, Richard; Fitzgerald, Kevin; Hendeles, Leslie; Hickey, Anthony J; Hochhaus, Günther; Laube, Beth L; Lucas, Paul; Lee, Sau L; Lyapustina, Svetlana; Li, Bing; O'Connor, Dennis; Parikh, Neil; Parkins, David A; Peri, Prasad; Pitcairn, Gary R; Riebe, Michael; Roy, Partha; Shah, Tushar; Singh, Gur Jai Pal; Sharp, Sandra Suarez; Suman, Julie D; Weda, Marjolein; Woodcock, Janet; Yu, Lawrence

    2010-02-01

    This March 2009 Workshop Summary Report was sponsored by Product Quality Research Institute (PQRI) based on a proposal by the Inhalation and Nasal Technology Focus Group (INTFG) of the American Association of Pharmaceutical Scientists (AAPS). Participants from the pharmaceutical industry, academia and regulatory bodies from the United States, Europe, India, and Brazil attended the workshop with the objective of presenting, reviewing, and discussing recommendations for demonstrating bioequivalence (BE) that may be considered in the development of orally inhaled drug products and regulatory guidances for new drug applications (NDAs), abbreviated NDAs (ANDAs), and postapproval changes. The workshop addressed areas related to in vitro approaches to demonstrating BE, biomarker strategies, imaging techniques, in vivo approaches to establishing local delivery equivalence and device design similarity. The workshop presented material that provided a baseline for the current understanding of orally inhaled drug products (OIPs) and identified gaps in knowledge and consensus that, if answered, might allow the design of a robust, streamlined method for the BE assessment of locally acting inhalation drugs. These included the following: (1) cascade impactor (CI) studies are not a good 2 predictor of the pulmonary dose; more detailed studies on in vitro/in vivo correlations (e.g., suitability of CI studies for assessing differences in the regional deposition) are needed; (2) there is a lack of consensus on the appropriate statistical methods for assessing in vitro results; (3) fully validated and standardized imaging methods, while capable of providing information on pulmonary dose and regional deposition, might not be applicable to the BE of inhaled products mainly due to the problems of having access to radiolabeled innovator product; (4) if alternatives to current methods for establishing local delivery BE of OIPs cannot be established, biomarkers (pharmacodynamic or clinical

  17. Collective knowledge: Using a Consensus Conference approach to develop recommendations for physical activity and nutrition programs for persons with Type 2 diabetes

    Directory of Open Access Journals (Sweden)

    Tanya eBerry

    2012-12-01

    Full Text Available The purpose of this consensus conference was to have a lay panel of persons with type 2 diabetes (T2D work in collaboration with an expert panel of diabetes professionals to develop strategies designed to improve dietary and physical activity adherence in persons with T2D. Lay panel participants were 15 people living with T2D. The seven experts had expertise in exercise management, cardiovascular risk factors, community-based lifestyle interventions, healthy weight strategies, the glycemic index, exercise motivation, and social, environmental and cultural interactions. All meetings were facilitated by a professional, neutral facilitator. During the conference each expert gave a 15-minute presentation answering questions developed by the lay panel and all panel members worked to generate suggestions for programs and ways in which the needs of persons with T2D may be better met. A subgroup of the lay panel used the suggestions created from the conference to generate a final list of recommendations. Recommendations were categorized into 1 diagnosis/awareness (e.g., increasing awareness about T2D in the general public, need for lifelong self-monitoring post-diagnosis; 2 education for the person with diabetes (e.g., periodic refresher courses, professionals (e.g., regular interactions between researchers and persons with T2D so researchers better understand the needs of the affected population, and the community (e.g., support for families and employers; and 3 ongoing support (e.g., peer support groups. The recommendations from the conference can be used by researchers to design and evaluate physical activity and nutrition programs. The results can also be of use to policy makers and health promoters interested in increasing adherence to physical activity and nutrition guidelines among persons with T2D.

  18. Collective knowledge: using a consensus conference approach to develop recommendations for physical activity and nutrition programs for persons with type 2 diabetes

    Science.gov (United States)

    Berry, Tanya R.; Chan, Catherine B.; Bell, Rhonda C.; Walker, Jessica

    2012-01-01

    The purpose of this consensus conference was to have a lay panel of persons with type 2 diabetes (T2D) work in collaboration with an expert panel of diabetes professionals to develop strategies designed to improve dietary and physical activity adherence in persons with T2D. Lay panel participants were 15 people living with T2D. The seven experts had expertise in exercise management, cardiovascular risk factors, community-based lifestyle interventions, healthy weight strategies, the glycemic index, exercise motivation, and social, environmental and cultural interactions. All meetings were facilitated by a professional, neutral facilitator. During the conference each expert gave a 15-min presentation answering questions developed by the lay panel and all panel members worked to generate suggestions for programs and ways in which the needs of persons with T2D may be better met. A subgroup of the lay panel used the suggestions created from the conference to generate a final list of recommendations. Recommendations were categorized into (1) diagnosis/awareness (e.g., increasing awareness about T2D in the general public, need for lifelong self-monitoring post-diagnosis); (2) education for the person with diabetes (e.g., periodic “refresher” courses), professionals (e.g., regular interactions between researchers and persons with T2D so researchers better understand the needs of the affected population), and the community (e.g., support for families and employers); and (3) ongoing support (e.g., peer support groups). The recommendations from the conference can be used by researchers to design and evaluate physical activity and nutrition programs. The results can also be of use to policy makers and health promoters interested in increasing adherence to physical activity and nutrition guidelines among persons with T2D. PMID:23248617

  19. Pharmacological screening of plants recommended by folk medicine as anti-snake venom: I. Analgesic and anti-inflammatory activities

    Directory of Open Access Journals (Sweden)

    Bettina M. Ruppelt

    1991-01-01

    Full Text Available We have observed that several plants used popularly as anti-snake venom show anti-inflammatory activity. From the list prepared by Rizzini, Mors and Pereira some species have been selected and tested for analgesic activity (number of contortions and anti-inflammatory activity (Evans blue dye diffusion - 1% solution according to Whittle's technique (intraperitoneal administration of 0.1 N-acetic acid 0.1 ml/10 g in mice. Previous oral administration of a 10% infusion (dry plant or 20% (fresh plant corresponding to 1 or 2 g/Kg of Apuleia leiocarpa, Casearia sylvestris, Brunfelsia uniflora, Chiococca brachiata, Cynara scolymus, Dorstenia brasiliensis, Elephantopus scaber, Marsypianthes chamaedrys, Mikania glomerata and Trianosperma tayuya demonstrated analgesic and/or anti-inflammatory activities of varied intensity

  20. Trends in Adults Receiving a Recommendation for Exercise or Other Physical Activity from a Physician or Other Health ...

    Science.gov (United States)

    ... advice to exercise vary with having selected chronic health conditions? Between 2000 and 2010, receipt of advice from a physician to do exercise or physical activity increased for adults with hypertension, cardiovascular disease, cancer, and diabetes ( Figure 4 ). Adults with ...

  1. Special report: workshop on 4D-treatment planning in actively scanned particle therapy--recommendations, technical challenges, and future research directions.

    Science.gov (United States)

    Knopf, Antje; Bert, Christoph; Heath, Emily; Nill, Simeon; Kraus, Kim; Richter, Daniel; Hug, Eugen; Pedroni, Eros; Safai, Sairos; Albertini, Francesca; Zenklusen, Silvan; Boye, Dirk; Söhn, Matthias; Soukup, Martin; Sobotta, Benjamin; Lomax, Antony

    2010-09-01

    This article reports on a 4D-treatment planning workshop (4DTPW), held on 7-8 December 2009 at the Paul Scherrer Institut (PSI) in Villigen, Switzerland. The participants were all members of institutions actively involved in particle therapy delivery and research. The purpose of the 4DTPW was to discuss current approaches, challenges, and future research directions in 4D-treatment planning in the context of actively scanned particle radiotherapy. Key aspects were addressed in plenary sessions, in which leaders of the field summarized the state-of-the-art. Each plenary session was followed by an extensive discussion. As a result, this article presents a summary of recommendations for the treatment of mobile targets (intrafractional changes) with actively scanned particles and a list of requirements to elaborate and apply these guidelines clinically.

  2. ICRS Recommendation Document

    DEFF Research Database (Denmark)

    Roos, Ewa M.; Engelhart, Luella; Ranstam, Jonas

    2011-01-01

    Abstract Objective: The purpose of this article is to describe and recommend patient-reported outcome instruments for use in patients with articular cartilage lesions undergoing cartilage repair interventions. Methods: Nonsystematic literature search identifying measures addressing pain and funct......Abstract Objective: The purpose of this article is to describe and recommend patient-reported outcome instruments for use in patients with articular cartilage lesions undergoing cartilage repair interventions. Methods: Nonsystematic literature search identifying measures addressing pain...... constructs at all levels according to the International Classification of Functioning. Conclusions: Because there is no obvious superiority of either instrument at this time, both outcome measures are recommended for use in cartilage repair. Rescaling of the Lysholm Scoring Scale has been suggested......, and confirmatory longitudinal studies are needed prior to recommending this scale for use in cartilage repair. Inclusion of a generic measure is feasible in cartilage repair studies and allows analysis of health-related quality of life and health economic outcomes. The Marx or Tegner Activity Rating Scales...

  3. TSH-Based Protocol, Tablet Instability, and Absorption Effects on L-T4 Bioequivalence

    Science.gov (United States)

    DiStefano, Joseph J.

    2009-01-01

    Background FDA Guidance for pharmacokinetic (PK) testing of levothyroxine (L-T4) for interbrand bioequivalence has evolved recently. Concerns remain about efficacy and safety of the current protocol, based on PK analysis following supraphysiological L-T4 dosing in euthyroid volunteers, and recent recalls due to intrabrand manufacturing problems also suggest need for further refinement. We examine these interrelated issues quantitatively, using simulated what-if scenarios testing efficacy of a TSH-based protocol and tablet stability and absorption, to enhance precision of L-T4 bioequivalence methods. Methods We use an updated simulation model of human thyroid hormone regulation quantified and validated from data that span a wide range of normal and abnormal thyroid system function. Bioequivalence: We explored a TSH-based protocol, using normal replacement dosing in simulated thyroidectomized patients, switching brands after 8 weeks of full replacement dosing. We simulated effects of tablet potency differences and intestinal absorption differences on predicted plasma TSH, T4, and triiodothyronine (T3) dynamics. Stability: We simulated effects of potency decay and lot-by-lot differences in realistic scenarios, using actual tablet potency data spanning 2 years, comparing the recently reduced 95–105% FDA-approved potency range with the original 90–110% range. Results A simulated decrease as small as 10–15% in L-T4 or its absorption generated TSH concentrations outside the bioequivalence target range (0.5–2.5 mU/L TSH), whereas T3 and T4 plasma levels were maintained normal. For a 25% reduction, steady-state TSH changed 300% (from 1.5 to 6 mU/L) compared with <25% for both T4 and T3 (both within their reference ranges). Stability: TSH, T4, and T3 remained within normal ranges for most potency decay scenarios, but tablets of the same dose strength and brand were not bioequivalent between lots and between fresh and near-expired tablets. Conclusions A

  4. Does a mere request to recommend have an impact on the customer’s word-of-mouth activity?

    DEFF Research Database (Denmark)

    Mattsson, Jan; Söderlund, Magnus

    encounters) to provide WOM would have a positive impact on WOM activity. We base this assumption on the question-behavior effect identified with regard to questions in questionnaires, on reciprocity theory, and on arguments related to customer benefits that may be evoked by a request for WOM. This purpose...... of this study, then, is to examine in empirical terms if a mere request to customers to engage in unrewarded WOM (i.e., a request made by firm representatives in service encounter contexts) would have an impact on the customer’s WOM activity. Our empirical data were collected with a questionnaire to customers...

  5. Acute genital ulcers in nonsexually active young girls: case series, review of the literature, and evaluation and management recommendations.

    Science.gov (United States)

    Rosman, Ilana S; Berk, David R; Bayliss, Susan J; White, Andrew J; Merritt, Diane F

    2012-01-01

    Acute genital ulcers rarely occur in nonsexually active young girls. When present, they can cause significant physical and emotional distress for the patient and her parents, and prompt an evaluation for sexual abuse and sexually transmitted diseases. With this review, we aim to further characterize acute genital ulcers in nonsexually active young girls by reviewing the medical records of patients with this disorder and to offer an approach to the diagnosis, evaluation, and treatment of acute genital ulcers based on our understanding and knowledge of this condition. We retrospectively review our understanding and knowledge of acute genital ulcers in nonsexually active girls at a pediatric hospital. A review of the recent literature on acute genital ulcers and a multidisciplinary approach to the diagnosis, evaluation, and treatment of acute genital ulcers are also presented. Twelve patients presented with acute genital ulcers, 11 of which were hospitalized for evaluation and pain management. Extensive work-up failed to reveal a specific infectious or autoimmune etiology in all but one patient, who was diagnosed with acute mycoplasma pneumonia. Acute genital ulcers in nonsexually active young girls likely represent a form of idiopathic vulvar aphthosis. Evaluation of a first episode of acute genital ulcers with mild prodromal symptoms should be limited. Treatment consists primarily of supportive care and symptom relief.

  6. Chronic inflammatory demyelinating polyneuropathy disease activity status: recommendations for clinical research standards and use in clinical practice

    NARCIS (Netherlands)

    K.C. Gorson; I.N. van Schaik; I.S.J. Merkies; R.A. Lewis; R.J. Barohn; C.L. Koski; D.R. Cornblath; R.A.C. Hughes; A.F. Hahn; M. Baumgarten; J. Goldstein; J. Katz; M. Graves; G. Parry; P.A. van Doorn

    2010-01-01

    Defining long-term outcomes in chronic inflammatory demyelinating polyneuropathy (CIDP) has been complicated by varying definitions of treatment response and differing scales measuring impairment or disability. An expert panel was convened to devise a CIDP Disease Activity Status (CDAS) and to class

  7. Translation of moderate-to-vigorous physical activity recommendations into pedometer-based stepping targets in the Lower Mississippi Delta

    Science.gov (United States)

    The Lower Mississippi Delta (LMD) region of the United States is characterized by high levels of poverty, physical inactivity, obesity, and related chronic diseases. There is a pressing need to identify new strategies that will increase adherence to physical activity guidelines. Walking is an import...

  8. Dietary Recommendations for Healthy Children

    Science.gov (United States)

    ... Restaurant Deciphering the Menu Ordering Your Meal Eating Fast Food Dining Out Tips by Cuisine Physical Activity Fitness ... Food and Beverage Toolkit Dietary Recommendations for Healthy Children Updated:Jul 22,2016 The American Heart Association ...

  9. Extraterritorial reach of the FCPA: recommendations for U.S. medical device companies with activities in Europe.

    Science.gov (United States)

    Vollebregt, Erik

    2010-01-01

    Traditionally medical devices companies manage business compliance with anti-corruption and anti-fraud rules in a document-oriented way that does not always yield optimal results for the company. As a result, compliance issues are not optimally managed by the companies. Now that medical devices companies become ever more internationally active, they must also take into account the international dimensions of business compliance. This article intends to provide U.S. medical devices companies with activities in Europe with an insight in business compliance risks in the European Union (EU) and the risks related to U.S. statutes that may be applicable to a U.S. company's activities overseas. The article proposes a process-oriented and IT-supported way of structuring an international business compliance program, resulting in increased effectiveness of the program and increased competitiveness and risk management of the company as well as a high degree of acceptance of the procedures by the company's employees.

  10. The Universal Recommender

    CERN Document Server

    Kunegis, Jérôme; Umbrath, Winfried

    2009-01-01

    We describe the Universal Recommender, a recommender system for semantic datasets that generalizes domain-specific recommenders such a content-based, collaborative, social, bibliographic, lexicographic, hybrid and other recommenders. In contrast to existing recommender systems, the Universal Recommender applies to any dataset that allows a semantic representation. We describe the scalable three-stage architecture of the Universal Recommender and its application to Internet Protocol Television (IPTV). To achieve good recommendation accuracy, several novel machine learning and optimization problems are identified. We finally give a brief argument supporting the need for machine learning recommenders.

  11. Global Surveillance of In Vitro Activity of Micafungin against Candida: a Comparison with Caspofungin by CLSI-Recommended Methods

    Science.gov (United States)

    Pfaller, M. A.; Boyken, L.; Hollis, R. J.; Messer, S. A.; Tendolkar, S.; Diekema, D. J.

    2006-01-01

    Micafungin is an echinocandin antifungal agent that has recently been approved for the prevention of invasive fungal infection and the treatment of esophageal candidiasis. Prospective sentinel surveillance for the emergence of in vitro resistance to micafungin among invasive Candida sp. isolates is indicated. We determined the in vitro activity of micafungin against 2,656 invasive (bloodstream or sterile site) unique patient isolates of Candida spp. collected from 60 medical centers worldwide in 2004 and 2005. We performed antifungal susceptibility testing according to the Clinical and Laboratory Standards Institute (CLSI) M27-A2 method and used a 24-hour prominent inhibition endpoint for determination of the MIC. Caspofungin was tested in parallel against all isolates. Of 2,656 invasive Candida sp. isolates, species distribution was 55.6% Candida albicans, 14.4% Candida parapsilosis, 13.4% Candida glabrata, 10.1% Candida tropicalis, 2.4% Candida krusei, 1.7% Candida guilliermondii, 0.9% Candida lusitaniae, 0.6% Candida kefyr, and 0.9% other Candida species. Overall, micafungin was very active against Candida (MIC50/MIC at which 90% of the isolates tested are inhibited [MIC90], 0.015/1 μg/ml; 96% inhibited at a MIC of ≤1 μg/ml, 100% inhibited at a MIC of ≤2 μg/ml) and comparable to caspofungin (MIC50/MIC90, 0.03/0.25 μg/ml; 99% inhibited at a MIC of ≤2 μg/ml). Results by species, expressed as MIC50/MIC90 (micrograms per milliliter), were as follows: C. albicans, 0.015/0.03; C. glabrata, 0.015/0.015; C. tropicalis, 0.03/0.06; C. krusei, 0.06/0.12; C. kefyr, 0.06/0.06; C. parapsilosis, 1/2; C. guilliermondii, 0.5/1; C. lusitaniae, 0.12/0.25; other Candida spp., 0.25/1. Although the species distribution varied considerably among the different geographic regions, there was no difference in micafungin activity across the regions. Micafungin has excellent in vitro activity against invasive clinical isolates of Candida from centers worldwide. PMID:17021079

  12. Complete dataset for 2-treatment, 2-sequence, 2-period efavirenz bioequivalence study conducted with nightly dosing

    Directory of Open Access Journals (Sweden)

    Manuel Ibarra

    2016-06-01

    Full Text Available The efavirenz pharmacokinetic raw data presented in this article was obtained in an average bioequivalence study between a local brand and Stocrin (Merck Sharp & Dohme, purchased from Australia, batch H009175, expiration date November 2013. Dose was administered at night (9:00 p.m. two hours after food intake. Fourteen healthy subjects, 8 women and 6 men, completed the study. For each subject, 15 data points until 96 h post-administration are included. Subject demographic characteristics and sequences of administration are provided along with individual pharmacokinetic profiles of efavirenz obtained for both formulations after a single oral dose of 600 mg. This data provides information in support of the research article “Sex-by-formulation interaction assessed through a bioequivalence study of efavirenz tablets” [1].

  13. Complete dataset for 2-treatment, 2-sequence, 2-period efavirenz bioequivalence study conducted with nightly dosing.

    Science.gov (United States)

    Ibarra, Manuel; Magallanes, Laura; Lorier, Marianela; Vázquez, Marta; Fagiolino, Pietro

    2016-06-01

    The efavirenz pharmacokinetic raw data presented in this article was obtained in an average bioequivalence study between a local brand and Stocrin (Merck Sharp & Dohme, purchased from Australia, batch H009175, expiration date November 2013). Dose was administered at night (9:00 p.m.) two hours after food intake. Fourteen healthy subjects, 8 women and 6 men, completed the study. For each subject, 15 data points until 96 h post-administration are included. Subject demographic characteristics and sequences of administration are provided along with individual pharmacokinetic profiles of efavirenz obtained for both formulations after a single oral dose of 600 mg. This data provides information in support of the research article "Sex-by-formulation interaction assessed through a bioequivalence study of efavirenz tablets" [1].

  14. Comparison of bioequivalence study regulatory requirements for human and veterinary drugs.

    Science.gov (United States)

    Grabowski, Tomasz; Marczak, Monika; Jaroszewski, Jerzy Jan; Whitmire, Monica

    2012-11-01

    Guidelines published by the European Union Regulatory Authority, regarding the planning of bioequivalence studies, are the primary source of knowledge about the study design optimization. The goal of this paper is to compare the key elements (27 points) of bioequivalence study optimization based on a comparison of the two European Medicines Agency guidelines relating to medicines used for humans (HB) and to veterinary drugs (AB). In case of the latter, one can get the impression that the issues of species differences in relation to the physiology and anatomy have been completely ignored. Many details that the AB guideline omits are included in the new HB guideline and were present in many other guidelines from the last 20 years. Most have not been adopted by the AB document, even though they are the product of many years of work of many teams and specialists from various agencies in the regulatory affairs field.

  15. Reference datasets for 2-treatment, 2-sequence, 2-period bioequivalence studies.

    Science.gov (United States)

    Schütz, Helmut; Labes, Detlew; Fuglsang, Anders

    2014-11-01

    It is difficult to validate statistical software used to assess bioequivalence since very few datasets with known results are in the public domain, and the few that are published are of moderate size and balanced. The purpose of this paper is therefore to introduce reference datasets of varying complexity in terms of dataset size and characteristics (balance, range, outlier presence, residual error distribution) for 2-treatment, 2-period, 2-sequence bioequivalence studies and to report their point estimates and 90% confidence intervals which companies can use to validate their installations. The results for these datasets were calculated using the commercial packages EquivTest, Kinetica, SAS and WinNonlin, and the non-commercial package R. The results of three of these packages mostly agree, but imbalance between sequences seems to provoke questionable results with one package, which illustrates well the need for proper software validation.

  16. Implementation of a reference-scaled average bioequivalence approach for highly variable generic drug products of agomelatine in Chinese subjects

    Directory of Open Access Journals (Sweden)

    Fang Tang

    2016-01-01

    Full Text Available The aim of this study was to apply the reference-scaled average bioequivalence (RSABE approach to evaluate the bioequivalence of 2 formulations of agomelatine, and to investigate the pharmacokinetic properties of agomelatine in Chinese healthy male subjects. This was performed in a single-dose, randomized-sequence, open-label, four-way crossover study with a one-day washout period between doses. Healthy Chinese males were randomly assigned to receive 25 mg of either the test or reference formulation. The formulations were considered bioequivalent if 90% confidence intervals (CIs for the log-transformed ratios and ratio of geometric means (GMR of AUC and Cmax of agomelatine were within the predetermined bioequivalence range based on RSABE method. Results showed that both of the 90% CIs for the log-transformed ratios of AUC and Cmax of 7-desmethyl-agomelatine and 3-hydroxy-agomelatine were within the predetermined bioequivalence range. The 90% CIs for natural log-transformed ratios of Cmax, AUC0–t and AUC0–∞ of agomelatine (104.42–139.86, 101.33–123.83 and 97.90–117.94 were within the RSABE acceptance limits, and 3-hydroxy-agomelatine (105.55–123.03, 101.95–109.10 and 101.72–108.70 and 7-desmethyl-agomelatine (104.50–125.23, 102.36–111.50 and 101.62–110.64 were within the FDA bioequivalence definition intervals (0.80–1.25 for AUC and 0.75–1.33 for Cmax. The RSABE approach was successful in evaluating the bioequivalence of these two formulations.

  17. Multiple dose bioequivalence study with josamycin propionate, a drug with highly variable kinetics, in healthy volunteers.

    Science.gov (United States)

    Van Hoogdalem, E J; Terpstra, I J; Krauwinkel, W J; Volkers-Kamermans, N J; Baven, A L; Verschoor, J S

    1996-05-01

    Josamycin is a macrolide antibiotic with considerable intra- and interindividual variability in kinetics. In the present study bioequivalence of an intact and dispersed josamycin Solutab tablet, containing 1,000 mg of josamycin in the form of josamycin propionate ester, was tested versus a Josacine 1,000 mg reference sachet. The design of this bioequivalence study was adapted to the drug's pharmacokinetic variability, comprising testing in steady-state, testing the reference in replicate, and maintaining a widened bioequivalence margin. The study was performed in a group of 24 male and 12 female healthy subjects, according to a 3-treatment 4-period crossover design. Blood sampling for establishing josamycin propionate and josamycin base serum level profiles were collected during the 12 h dosing interval on day 4. Steady-state serum levels were reached on day 4. With the reference sachet mean peak levels of 1.02 micrograms/ml and 0.36 microgram/ml were observed for parent drug and metabolite, respectively, reached at peak times of 1.5 h and 1.8 h. Comparable profiles were observed with the intact and dispersed Solutab tablets, both tending towards higher serum levels than the sachet. In terms of josamycin propionate levels as well as josamycin base levels, the intact and dispersed Solutab tablet was bioequivalent with the referent sachet within the preset 0.70-1.43 margins. Variability in josamycin kinetics proved to be substantial, maximum differences in peak levels and AUC values being about 10-fold between individuals, and 3-fold within individuals. Retrospectively, the multiple dosing regimen appeared not to result in a clear reduction of intrasubject variability.

  18. Pharmacokinetic and bioequivalence studies of immediate release diclofenac potassium tablets (50mg) in healthy volunteers.

    Science.gov (United States)

    Ali, Huma; Shoaib, Muhammad Harris; Zafar, Farya; Hanif, Muhammad; Bushra, Rabia; Naz, Asia; Khursheed, Raheela

    2016-09-01

    This study was conducted with the aim to determine the pharmacokinetic and bioequivalence of diclofenac potassium 50 mg test (F4) tablet formulation with reference product (Caflam). Present study was single dose, randomized, two phase cross over design, conducted in 12 healthy Pakistani volunteers and planned in accordance with FDA guidelines. In this study a simple, selective, sensitive and reproducible HPLC procedure was developed and validated for the estimation of diclofenac potassium in plasma. The process was validated in the range of 50 - 0.05 µg.mL-1 and used in bioequivalence trial of two products. Multiple blood samples were collected at various time points (0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12 and 14 hr after treating volunteers with test (F4) and marketed reference brand. Plasma separation and deproteination were carried out with acetonitrile; samples (20µL) were injected using the validated HPLC method. Various pharmacokinetic parameters (compartmental and noncompartmental) were estimated using KineticaTM 4.4.1 (Thermo Electron Corp. USA). Bioequivalence among the products was established by calculating the 90% CI with log and non log transformed data for Cmaxcalc, Tmaxcalc, AUC0-∞, AUCtot and AUClast using two way ANOVA and Schirmann's Two one sided t- test. No significant difference was found between log and non-log data. The 90% confidence interval values using log transformed data for AUC0-∞ (0.997-1.024), AUCtot (1.004-1.031), AUClast (0.997 -1.024), Cmaxcalc (0.994-1.007) and Tmaxcalc (0.996-1.013) for the trial and reference products were found within the FDA acceptable limits of 0.8-1.25. Results were further verified by the Schirmann's one-sided t test. Results showed the bioequivalence of test and reference formulations. Both the products were well tolerated.

  19. In vitro bioequivalence study of nine brands of artesunate tablets marketed in Nigeria

    Directory of Open Access Journals (Sweden)

    C.O. Esimone

    2008-02-01

    Full Text Available Background & objectives: The availability of numerous brands of artesunate in our drug market today places clinicians and pharmacists in a difficult situation of choice of a suitable brand or the possibility of alternative use. The aim of the present study was to predict the bioequivalence of nine brands of artesunate tablets marketed in Nigeria using in vitro tests. Methods: The in vitro dissolution study was carried out on the nine brands of artesunate tablets using the basket method according to US Pharmacopoeia (USP guidelines. Other general quality assessment tests like hardness and disintegration time were also determined.Results: All the brands tested passed the British Pharmacopoeia (BP standard for disintegration time. Only AT2, AT4, AT6 and AT9 passed the standard for hardness. There were significant differences in the dissolution profiles of the nine brands. All the brands except AT1, however, released >70% of artesunate within 30 min. Four of the brands AT5, AT6, AT7 and AT8 exhibited >90% dissolution in <10 min. The other brands AT1, AT2, AT3, AT4 and AT9 (innovator brand have calculated similarity factors of 23.8, 59.8, 50, 54.8 and 100.Interpretation & conclusion: Based on the in vitro tests, AT5, AT6, AT7 and AT8 are considered bioequivalent and interchangeable, while AT2, AT3 and AT4 are considered bioequivalent and interchangeable with the innovator brand (AT9. AT1 has very low dissolution rate, which will likely result in poor bioavailability. The results show the need for constant monitoring of new brands of artesunate introduced into the drug market to ascertain bioequivalence and conformity with pharmacopoeia standards.

  20. Bioequivalence study of two formulations of candesartan cilexetil tablet in healthy subjects under fasting conditions

    OpenAIRE

    Tjandrawinata RR; Setiawati E; Yunaidi DA; Simanjuntak R; Santoso ID; Susanto LW

    2013-01-01

    Raymond R Tjandrawinata,1 Effi Setiawati,2 Danang Agung Yunaidi,2 Ronal Simanjuntak,2 Iwan Dwi Santoso,2 Liana W Susanto1 1Dexa Laboratories of Biomolecular Sciences (DLBS), Cikarang, Indonesia; 2Bioavailability and Bioequivalence Laboratory, PT Equilab International, Jakarta, Indonesia Introduction: The present study was conducted to compare the bioavailability of two candesartan cilexetil 16 mg tablet formulations (test and reference formulations). Materials and methods: This study was a r...

  1. Determination of lamivudine in human plasma by HPLC and its use in bioequivalence studies.

    Science.gov (United States)

    Kano, Eunice Kazue; dos Reis Serra, Cristina Helena; Koono, Eunice Emiko Mori; Andrade, Simone Schramm; Porta, Valentina

    2005-06-13

    A simple, accurate, precise and sensitive high-performance liquid chromatographic (HPLC) method with ultraviolet detection was developed to quantificate lamivudine (3-TC) in human plasma samples from bioequivalence studies. 3-TC and stavudine (internal standard, I.S.) were extracted from 0.5 ml of human plasma by acetonitrile protein precipitation. The method was validated over a concentration range of 0.05-3.00 microg/ml and used in a bioequivalence trial between two lamivudine formulations, to assess its usefulness in this kind of study. FURP-lamivudine (Fundação para o Remédio Popular, Brazil, as test formulation) and Epivir (GlaxoSmithKline, Brazil, as reference formulation) were evaluated following a single 150 mg oral dose to 24 healthy volunteers of both genders. The dose was administered after an overnight fast according to a two-way crossover design. Bioequivalence between the products was determined by calculating 90% confidence intervals (90% CI) for the ratio of Cmax, AUC0-t and AUC0-inf values for the test and reference products, using logarithmic transformed data. The 90% confidence intervals for the ratio of Cmax (0.86-1.06), AUC0-t (0.96-1.04) and AUC0-inf (0.97-1.05) values for the test and reference products are within the 0.80-1.25 interval proposed by FDA and EMEA. It was concluded that the two 3-TC formulations are bioequivalent in their rate and extent of absorption, and thus, may be used interchangeably.

  2. Assessment of polymorphic metabolite data in bioavailability/bioequivalence studies - considerations and challenges

    OpenAIRE

    Srinivas, Nuggehally R.

    2011-01-01

    Bioavailability (BA)/ bioequivalence (BE) studies are the cornerstone for the approval of generic drugs. While BA/BE assessment involving the pharmacokinetic data of the parent compound has been routinely performed, the introduction of the assessment of metabolite(s) data, alone or in addition to parent compound, has also emerged. In this context, the assessment of BA/BE of metabolite(s) may pose additional complexities and challenges, if the metabolic pathway is under the influence of a poly...

  3. Tests for bioequivalence of control media and test media in studies of toxicity

    Energy Technology Data Exchange (ETDEWEB)

    Erickson, W.P.; McDonald, L.L. [Western EcoSystems Technology, Inc., Cheyenne, WY (United States)

    1995-07-01

    Statistical tests of the classical (null) hypothesis--that there is no difference in effects of control media and tested--are commonly used to make statistical inferences toward the no-observed-adverse-effect concentration. However, failing to rejects this hypothesis is not considered as scientific proof the hypothesis is true. An effect may exist, but high variation due to inadequate replication, variation in experimental units, or imprecise measurement techniques may yield data for which the hypothesis is not rejected. An experiment may also be too precise, yielding effects that are statistically significant but not biologically important. The authors propose the use of tests of bioequivalence of control media and test media to alleviate these unsatisfactory characteristics of tests and of the classical hypotheses for regulatory decisions. They review and illustrate the test for bioequivalence using acute and chronic toxicity data. They also define a procedure for determining the level of effect at which there will be high power to refute the hypothesis that there is a lack of bioequivalence if in fact the biological response in the control media is identical to the responses in the test media.

  4. Piroxicam immediate release formulations: A fasting randomized open-label crossover bioequivalence study in healthy volunteers.

    Science.gov (United States)

    Helmy, Sally A; El-Bedaiwy, Heba M

    2014-11-01

    Piroxicam is a NSAID with analgesic and antipyretic properties, used for the treatment of rheumatoid diseases. The aim of this study was to evaluate the bioequivalence of two brands of piroxicam capsules (20 mg) in 24 Egyptian volunteers. The in vivo study was established according to a single-center, randomized, single-dose, laboratory-blinded, 2-period, 2-sequence, crossover study with a washout period of 3 weeks. Under fasting conditions, 24 healthy male volunteers were randomly selected to receive a single oral dose of one capsule (20 mg) of either test or reference product. Plasma samples were obtained over a 144-hour interval and analyzed for piroxicam by HPLC with UV detection. The pharmacokinetic parameters Cmax , tmax , AUC0-t , AUC0-∞ , Vd /F, Cl/F, and t1/2 were determined from plasma concentration-time profiles. The 90% confidence intervals for the ratio of log transformed values of Cmax , AUC0-t , and AUC0-∞ of the two treatments were within the acceptable range (0.8-1.25) for bioequivalence. From PK perspectives, the two piroxicam formulations were considered bioequivalent, based on the rate and extent of absorption. No adverse events occurred or were reported after a single 20-mg piroxicam and both formulations were well-tolerated.

  5. Bioequivalence study with lapatinib powder for oral suspension and the original tablet formulation in cancer patients.

    Science.gov (United States)

    Koch, Kevin M; Ferron-Brady, Geraldine; Lemmon, Colleen; Cartee, Leanne; Hollyfield, Hedy; D'Amelio, Anthony M; Piepszak, Alexandra; Swaby, Ramona F; Curran, David; Arya, Niki

    2015-01-01

    Lapatinib is approved for use in various therapeutic combinations for treating metastatic breast cancers that over-express HER2. To deliver the approved doses, up to six large tablets need to be ingested with the current 250-mg tablets. For ease of ingestion, a powder for oral suspension was developed. This study was an open-label, randomized, adaptive design, two-period crossover bioequivalence study of the powder for suspension relative to the commercial tablet at steady state following once daily dosing for 7 days in patients with advanced cancer. To minimize the number of cancer patients required for a pivotal bioequivalence study (144 in this case), a four-stage adaptive group sequential design with interim analyses after every 36 subjects was implemented to allow for early termination. Bioequivalence for the oral suspension relative to the commercial tablet was demonstrated in both the first (and only) interim analysis and the final analysis, as the 90% confidence intervals for the treatment comparison ratios for both AUC0-24 and Cmax were contained within the acceptance criteria (0.80, 1.25). Additionally, there was no statistical difference in tlag or tmax , suggesting no difference in the absorption rate between treatments. There were no unexpected safety findings during this study.

  6. Pharmacokinetics and bioequivalence testing of five commercial formulations of omeprazole in the horse.

    Science.gov (United States)

    Sykes, B W; Underwood, C; Greer, R; McGowan, C M; Mills, P C

    2016-02-01

    Omeprazole is widely used in the treatment of equine gastric ulcer syndrome. To date, little is known about the relative pharmacokinetics of the different formulations making comparisons between products difficult. The objectives of the study were to investigate the relative pharmacokinetics of five commercially available formulations of omeprazole in the horse and to test for bioequivalence of four of the formulations using one of the formulations as a reference standard. Twelve mature Thoroughbred horses were fasted for 16 h then administered 2 g of each formulation in a cross-over design. Serial blood samples were collected and plasma omeprazole concentration was determined by ultra high-performance liquid chromatography-mass spectrometry (UHPLC-MS). No significant differences were present between three of the formulations and the reference formulation, while the fourth formulation had a lower Cmax and longer Tmax than the reference formulation. Bioequivalence against the reference formulation could not be demonstrated for any of the formulations tested. The findings of the study suggested that the method of protection utilised by different formulations of omeprazole (enteric-coated granules vs. buffering) does not significantly alter the pharmacokinetics of the drug. Further work to establish bioequivalence is needed before direct comparisons can be drawn between different formulations.

  7. Exact calculation of power and sample size in bioequivalence studies using two one-sided tests.

    Science.gov (United States)

    Shen, Meiyu; Russek-Cohen, Estelle; Slud, Eric V

    2015-01-01

    The number of subjects in a pharmacokinetic two-period two-treatment crossover bioequivalence study is typically small, most often less than 60. The most common approach to testing for bioequivalence is the two one-sided tests procedure. No explicit mathematical formula for the power function in the context of the two one-sided tests procedure exists in the statistical literature, although the exact power based on Owen's special case of bivariate noncentral t-distribution has been tabulated and graphed. Several approximations have previously been published for the probability of rejection in the two one-sided tests procedure for crossover bioequivalence studies. These approximations and associated sample size formulas are reviewed in this article and compared for various parameter combinations with exact power formulas derived here, which are computed analytically as univariate integrals and which have been validated by Monte Carlo simulations. The exact formulas for power and sample size are shown to improve markedly in realistic parameter settings over the previous approximations.

  8. Non-exercise Estimation of V02max Using a Dichotomy of Meeting or Not Meeting DHHS Physical Activity Recommendations

    Science.gov (United States)

    Wier, Larry T.; Jackson, Allen W.; Jackson, Andrew S.

    2009-01-01

    The physical activity guidelines (PAG) established by the US Dept. of Health and Human Services in 2008 is consistent with a rating of >/= 6 on the 11-point NASA Physical Activity Status Scale (PASS). Wier, et. al. developed non-exercise models for estimating VO2(sub max) from a combination of PASS, age, gender and either waist girth (WG) (R = 0.810, SEE= 4.799 ml/kg/min), %Fat (R = 0. 817, SEE = 4.716 ml/kg/min) or BMI (R = 0.802, SEE = 4.900 ml . kg-1. min -1 ). PURPOSE: to develop non-exercise models to estimate VO2max from age, gender, body composition (WG, %Fat, BMI) and PASS dichotomized at meets or does not meet the PAG (PAG-PASS), and to compare the accuracy of the PAG-PASS models with the models using the 11-point PASS. METHODS: 2417 men and 384 women were measured for VO2max by indirect calorimetry (RER >1.1); age (yr), gender by M = 1, W = 0; WG at the umbilicus; %fat by skin-folds, BMI by weight (kg) divided by height squared (m 2 ) , and PAGPASS by PASS 6 = 1. RESULTS: Three models were developed by multiple regression to estimate VO2(sub max) from age, gender, PAG-PASS and either WG (R = 0.790, SEE=5.019 ml/kg/min), %FAT (R= 0.080, SEE = 4.915 ml/kg/min) or BMI (R = 0.777, SEE = 5.162ml/kg/min). Cross-validation by the PRESS technique confirmed these statistics. Simple correlations between measured VO2(sub max) and estimates from the PAG-PASS models with WG, %Fat and BMI were 0.790, 0.800 and 0.777, minimally different from the correlations obtained with the PASS models (0.810, 0.810, and 0.802). PAG-PASS and PASS model constant errors were also similar: VO2(sub max) between 30 and 50 ml/kg/min (70% of the sample) but > 1 ml/kg/min for VO2(sub max) 50 ml/kg/min. CONCLUSIONS: Non-exercise models using the combined effects of age, gender, body composition and the dichotomized PAG-PASS provide estimates of VO2(sub max) that are accurate for most adults, and the accuracy of these models are similar to previously published models using the 11-point PASS.

  9. Use of depuration compounds in passive air samplers: results from active sampling-supported field deployment, potential uses, and recommendations.

    Science.gov (United States)

    Moeckel, Claudia; Harner, Tom; Nizzetto, Luca; Strandberg, Bo; Lindroth, Anders; Jones, Kevin C

    2009-05-01

    Depuration compounds (DCs) are added to passive air samplers (PAS) prior to deployment to account for the wind-dependency of the sampling rate for gas-phase compounds. This correction is particularly useful for providing comparable data for samplers that are deployed in different environments and subject to different meteorological conditions such as wind speeds. Two types of PAS--the polyurethane foam (PUF) disk sampler and semipermeable membrane devices (SPMDs)--were deployed at eight heights on a 100 m tower to test whether the DC approach could yield air concentrations profiles for PCBs and organochlorine pesticides and account for the wind speed gradient with height. Average wind speeds ranged from 0.3 to 4.5 m s(-1) over the 40 day deployment, increasing with height Two low volume active air samples (AAS), one collected at 25 m and one at 73 m over the 40 day deployment showed no significant concentration differences for target compounds. As expected, the target compounds taken up by PAS reflected the wind profile with height This wind-dependency of the PAS was also reflected in the results of the DCs. A correction based on the DC approach successfully accounted for the effect of wind on PAS sampling rates, yielding a profile consistent with the AAS. Interestingly, in terms of absolute air concentrations, there were differences between the AAS and PAS-derived values for some target compounds. These were attributed to different sampling characteristics of the two approaches that may have resulted in slightly different air masses being sampled. Based on the results of this study, guidelines are presented for the use of DCs and for the calibration of PAS using AAS.

  10. Bioequivalence study of two formulations of bisoprolol fumarate film-coated tablets in healthy subjects

    Directory of Open Access Journals (Sweden)

    Tjandrawinata RR

    2012-10-01

    Full Text Available Raymond R Tjandrawinata,1 Effi Setiawati,2 Danang Agung Yunaidi,2 Iwan Dwi Santoso,2 Arini Setiawati,3 Liana W Susanto11Dexa Laboratories of Biomolecular Sciences (DLBS, Cikarang, Indonesia; 2Bioavailability and Bioequivalence Laboratory, Equilab International, Jakarta, Indonesia; 3Department of Pharmacology and Therapeutics, University of Indonesia, Jakarta, IndonesiaBackground: The present study was conducted to compare the bioavailability of two bisoprolol fumarate 5 mg film-coated tablet formulations (test and reference formulations.Patients and methods: This study was a randomized, single-blind, two-period, two-sequence crossover study that included 18 healthy adult male and female subjects under fasting condition. The pharmacokinetic parameters were determined based on the concentrations of bisoprolol (CAS 66722-44-9, using ultraperformance liquid chromatography with a tandem mass spectrometer detector. In each of the two study periods (separated by a washout of 1 week a single dose of test or reference product was administered. The pharmacokinetic parameters assessed were area under the plasma concentration-time curve from time zero to 48 hours (AUCt, AUC from time zero to infinity (AUCinf, the peak plasma concentration of the drug (Cmax, time needed to achieve Cmax (tmax, and the elimination half-life (t½.Results: The geometric mean ratios (90% confidence intervals of the test drug/reference drug for bisoprolol were 101.61% (96.14%–107.38% for AUCt, 101.31% (95.66%–107.29% for AUCinf, and 100.28% (93.90%–107.09% for Cmax. The differences between the test and reference drug products for bisoprolol tmax and t½ values were not statistically significant (P > 0.05. There was no adverse event encountered during this bioequivalence test. The 90% confidence intervals of the test/reference AUC ratio and Cmax ratio of bisoprolol were within the acceptance range for bioequivalence.Conclusion: It was concluded that the two bisoprolol film

  11. Bioequivalence study of two formulations of candesartan cilexetil tablet in healthy subjects under fasting conditions

    Directory of Open Access Journals (Sweden)

    Tjandrawinata RR

    2013-08-01

    Full Text Available Raymond R Tjandrawinata,1 Effi Setiawati,2 Danang Agung Yunaidi,2 Ronal Simanjuntak,2 Iwan Dwi Santoso,2 Liana W Susanto1 1Dexa Laboratories of Biomolecular Sciences (DLBS, Cikarang, Indonesia; 2Bioavailability and Bioequivalence Laboratory, PT Equilab International, Jakarta, Indonesia Introduction: The present study was conducted to compare the bioavailability of two candesartan cilexetil 16 mg tablet formulations (test and reference formulations. Materials and methods: This study was a randomized, single- blind, two-period, cross-over study which included 24 healthy adult male and female subjects under fasting conditions. The pharmacokinetic parameters were determined based on the concentrations of candesartan (CAS 139481-59-7, using ultra-pressure high-performance liquid chromatography with a tandem mass spectrometer detector. In each of the two study periods (separated by a washout period of 1 week, a single dose of test or reference product was administered. The pharmacokinetic parameters assessed were area under the plasma concentration time curve (AUC from time 0 hours to 24 hours, AUC from time zero to infinity, the peak plasma concentration of the drug (Cmax, time to achieve the Cmax, and the elimination half-life. Results: The geometric mean ratios (90% confidence interval of the test drug/reference drug for candesartan were 100.92% (92.15%–110.52% for the AUC from 0 hours to 24 hours, 100.24% (92.24%–108.95% for the AUC from time zero to infinity, and 106.71% (93.20%–122.18% for the Cmax. The differences between the test and reference product in the time to achieve Cmax values and elimination half-life values were not statistically significant (P > 0.05. The 90% confidence intervals of the test/reference AUC ratio and Cmax ratio of candesartan were within the acceptance range for bioequivalence. There was no adverse event encountered during this bioequivalence study. Conclusion: It was concluded that the two candesartan tablet

  12. An open-label,randomized,cross-over bioequivalence study of lafutidine 10 mg under fasting condition

    Institute of Scientific and Technical Information of China (English)

    Bhupesh; Dewan; Raghuram; Chimata

    2010-01-01

    AIM:To assess the relative bioavailability and pharmacokinetic properties of two formulations(test and reference) of Lafutidine 10 mg.METHODS:The study was performed as an open label,randomized,two-way,two-period,two-treatment,single dose cross-over bioequivalence study,under non-fed condition to compare the pharmacokinetic prof iles of the lafutidine formulation manufactured by Emcure Pharmaceuticals Ltd.,India using an indigenously developed active pharmaceutical ingredient(API) and the commercially available Stogra formulation,of UCB Japan Co.,Ltd.,Japan.The two treatments were separated by a washout period of 5 d.After an overnight fasting period of 10 h,the subjects were administered either the test or the reference medication as per the randomization schedule.Blood samples were collected at intervals up to 24 h,as per the approved protocol.Concentrations of lafutidine in plasma were analyzed by a validated liquid chromatography/tandem mass spectrometry(LC/MS/MS) method,and a non-compartmental model was used for pharmacokinetic analysis.The pharmacokinetic parameters were subjected to a 4-way ANOVA accounting for sequence,subjects,period and treatment.Statistical significance was evaluated at 95% conf idence level(P ≥ 0.05).RESULTS:The mean(±SD) values of the pharmacokinetic parameters(test vs reference) were Cmax(265.15±49.84 ng/mL vs 246.79±29.30 ng/mL,P<0.05),Area under the curve(AUC)(0-t)(1033.13±298.74 ng.h/mL vs 952.93±244.07 ng.h/mL,P < 0.05),AUC(0-∞)(1047.61±301.22 ng.h/mL vs 964.21±246.45 ng.h/mL,P<0.05),and tv2(1.92±0.94 h vs 2.05±1.01 h,P<0.05).The 90% conf idence intervals(CI) for the test/reference ratio of mean Cmax,AUC(0-t),and AUC(0-∞) were within the acceptable range of 80.00 to 125.00.The mean times(± SD) to attain maximal plasma concentration(tmax) of lafutidine were 0.95±0.24 h vs 1.01±0.29 h(P<0.05) for the test and the reference formulations respectively.Both the formulations were well tolerated.

  13. Habitat and population management recommendations for your consideration

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — Recommendations for management activities at Wheeler National Wildlife Refuge are discussed. Recommendations for cropland management, additional developments,...

  14. Microdialysis sampling for investigations of bioavailability and bioequivalence of topically administered drugs: current state and future perspectives

    DEFF Research Database (Denmark)

    Holmgaard, R; Nielsen, J B; Benfeldt, E

    2010-01-01

    by skin disease or barrier perturbation. A comparison between MD and other tissue sampling techniques reveals the advantages and limitations of the method. Subsequently, an in-depth discussion of the application of MD for the evaluation of bioavailability and bioequivalence of topical formulations...... is concluded by the current regulatory point of view. The future perspective includes further expansion and validation of the use of MD in the experimental and clinical setting as well as in the optimization of the method for regulatory purposes, i.e. the commercialization of bioequivalent, generic drug...

  15. Single dose bioequivalence study of two brands of olanzapine 10 mg tablets in Iranian healthy volunteers.

    Science.gov (United States)

    Zakeri-Milani, P; Islambulchilar, Z; Ghanbarzadeh, S; Valizadeh, H

    2013-07-01

    This single dose, randomized, open label, 2-period and crossover study in healthy Iranian adult volunteers was conducted to compare the bioavailability of 2 branded formulations of olanzapine 10 mg tablets. 24 volunteers received one tablet of each olanzapine 10 mg formulation. Drugs were administered after a 12 h overnight fast in each of 2 treatment days which separated by a 2-week washout period. Serial blood samples were collected over a period of 72 h. Plasma was analyzed using a validated high performance liquid chromatography method with ultraviolet detection in the range of 2-24 ng/mL with a lower limit of quantitation of 1.25 ng/mL. A non-compartmental method was employed to determine the pharmacokinetic properties (Cmax, Tmax, AUC0-t, AUC0-∞ and T1/2) to test to bioequivalence. Cmax, AUC0-t and AUC0-∞ were used to test the bioequivalence after log-transformation of plasma data. The mean (SD) Cmax, AUC0-t and AUC0-∞ for the test formulation were 15.82 (3.15) ng/mL, 447.19 (100.64) ng.h/L and 570.75 (130.55) ng.h/L respectively. Corresponding values for the test formulation were 15.72 (4.25) ng/mL, 440.37 (98.75) ng.h/mL and 558.66 (129.57) ng.h/mL. For test formulation vs. the reference formulation, the 90% CIs of the least squares mean test/reference ratios of Cmax, AUC0-t and AUC0-∞ were 97.6-110.0%, 96.4-109.4% and 97.3-109.2%. In these volunteers, based on the FDA regulatory definition, results from the pharmacokinetic analysis suggested that the test and reference formulations of olanzapine 10 mg tablets were bioequivalent.

  16. Solid state NMR and bioequivalence comparison of the pharmacokinetic parameters of two formulations of clindamycin

    KAUST Repository

    Al-Talla, Zeyad

    2011-01-01

    Objective: The purpose of this study was to compare the pharmacokinetic parameters and determine the bioequivalence of a generic formulation of clindamycin that is sold in the local markets in the Middle East (Clindox® 150 mg capsule; test) with a reference formulation (Dalacin C® 150 mg capsule) in healthy adult male volunteers. Methods: A single-dose, open-label, 2-period crossover study was conducted. Healthy male volunteers were randomly assigned to oral administration of a single treatment of the reference and test formulations. The same groups were given the alternate formulation. After dosing, serial blood samples were withdrawn for a period of 24 h. Serum harvested from the blood samples was analyzed for clindamycin by high performance liquid chromatography (HPLC) with ultraviolet detection. Pharmacokinetic parameters, including AUC0-∞, AUC 0-t, Cmax, Ke, tmax and t 1/2 were determined from the serum concentrations for both formulations (test and reference). The products were tested for bioequivalence after log-transformation of the data. Results: 24 healthy adult male volunteers from Jordan (mean [SD] age, 28.8 (7.7) years (range 19-45 years); height, 175.8 (10.6) cm (range 159.0-192.0 cm); weight, 75.6 (11.0) kg (range 58-101 kg); and body mass index, 24.4 (1.8) kg/m2 (range 21.3-28 kg/m2)) were enrolled in and completed the study. The 13C NMR spectra for both Dalacin C® and Clindox® showed 18 distinct lines associated with the 18 different carbon atoms. Conclusion: The statistical comparison suggested that Clindox® capsules are bioequivalent to Dalacin C® capsules. The 13C CPMAS results confirmed that the two drugs exhibit typical clindamycin spectra. ©2011 Dustri-Verlag Dr. K. Feistle.

  17. Bioequivalence of two oral formulations of triflusal capsules in healthy volunteers.

    Science.gov (United States)

    Quetglas, Emilio García; Campanero, Miguel Angel; Sádaba, Belén; Escolar, Manuel; Azanza, Jose Ramón

    2008-01-01

    Triflusal (CAS 322-79-2) is an antiplatelet agent related to salicylates used in several European and Latin American countries in the treatment of cardiovascular diseases. The aim of this paper was to evaluate the bioequivalence of triflusal derived from two preparations using both parent drug and metabolite pharmacokinetic data. The bioavailabolity was measured in 24 healthy male Caucasian volunteers following a single oral dose (600 mg) of the test or reference products in the fasting state. Blood samples were collected for 120 h. Plasma concentrations of triflusal and its metabolite 3-hydroxy-4-trifluoromethylbenzoic acid (HTB) were analyzed by high-performance liquid chromatography with UV and fluorescence detection, respectively. The non-compartmental method was used for pharmacokinetic analysis. Log-transformed Cmax, AUC0-t and AUC0-infinity were tested for bioequivalence using ANOVA and Schuirmann's two-one sided t-test. Tmax was analyzed by nonparametric pharmacokinetic parameters of triflusal and HTB derived from the two formulations were nearly consistent with previous observations. Triflusal parameters derived from the test and reference drug were as follows: Cmax (16.85 +/- 11.41 vs 14.48 +/- 7.22 mg/l), AUC0-t (18.43 +/- 10.91 vs 16.22 +/- 7.58 mg/l per hour), Tmax (1 range 0.25-2h vs 0.875 range 0.25-1.5 h), and t(1/2) (0.49 +/- 00.27 vs 0.76 +/- 0.64). HTB parameters after test and reference formulation administration were as follows: Cmax (68.13 +/- 23.05 vs 65.51 +/- 19.44 mg/l), AUC0-t (2748.18 +/- 971.91 vs 2877.97 +/- 881.2 h x mg/l), AUC0-infinity (3350.15 +/- 1182.62 vs 3372.49 +/- 1110.35 h x mg/l), Tmax (2 range 1-10 h vs 2 range 0.75-12 h), and t(1/2) (42.19 +/- 7.82 vs 43.13 +/- 6.56 h). 90% of confidence intervals for the test/reference ratio of Cmax AUC0-t and AUC0-infinity derived from both triflusal and HTB were found within the range of 80%-125% acceptable for bioequivalence. No significant difference was found between the Tmax values

  18. Pharmacokinetics and bioequivalence of ranitidine and bismuth derived from two compound preparations

    Institute of Scientific and Technical Information of China (English)

    Quan Zhou; Zou-Rong Ruan; Hong Yuan; Bo Jiang; Dong-Hang Xu

    2006-01-01

    AIM: To evaluate the bioequivalence of ranitidine and bismuth derived from two compound preparations.METHODS: The bioavailability was measured in 20healthy male Chinese volunteers following a single oral dose (equivalent to 200 mg of ranitidine and 220 mg of bismuth) of the test or reference products in the fasting state. Then blood samples were collected for 24 h.Plasma concentrations of ranitidine and bismuth were analyzed by high-performance liquid chromatography and inductively coupled plasma-mass spectrometry (ICPMS), respectively. The non-compartmental method was used for pharmacokinetic analysis. Log-transformed Cmax,AUC(0-t) and AUC(0-∞) were tested for bioequivalence using ANOVA and Schuirmann two-one sided t-test. Tmax was analyzed by Wilcoxon's test.RESULTS: Various pharmacokinetic parameters of ranitidine derived from the two compound preparations,including Cmax, AUC(0-t), AUC(0-∞), Tmax and T1/2, were nearly consistent with previous observations. These parameters derived from test and reference drug were as follows: Cmax(0.67 ± 0.21 vs 0.68 ± 0.22mg/L), AUC(0-t)(3.1 ± 0.6 vs 3.0 ± 0.7 mg/L per hour),AUC(0-∞)(3.3 ± 0.6 vs 3.2 ± 0.8 mg/L per hour),Tmax (2.3 ± 0.9 vs 2.1 ± 0.9 h) and T1/2 (2.8 ± 0.3 vs 3.1± 0.4 h). In addition, double-peak absorption profiles of ranitidine were found in some Chinese volunteers.For bismuth, those parameters derived from test and reference drug were as follows: Cmax (11.80 ± 7.36 vs 11.40 ± 6.55 μg/L),AUC(0-t) (46.65 ± 16.97 vs 47.03 ±21.49 μg/L per hour), Tmax (0.50 ± 0.20 vs 0.50 ± 0.20 h)and T1/2 (10.2 ± 2.3 vs 13.0 ± 6.9 h). Ninety percent of confidence intervals for the test/reference ratio of Cmax,AUC(0-t) and AUC(0-∞) derived from both ranitidine and bismuth were found within the bioequivalence acceptable range of 80%-125%. No significant difference was found in Tmax derived from both ranitidine and bismuth.CONCLUSION: The two compound preparations are bioequivalent and may be prescribed

  19. Assessment of polymorphic metabolite data in bioavailability/bioequivalence studies - considerations and challenges

    Directory of Open Access Journals (Sweden)

    Nuggehally R Srinivas

    2011-01-01

    Full Text Available Bioavailability (BA/ bioequivalence (BE studies are the cornerstone for the approval of generic drugs. While BA/BE assessment involving the pharmacokinetic data of the parent compound has been routinely performed, the introduction of the assessment of metabolite(s data, alone or in addition to parent compound, has also emerged. In this context, the assessment of BA/BE of metabolite(s may pose additional complexities and challenges, if the metabolic pathway is under the influence of a polymorphic enzyme. This communication provides brief perspectives on the challenges and study design considerations for the assessment of polymorphic metabolite in BA/BE studies.

  20. WORLD HEALTH ORGANIZATION’S GUIDELINES FOR BIOEQUIVALENCE STUDIES USING PHARMACOKINETIC MEASUREMENTS

    Directory of Open Access Journals (Sweden)

    Malik Ajay

    2011-11-01

    Full Text Available The purpose of this study is to understand World Health Organization’s guidelines for Bioequivalence studies in humans. It is important for anyone preparing a trial of a medicinal product in humans that the specific aims, problems and risks or benefits of the proposed human study be thoroughly considered and that the chosen design be scientifically sound and ethically justified. All research involving human subjects should be conducted in accordance with the ethical principles, including respect for persons, beneficence (maximize benefits and minimize harms and wrongs and non- maleficence (do no harm.

  1. Recommendation system for trip planning

    OpenAIRE

    Hlupič, Marko

    2011-01-01

    The thesis describes a web application used for recommending tourist destinations and trip planning. Given that one location offers several tourist attractions and activities, the destination is divided into a location, containing only the name and the corresponding region, and the possible activity that could take place in that location. The users choose some activities and later on decide whether these locations met their expectations or not. The application is divided into two parts: the f...

  2. OARSI Clinical Trials Recommendations

    DEFF Research Database (Denmark)

    McAlindon, T. E.; Driban, J. B.; Henrotin, Y.;

    2015-01-01

    The goal of this document is to update the original OARSI recommendations specifically for the design, conduct, and reporting of clinical trials that target symptom or structure modification among individuals with knee osteoarthritis (OA). To develop recommendations for the design, conduct...... and index knee, describing interventions, patient-reported and physical performance measures, structural outcome measures, biochemical biomarkers, and reporting recommendations. In summary, the working group identified 25 recommendations that represent the current best practices regarding clinical trials...... that target symptom or structure modification among individuals with knee OA. These updated recommendations incorporate novel technologies (e.g., magnetic resonance imaging (MRI)) and strategies to address the heterogeneity of knee OA....

  3. Trust for intelligent recommendation

    CERN Document Server

    Bhuiyan, Touhid

    2013-01-01

    Recommender systems are one of the recent inventions to deal with the ever-growing information overload in relation to the selection of goods and services in a global economy. Collaborative Filtering (CF) is one of the most popular techniques in recommender systems. The CF recommends items to a target user based on the preferences of a set of similar users known as the neighbors, generated from a database made up of the preferences of past users. In the absence of these ratings, trust between the users could be used to choose the neighbor for recommendation making. Better recommendations can b

  4. 21 CFR 320.26 - Guidelines on the design of a single-dose in vivo bioavailability or bioequivalence study.

    Science.gov (United States)

    2010-04-01

    ...-dose study should be crossover in design, unless a parallel design or other design is more appropriate... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Guidelines on the design of a single-dose in vivo... Guidelines on the design of a single-dose in vivo bioavailability or bioequivalence study. (a)...

  5. Fluorescence detection of tramadol in healthy Chinese volunteers by high-performance liquid chromatography and bioequivalence assessment

    Directory of Open Access Journals (Sweden)

    Zhou X

    2015-02-01

    Full Text Available Xiao Zhou, Ji Liu Department of Anesthesia, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China Abstract: This study developed a revised high-performance liquid chromatography fluorescence method to determine plasma tramadol concentration, and thereby to examine the bioequivalence of two tramadol formulations among healthy male Chinese volunteers. The study used a double-blind, randomized, 2×2 crossover-design principle. Calculated pharmacokinetic parameters for both formulations were consistent with previous reports. According to the observation of vital signs and laboratory measurement, no subjects had any adverse reactions. The geometric mean ratios (90% confidence interval of the test drug/reference drug for tramadol were 100.2% (95.3%–103.4% for the area under the plasma concentration–time curve (AUC from time zero to the last measurable concentration, 99.6% (94.2%–102.7% for the AUC from administration to infinite time, and 100.8% (93.1%–106.4% for maximum concentration. For the 90% confidence intervals of the test/reference AUC ratio and maximum concentration ratio of tramadol, both were in the acceptance range for bioequivalence. According to the two preparations by pharmacokinetic parameter statistics, the half-life, mean residence time, and clearance values showed no significant statistical differences. Therefore, the conclusion of this study was that the two tramadol formulations (tablets and capsules were bioequivalent. Keywords: tramadol hydrochloride, in vitro release, pharmacokinetic, bioequivalence, fluorescence detector

  6. Bioequivalence and tolerability assessment of a novel intravenous ciclosporin lipid emulsion compared to branded ciclosporin in Cremophor ® EL

    DEFF Research Database (Denmark)

    Ehinger, Karl Henrik Johannes; Hansson, Magnus Joakim; Sjövall, Fredrik;

    2013-01-01

    of the pharmacokinetics of two formulations of intravenous ciclosporin. Fifty-two healthy volunteer subjects were administered 5 mg/kg of each of the two formulations of ciclosporin as a 4-h intravenous infusion. The last blood sample was acquired 48 h after the end of the infusion. Bioequivalence assessments according...

  7. Bioequivalence Study of Tramadol + Paracetamol (37.5 + 325 mg In Healthy Human Volunteers in Fasting Condition

    Directory of Open Access Journals (Sweden)

    S. Dhanure

    2013-10-01

    Full Text Available The bioequivalence between test and reference Tramadol and Paracetamol (37.5 + 325 mg tablets was determined in 36 healthy subjects after a single dose in a randomized crossover study under fasting condition. Plasma concentrations were monitored over a period of 24 hour after the drug administration by validated LC/MS/MS analytical method. The pharmacokinetic parameters Cmax, AUC0-t, AUC0-∞, AUC0-t / AUC0-∞, Tmax, Kel and t½ were determined from plasma concentration time profile of both formulations and found to be acceptable. The calculated pharmacokinetic parameters were compared statistically to evaluate bioequivalence between the test and reference products. The analysis of variance did not show any significant difference between the two formulations and 90 % confidence intervals for the ratio of Cmax (92.29 -104.18 %, AUC0-t (99.52 - 104.11 % and AUC0-∞ (99.05 - 104.22 % for tramadol and Cmax (93.56 - 110.27 %, AUC0-t (96.37 - 102.70 % and AUC0-∞ (97.22-103.28 % for paracetamol test and reference products were within the 80 – 125 % interval, satisfying the bioequivalence criteria the US Food and Drug Administration Guidelines. These results indicate that the test and the reference products of Tramadol and Paracetamol are bioequivalent.

  8. Influence of a microemulsion vehicle on cutaneous bioequivalence of a lipophilic model drug assessed by microdialysis and pharmacodynamics

    DEFF Research Database (Denmark)

    Kreilgaard, Mads; Kemme, M J; Burggraaf, J;

    2001-01-01

    The aim of the study was to investigate the cutaneous bioequivalence of a lipophilic model drug (lidocaine) applied in a novel topical microemulsion vehicle, compared to a conventional oil-in-water (O/W) emulsion, assessed by a pharmacokinetics microdialysis model and a pharmacodynamic method....

  9. Pharmacogenetic relevance of the CYP2C9*3 allele in a tenoxicam bioequivalence study performed on Spaniards.

    Science.gov (United States)

    Peiró, A M; Novalbos, J; Zapater, P; Moreu, R; López-Rodríguez, R; Rodríguez, V; Abad-Santos, F; Horga, J F

    2009-01-01

    We performed a study to quantify CYP2C9 and CYP2C8 alleles influence on the variability observed in tenoxicam pharmacokinetic (PK) and implication in a bioequivalence study design performed on Spaniards. Eighteen healthy volunteers were included in an open, randomized, crossover, phase I bioequivalence study. Significant increases were found in CYP2C9*3 alleles vs. *1 and *2 in AUC(0-infinity) (median (min-max)): 256 (230-516) vs. 150 (100-268) and 169 (124-197) microg h/mL (p<0.01) and half-life time (t1/2) 102 (79-36) vs. 56 (45-94) and 64 (60-80)h (p<0.01). Non-significant differences were observed in C(max) 1.9 (1.8-2.9) vs. 2.4 (1.7-3.4), 2.5 (1.6-2.9) microg/mL or in according to CYP2C8 alleles presence. CYP2C9*3 allele is associated to a longer elimination time of tenoxicam. PK parameters calculated in bioequivalence studies (AUC(0-infinity), t1/2) may be influenced by the presence of CYP2C9*3 allele resulting in a high variability. Thus, bioequivalence studies of tenoxicam formulations should be designed considering genotype profile.

  10. Bioequivalence in dogs of a meloxicam formulation administered as a transmucosal oral mist with an orally administered pioneer suspension product.

    Science.gov (United States)

    Lees, P; Cheng, Z; Keefe, T J; Weich, E; Bryd, J; Cedergren, R; Cozzi, E

    2013-02-01

    A mucosal mist formulation of meloxicam, administered as a spray into the mouth (test article), was compared for bioequivalence to a pioneer meloxicam suspension for oral administration (reference article). Pharmacokinetic profiles and average bioequivalence were investigated in 20 dogs. The study design comprised a two-period, two-sequence, two-treatment cross-over design, with maximum concentration (C(max)) and area under plasma concentration-time curve to last sampling time (AUC(last)) used as pivotal bioequivalence variables. Bioequivalence of the products was confirmed, based on relative ratios of geometric mean concentrations (and 90% confidence intervals within the range 0.80-1.25) for C(max) of 101.9 (97.99-106.0) and for AUC(last) of 97.24 (94.44-100.1). The initial absorption of meloxicam was more rapid for the test article, despite virtually identical C(max) values for the two products. Mean elimination half-lives were 29.6 h (test article) and 30.0 h (reference article). The meloxicam plasma concentration-time profiles were considered in relation to published data on the inhibition of the cyclooxygenase-1 (COX-1) and COX-2 isoenzymes by meloxicam.

  11. Intercambiabilidad de opioides y moléculas bioequivalentes Opioid switching and bioequivalent molecules

    Directory of Open Access Journals (Sweden)

    M.D. Rodrigo

    2010-03-01

    Full Text Available Ante la alerta creada por dos situaciones que inciden, de manera significativa, en el entorno de la actividad clínica de los médicos que tratan el dolor, y que son: por un lado, la intercambiabilidad de moléculas bioequivalentes y, por el otro, las directrices emitidas por alguna consejería de salud en el fomento del uso de morfina frente a otros opioides como analgésico opioide de primera elección, el Grupo de Trabajo de Opioides de la Sociedad Española del Dolor -considerando que ambas pueden llevar a actuaciones en la práctica clínica que no se ajustan a la evidencia científica disponible- analiza estos dos hechos a partir del informe de experto del Dr. Cecilio Álamo, realizado en mayo de 2009, sobre la intercambiabilidad clínica de opioides potentes. Tras una revisión en profundidad de la bibliografía disponible a nivel nacional e internacional, así como de la posición de instituciones sanitarias europeas, entre otras, la Agencia Francesa del Medicamento y la Royal Pharmaceutical Society del Reino Unido, emite las conclusiones siguientes: 1. No creemos justificada la intercambiabilidad de opioides potentes entre sí, ya sean genéricos o de marca. 2. Ante las ventajas que aportan las nuevas moléculas con diferentes formulaciones (tanto por vía oral como por vía transdérmica, podemos afirmar que hay otras opciones terapéuticas frente al uso de morfina como analgésico opioide de primera elección.Due to the alert created due to two important incidents that took place involving the clinical activity of doctors who treat pain (one is the switching of bioequivalent molecules, and the other is the directives issued by a Health Department on encouraging the use of morphine instead of other opioids as first choice analgesic opioid, the Working Group of the Spanish Pain Society, considering that both can affect the activities in clinical practices that do not adapt to the available scientific evidence, analysed these two facts

  12. Wind Farm Recommendation Report

    Energy Technology Data Exchange (ETDEWEB)

    John Reisenauer

    2011-05-01

    On April 21, 2011, an Idaho National Laboratory (INL) Land Use Committee meeting was convened to develop a wind farm recommendation for the Executive Council and a list of proposed actions for proceeding with the recommendation. In terms of land use, the INL Land Use Committee unanimously agrees that Site 6 is the preferred location of the alternatives presented for an INL wind farm. However, further studies and resolution to questions raised (stated in this report) by the INL Land Use Committee are needed for the preferred location. Studies include, but are not limited to, wind viability (6 months), bats (2 years), and the visual impact of the wind farm. In addition, cultural resource surveys and consultation (1 month) and the National Environmental Policy Act process (9 to 12 months) need to be completed. Furthermore, there is no documented evidence of developers expressing interest in constructing a small wind farm on INL, nor a specific list of expectations or concessions for which a developer might expect INL to cover the cost. To date, INL assumes the National Environmental Policy Act activities will be paid for by the Department of Energy and INL (the environmental assessment has only received partial funding). However, other concessions also may be expected by developers such as roads, fencing, power line installation, tie-ins to substations, annual maintenance, snow removal, access control, down-time, and remediation. These types of concessions have not been documented, as a request, from a developer and INL has not identified the short and long-term cost liabilities for such concessions should a developer expect INL to cover these costs. INL has not identified a go-no-go funding level or the priority this Wind Farm Project might have with respect to other nuclear-related projects, should the wind farm remain an unfunded mandate. The Land Use Committee recommends Legal be consulted to determine what, if any, liabilities exist with the Wind Farm Project and

  13. Pharmacokinetics and bioequivalence of 2 meloxicam oral dosage formulations in healthy adult horses.

    Science.gov (United States)

    Vivancos, Melanie; Barker, Jessica; Engbers, Sarah; Fischer, Carrie; Frederick, Jami; Friedt, Heather; Rybicka, Joanna M; Stastny, Tereza; Banse, Heidi; Cribb, Alastair E

    2015-07-01

    Meloxicam, a non-steroidal anti-inflammatory drug, is approved for use in horses in several countries, but an equine formulation is not available in North America. However, meloxicam is being used in an extra-label manner in horses in Canada. The purpose of this study, therefore, was to assess the bioequivalence of an approved oral meloxicam suspension (Metacam 15 mg/mL for horses; Boehringer Ingelheim Vetmedica GmBH, Ingelheim, Germany) from the European Union with human meloxicam tablets (Meloxicam 15 mg tablets; TEVA Canada, Toronto, Ontario) compounded with molasses to improve palatability and administration. The geometric mean ratios (GMR test/reference) and the 90% confidence intervals of the pivotal pharmacokinetic parameters (area under the curve and maximum concentration) were within the defined limits of 80% to 125% generally accepted for products to be considered bioequivalent. Therefore, use of human meloxicam tablets compounded with molasses would be expected to produce a similar clinical response in horses as the approved oral product from the European Union.

  14. Bioequivalence study of 400 and 100 mg imatinib film-coated tablets in healthy volunteers.

    Science.gov (United States)

    Ostrowicz, Andrzej; Mikołajczak, Przemysław L; Wierzbicka, Marzena; Boguradzki, Piotr

    2014-01-01

    The aim of the study was to investigate the bioavailability of a generic product of 100 mg and 400 mg imatinib film-coated tablets (test) as compared to that of a branded product (reference) at the same strength to determine bioequivalence. The secondary objective of the study was to evaluate tolerability of both products. An open-label, randomized, crossover, two-period, single-dose, comparative study was conducted in 43 (Imatynib-Biofarm 100 mg film-coated tablet) and in 42 (Imatynib-Biofarm 400 mg film-coated tablet), brand name Imatenil, Caucasian healthy volunteers in fed conditions. A single oral dose administration of the test or reference product was separated by 14-day washout period. The imatinib and its metabolite N-desmethyl imatinib concentrations were determined using a validated LC MS/MS method. The results of the single-dose study in healthy volunteers indicated that the film-coated tablets of Imatynib-Biofarm 100 mg and 400 mg film-coated tablets manufactured by Biofarm Sp. z o.o. (test products) are bioequivalent to those of Glivec 100 mg and 400 mg film-coated tablets manufactured by Novartis Pharma GmbH (reference products). Both products in the two doses of imatinib were well tolerated.

  15. Generics Substitution, Bioequivalence Standards, and International Oversight: Complex Issues Facing the FDA.

    Science.gov (United States)

    Bate, Roger; Mathur, Aparna; Lever, Harry M; Thakur, Dinesh; Graedon, Joe; Cooperman, Tod; Mason, Preston; Fox, Erin R

    2016-03-01

    The regulations for assessing the quality of generic drugs and their bioequivalence to innovator products are outdated and need to be substantially modernized. There are multiple reasons why these changes are needed, including: (i) the regulations remain largely unchanged since the passage of the Hatch-Waxman Act in 1984; (ii) medication therapies have become substantially more complex over the three decades since the passage of the Act; (iii) a switch from an innovator drug to a generic drug, or switching from one generic to another, is not a benign process - there is substantial clinical professional judgment involved and in some instances these decisions should be better informed; and (iv) pharmaceutical ingredients for finished products, whether innovator or generic, are from multiple sources of supply, adding variability in their production, and which may not be accounted for in specification tolerances. When these elements are viewed together, they clearly suggest that more transparency of responsible manufacturers in product labels and updated standards for bioequivalence are required.

  16. An approximate approach to sample size determination in bioequivalence testing with multiple pharmacokinetic responses.

    Science.gov (United States)

    Tsai, Chen-An; Huang, Chih-Yang; Liu, Jen-Pei

    2014-08-30

    The approval of generic drugs requires the evidence of average bioequivalence (ABE) on both the area under the concentration-time curve and the peak concentration Cmax . The bioequivalence (BE) hypothesis can be decomposed into the non-inferiority (NI) and non-superiority (NS) hypothesis. Most of regulatory agencies employ the two one-sided tests (TOST) procedure to test ABE between two formulations. As it is based on the intersection-union principle, the TOST procedure is conservative in terms of the type I error rate. However, the type II error rate is the sum of the type II error rates with respect to each null hypothesis of NI and NS hypotheses. When the difference in population means between two treatments is not 0, no close-form solution for the sample size for the BE hypothesis is available. Current methods provide the sample sizes with either insufficient power or unnecessarily excessive power. We suggest an approximate method for sample size determination, which can also provide the type II rate for each of NI and NS hypotheses. In addition, the proposed method is flexible to allow extension from one pharmacokinetic (PK) response to determination of the sample size required for multiple PK responses. We report the results of a numerical study. An R code is provided to calculate the sample size for BE testing based on the proposed methods.

  17. Inference of bioequivalence for log-normal distributed data with unspecified variances.

    Science.gov (United States)

    Xu, Siyan; Hua, Steven Y; Menton, Ronald; Barker, Kerry; Menon, Sandeep; D'Agostino, Ralph B

    2014-07-30

    Two drugs are bioequivalent if the ratio of a pharmacokinetic (PK) parameter of two products falls within equivalence margins. The distribution of PK parameters is often assumed to be log-normal, therefore bioequivalence (BE) is usually assessed on the difference of logarithmically transformed PK parameters (δ). In the presence of unspecified variances, test procedures such as two one-sided tests (TOST) use sample estimates for those variances; Bayesian models integrate them out in the posterior distribution. These methods limit our knowledge on the extent that inference about BE is affected by the variability of PK parameters. In this paper, we propose a likelihood approach that retains the unspecified variances in the model and partitions the entire likelihood function into two components: F-statistic function for variances and t-statistic function for δ. Demonstrated with published real-life data, the proposed method not only produces results that are same as TOST and comparable with Bayesian method but also helps identify ranges of variances, which could make the determination of BE more achievable. Our findings manifest the advantages of the proposed method in making inference about the extent that BE is affected by the unspecified variances, which cannot be accomplished either by TOST or Bayesian method.

  18. BIOEQUIVALENCE STUDY OF TWO BRANDS OF PHENYTOIN SODIUM 100MG FORMULATIONS IN HEALTHY ADULT MALE RABBITS

    Directory of Open Access Journals (Sweden)

    Saroj Nepal , Suhrid Banskota , Nirmal Marasini, Biki Gupta , Shyam Prasad Lohani , Shova Basnet and Bal Mukunda Regmi*

    2013-01-01

    Full Text Available The objective of the study was to compare the bioavailability of a single oral 100 mg dose of two brands of phenytoin sodium formulations available in the Nepalese market. Formulation B was taken as test drug and compared with the innovator brand which was taken as reference standard. A randomized, two-way crossover study was done in six healthy adult male rabbits. All six rabbits received a single oral 100 mg dose of both the formulations with a two-week washout period between the formulations. Blood samples for plasma phenytoin levels were collected at 0.25, 1, 2, 4, 6, 8, 10, 12, 16, 24 hours. The pharmacokinetic parameters of the two brands of phenytoin sodium calculated were area under the concentration versus time curve from time zero to 24 hours (AUC 0–24, Area under the Curve from time zero to infinity (AUC0–∞, peak plasma concentration (Cmax and time of peak concentration (tmax. Formulation B failed to comply in terms of Area under the Curve (AUC, an important pharmacokinetic parameter to test bioequivalency, which was tested at significance level 0.05. This showed that the test formulation is not bioequivalent with the innovator. Taken together, our preliminary findings suggest that further studies in a large population is needed before switching phenytoin brands once a patient is carefully titrated to a given phenytoin brand.

  19. Percutaneous penetration of methyl nicotinate from ointments using the laser Doppler technique: bioequivalence and enhancer effects.

    Science.gov (United States)

    Remane, Yvonne; Leopold, Claudia S; Maibach, Howard I

    2006-12-01

    Laser Doppler flowmetry (LDF) may be used to quantify erythema response as a result of an increased cutaneous microcirculation induced by methyl nicotinate (MN). Bioequivalence of a test and a standard preparation (vehicles: light mineral oil and medium chain triglycerides, respectively) was confirmed according to the pilot study of the FDA Guidance for Industry "Topical dermatologic corticosteroids: In Vivo bioequivalence" applying the staggered application and synchronized removal method for one defined concentration. Furthermore, the influence of penetration enhancers (5% w/w Dimethylsulfoxide (DMSO) and 10% w/w diethylene glycol monoethyl ether) on MN penetration was investigated. It was shown that DMSO and diethylene glycol monoethyl ether altered cutaneous microcirculation and thus MN penetration in comparison to the standard formulation. However, true penetration enhancement could only be proved with diethylene glycol monoethyl ether resulting from an improved drug solubility in the skin which was confirmed by attenuated total reflectance fourier transform infrared spectroscopy (ATR-FTIR). Increased MN penetration by DMSO was only caused by thermodynamic effects, i.e. a decreased drug solubility in the vehicle.

  20. Effect of gastric emptying and entero-hepatic circulation on bioequivalence assessment of ranitidine.

    Science.gov (United States)

    Chrenova, J; Durisova, M; Mircioiu, C; Dedik, L

    2010-01-01

    The aim of study was to compare the bioavailability of ranitidine obtained from either Ranitidine (300 mg tablet; LPH® S.C. LaborMed Pharma S.A. Romania: the test formulation) and Zantac® (300 mg tablet; GlaxoSmithKline, Austria: the reference formulation). Twelve, Romanian, healthy volunteers were enrolled in the study. An open-label, two-period, crossover, randomized design was used. Plasma levels of ranitidine were determined using the validated, high-pressure liquid chromatography (HPLC) method. The physiologically motivated time-delayed model was used for the data evaluation and a paired Student's t-test and Schuirmann's two one-sided tests were carried out to compare parameters. Nonmodeling parameters (AUC(t), AUC, C(max), T(max)) were tested by the paired Student's t-test and the 90 confidence intervals of the geometric mean ratios were determined by Schuirmann's tests. Paired Student's t-test showed no significant differences between nonmodeling and modeling parameters. The results of the Schuirmann's tests however indicated significant statistical differences with reference to AUC(t), AUC, C(max), T(max) and other modeling parameters, especially MT(c) and τ(c). Schuirmann's tests revealed significant bioequivalence between ranitidine formulations using the modeling parameters MRT and n. The presented model can be useful as an additional tool to assess drug bioequivalence, by screening for disruptive parameters.

  1. Bioequivalence studies of 2 oral cefaclor capsule formulations in chinese healthy subjects.

    Science.gov (United States)

    Chen, J; Jiang, B; Lou, H; Yu, L; Ruan, Z

    2012-03-01

    An open-label, single-dose, randomized, crossover study was carried out in 20 Chinese healthy male subjects to compare the pharmacokinetics of 2 cefaclor (CAS 53994-73-3) formulations after administration of a single 250 mg dose of each drug with a 1-week wash-out period. Blood samples were collected before and with 6 h after drug administration. Plasma concentrations were determined by high-performance liquid chromatography (HPLC) with UV detector. 2 formulations were evaluated using the following pharmacokinetic parameters: AUC0-t, Cmax and tmax was analyzed nonparametrically. The 90% confidence interval (CI) of the ratios (teat/reference) of log-transformed AUC0-t and Cmax fell within the bioequivalence acceptance range of 80-125%. The results showed that the 90% CI of the ratios of AUC0-t and Cmax were 105.1% (101.0-109.4%) and 92.4% (82.5-103.4%), respectively, which therefore could conclude 2 oral cefaclor capsule formulations of cefaclor are bioequivalent. Both treatments showed similar tolerability and safety.

  2. Biopharmaceutical constants for carbamazepine immediate release tablets in simplifying bioequivalence studies

    Directory of Open Access Journals (Sweden)

    Nanayakkara Mangala

    2006-01-01

    Full Text Available Current study was undertaken in order to determine model biopharmaceutical constants for carbamazepine immediate release tablets (200 mg from documented data of plasma concentration vs time curves. The constants and the proposed methodology simplify bioequivalence determinations to blood sampling restricted only to two time points. Twelve volunteer drug plasma concentration (Cp determinations from a crossover design bioequivalence study were fitted into equations containing two rate processes. The optimized rate constants were used to generate the Cp vs time curves (generated curves. Generated curves were then differentiated (dCp/dt to obtain the first derivative curve for each volunteer from which times for highest rate of absorption (TAmaxn and highest rate of elimination (TEmaxn were determined. The corresponding highest rate of absorption and the highest rate of elimination for each individual were then obtained from the generated curve and named as Amaxn and Emaxn. Individual Amaxn and Emaxn values were then averaged to obtain the mean Amax and Emax. Out of the 24 determinations, a total of 13 Amaxn and 20 Emaxn values fell within ±20% of the overall mean. Final Amax and Emax values ware arrived at by averaging each set of individual 13 values and 20 values respectively. From these two mean coordinates, the corresponding constants, plasma drug concentration at the point of highest rate of absorption (CpAmax and corresponding time TAmax, as well as the plasma drug concentration at the point of highest rate of elimination (CpEmax and the corresponding time TEmax, were determined.

  3. Bioequivalence Studies of a Reformulated Dutasteride and Tamsulosin Hydrochloride Combination Capsule and a Commercially Available Formulation.

    Science.gov (United States)

    Kurczewski, Renee; Bowen, Chet; Collins, David; Zhu, John; Serbest, Gulyeter; Manyak, Michael

    2017-01-27

    A dutasteride 0.5 mg and tamsulosin hydrochloride 0.4 mg combination (DTC) capsule (Duodart(®) ) was reformulated to reduce the capsule size and enhance product stability. Bioequivalence of the reformulated DTC capsule with the commercial formulation was evaluated in 2 single-dose, open-label, randomized, 2-way crossover studies in healthy adult male volunteers. Subjects in a fasted or fed state received a single oral dose of either the reformulated DTC or the commercial formulation followed by a 28-day washout period between treatments. Blood samples were taken predose and up to 72 hours postdose for pharmacokinetic (PK) analysis of dutasteride and tamsulosin serum concentrations. From the serum concentration-vs-time data, a noncompartmental method was used to calculate the maximum observed serum concentration (Cmax ) and area under the serum concentration-time curve (AUC0-t ) for dutasteride and tamsulosin, and AUC0-∞ for tamsulosin. The 90% confidence intervals for the ratios of the Cmax and AUC0-t (for dutasteride and tamsulosin) and for AUC0-∞ (for tamsulosin) were all completely contained within the range of 80% to 125%; therefore, the reformulated DTC capsule is bioequivalent to the commercial formulation under both fed and fasted states.

  4. A preliminary model to avoid the overestimation of sample size in bioequivalence studies.

    Science.gov (United States)

    Ramírez, E; Abraira, V; Guerra, P; Borobia, A M; Duque, B; López, J L; Mosquera, B; Lubomirov, R; Carcas, A J; Frías, J

    2013-02-01

    Often the only available data in literature for sample size estimations in bioequivalence studies is intersubject variability, which tends to result in overestimation of sample size. In this paper, we proposed a preliminary model of intrasubject variability based on intersubject variability for Cmax and AUC data from randomized, crossovers, bioequivalence (BE) studies. From 93 Cmax and 121 AUC data from test-reference comparisons that fulfilled BE criteria, we calculated intersubject variability for the reference formulation and intrasubject variability from ANOVA. Lineal and exponential models (y=a(1-e-bx)) were fitted weighted by the inverse of the variance, to predict the intrasubject variability based on intersubject variability. To validate the model we calculated the coefficient of cross-validation of data from 30 new BE studies. The models fit very well (R2=0.997 and 0.990 for Cmax and AUC respectively) and the cross-validation correlation were 0.847 for Cmax and 0.572 for AUC. A preliminary model analyses allow us to estimate the intrasubject variability based on intersubject variability for sample size calculation purposes in BE studies. This approximation provides an opportunity for sample size reduction avoiding unnecessary exposure of healthy volunteers. Further modelling studies are desirable to confirm these results especially suggestions of the higher intersubject variability range.

  5. When are recommender systems useful?

    CERN Document Server

    Blattner, Marcel; Laureti, Paolo

    2007-01-01

    Recommender systems are crucial tools to overcome the information overload brought about by the Internet. Rigorous tests are needed to establish to what extent sophisticated methods can improve the quality of the predictions. Here we analyse a refined correlation-based collaborative filtering algorithm and compare it with a novel spectral method for recommending. We test them on two databases that bear different statistical properties (MovieLens and Jester) without filtering out the less active users and ordering the opinions in time, whenever possible. We find that, when the distribution of user-user correlations is narrow, simple averages work nearly as well as advanced methods. Recommender systems can, on the other hand, exploit a great deal of additional information in systems where external influence is negligible and peoples' tastes emerge entirely. These findings are validated by simulations with artificially generated data.

  6. Efficiently Computing Private Recommendations

    NARCIS (Netherlands)

    Erkin, Z.; Beye, M.; Veugen, P.J.M.; Lagendijk, R.L.

    2011-01-01

    Online recommender systems enable personalized service to users. The underlying collaborative filtering techniques operate on privacy sensitive user data, which could be misused by the service provider. To protect user privacy, we propose to encrypt the data and generate recommendations by processin

  7. Efficiently computing private recommendations

    NARCIS (Netherlands)

    Erkin, Z.; Beye, M.; Veugen, T.; Lagendijk, R.L.

    2011-01-01

    Online recommender systems enable personalized service to users. The underlying collaborative filtering techniques operate on privacy sensitive user data, which could be misused by the service provider. To protect user privacy, we propose to encrypt the data and generate recommendations by processin

  8. Using social ties in group recommendation

    OpenAIRE

    Bourke, Steven; McCarthy, Kevin; Smyth, Barry

    2011-01-01

    The social web is a mass of activity, petabytes of data are generated yearly. The social web has proven to be a great resource for new recommender system techniques and ideas. However it would appear that typically these techniques are not so social, as they only generate recommendations for a user acting alone. In this paper we take the social graph data and preference content (via Facebook) of 94 user study participants and generate social group recommendations for them and their friends. W...

  9. Un análisis crítico sobre las recomendaciones de actividad física en España A critical analysis of physical activity recommendations in Spain

    Directory of Open Access Journals (Sweden)

    Wojtek Jan Chodzko-Zajko

    2012-12-01

    Full Text Available Objetivo: Identificar los documentos oficiales de las comunidades autónomas en España que contengan recomendaciones sobre actividad física, para evaluar el grado de conformidad con las recomendaciones sobre actividad física para la salud de la Organización Mundial de la Salud (OMS. Métodos: Se realizó un análisis de contenido sobre 55 documentos de las consejerías de sanidad de los distintos gobiernos autonómicos que contienen recomendaciones sobre actividad física. Resultados: El 84% de las comunidades autónomas en España hacen algún tipo de recomendación sobre actividad física aeróbica y el 37% sobre fortalecimiento muscular. Sin embargo, las que tienen documentos en consonancia con los criterios de la OMS son: actividad física aeróbica (n=11, 58%, personas adultas (n=10, 53%, personas mayores (n=5, 26%, infancia/adolescentes (n=1, 5%; fortalecimiento muscular, personas adultas (n=6, 32%, personas mayores (n=3, 16%, infancia/adolescentes (n=1, 5%; equilibrio (n=5, 26%; al menos 10 minutos continuados de actividad física (n=6, 32%; recomiendan hasta 300 minutos semanales (n=10, 53%; intensidad de la actividad física (n=2, 11%. Conclusiones: Las recomendaciones hacen referencia a la actividad física aeróbica y apenas tienen en cuenta el fortalecimiento muscular. Una comunidad autónoma se ajusta a las recomendaciones de la OMS. Las comunidades con mayores índices de envejecimiento y mayor porcentaje de infancia/adolescentes casi no hacen recomendaciones sobre actividad física de acuerdo con las directrices de la OMS.Objective: To identify official documents with recommendations on physical activity published by the autonomous regions of Spain with the goal of evaluating their compliance with the physical activity recommendations of the World Health Organization (WHO. Methods: We conducted a content analysis of 55 documents of the ministries of health of several regional governments containing recommendations on physical

  10. Quantification of etodolac in human plasma for pharmacokinetics and bioequivalence studies in 27 Korean subjects.

    Science.gov (United States)

    Song, Il-Dong; Kang, Je-Seop; Kim, Hyun-Jin; Kim, Se-Mi; Zhao, Dong-Xu; Kim, Shin-Hee; Chun, Min-Young; Lee, Kyuhyun

    2017-01-16

    We developed a simple and validated liquid chromatography tandem mass spectrometry(LC-MS/MS) for quantification of etodolac using pioglitazone as an internal standard (IS) to assess pharmacokinetics and to appraise bioequivalence of two formulations of etodolac (reference and tested) in 27 healthy Korean subjects. Isocratic mobile phase consisted of 10 mM ammonium formate and acetonitrile were used to separate the analytes on a Gemini C18 column. Also, analytes were analyzed by MS/MS in multiple reaction monitoring (MRM) mode using the transitions of (M+H)+ ions, m/z 288.2→172.3 and m/z 357.1→134.2 for quantification of etodolac and IS each. The standard calibration curves displayed significant linearity within the range of 0.2-30.0 μg/mL (r2=0.9956, 1/x2 weighting) with LLOQ of 0.1 μg/mL. The retention times of etodolac and the IS were 0.77 min and 0.57 min each, indicating the high-throughput potential of the proposed method. The pharmacokinetic parameters were calculated from the plasma samples and data form the reference and test drugs were represented as follows; Area under plasma concentration-time curve (AUCt) (78.03 vs. 84.00 μg×h/mL), AUC∞ (86.67 vs. 93.92 μg×h/mL), maximal plasma concentration (Cmax) (19.49 vs. 18.94 μg/mL), time for maximal concentrations (Tmax) (2.13 vs. 2.26 h), Plasma elimination half-life (T1/2) (8.12 vs. 8.47 h), elimination rate constant (λz) (0.0853 vs. 0.0818 h-1). Pharmacokinetic parameters with 90% confidence interval fall within the bioequivalence range of 80-125%. Thus, the new testified method was successfully applied for the pharmacokinetic and bioequivalence studies for two etodolac formulations.

  11. Bioequivalence evaluation of sparse sampling pharmacokinetics data using bootstrap resampling method.

    Science.gov (United States)

    Shen, Meiyu; Machado, Stella G

    2016-12-01

    Bioequivalence studies are an essential part of the evaluation of generic drugs. The most common in vivo bioequivalence study design is the two-period two-treatment crossover design. The observed drug concentration-time profile for each subject from each treatment under each sequence can be obtained. AUC (the area under the concentration-time curve) and Cmax (the maximum concentration) are obtained from the observed drug concentration-time profiles for each subject from each treatment under each sequence. However, such a drug concentration-time profile for each subject from each treatment under each sequence cannot possibly be available during the development of generic ophthalmic products since there is only one-time point measured drug concentration of aqueous humor for each eye. Instead, many subjects will be assigned to each of several prespecified sampling times. Then, the mean concentration at each sampling time can be obtained by the simple average of these subjects' observed concentration. One profile of the mean concentration vs. time can be obtained for one product (either the test or the reference product). One AUC value for one product can be calculated from the mean concentration-time profile using trapezoidal rules. This article develops a novel nonparametric method for obtaining the 90% confidence interval for the ratio of AUCT and AUCR (or CT,max/CR,max) in crossover studies by bootstrapping subjects at each time point with replacement or bootstrapping subjects at all sampling time points with replacement. Here T represents the test product, and R represents the reference product. It also develops a novel nonparametric method for estimating the standard errors (SEs) of AUCh and Ch,max in parallel studies by bootstrapping subjects treated by the hth product at each time point with replacement or bootstrapping subjects treated by the hth product at all sampling time points with replacement, h = T, R. Then, 90% confidence intervals for AUCT/AUCR and CT

  12. Haloperidol dose when used as active comparator in randomized controlled trials with atypical antipsychotics in schizophrenia: Comparison with officially recommended doses

    NARCIS (Netherlands)

    Hugenholtz, Greg; Heerdink, E.R.; Stolker, J.J.; Meijer, W.E.E.; Egberts, A.C.G.; Nolen, W.A.

    2006-01-01

    Objective: To determine the doses of haloperidol as a comparator drug in randomized controlled trials (RCTs) with atypical antipsychotics in patients with schizophrenia and to compare these doses with the officially recommended doses for haloperidol in the United States and the United Kingdom. Data

  13. Haloperidol dose when used as active comparator in randomized controlled trials with atypical antipsychotics in schizophrenia : Comparison with officially recommended doses

    NARCIS (Netherlands)

    Hugenholtz, Gerard W. K.; Heerdink, Eibert R.; Stolker, Joost J.; Meijer, Welmoed E. E.; Egberts, Antoine C. G.; Nolen, Willem A.

    2006-01-01

    Objective: To determine the doses of haloperidol as a comparator drug in randomized controlled trials (RCTs) with atypical antipsychotics in patients with schizophrenia and to compare these doses with the officially recommended doses for haloperidol in the United States and the United Kingdom. Data

  14. Application of dermal microdialysis for the evaluation of bioequivalence of a ketoprofen topical gel

    DEFF Research Database (Denmark)

    Tettey-Amlalo, Ralph Nii Okai; Kanfer, Isadore; Skinner, Michael F

    2008-01-01

    The purpose was to investigate dermal microdialysis (DMD) for the assessment of the bioavailability of a ketoprofen topical gel formulation and to evaluate this technique as a tool for the determination of bioequivalence. Four microdialysis probes were inserted into the dermis on the volar aspect...... of the forearms of 18 human subjects and the probes were perfused with normal saline for 60 min. A ketoprofen (2.5%, m/m) gel formulation (50mg) was applied to the skin directly overlying the probes and samples were collected at 30 min intervals for 5h. With the probes still in place in the dermis each site...... was scanned by ultrasound to determine the implantation depth of these probes. Ketoprofen concentration in dialysates was determined by LC-MS/MS. The area under the curve obtained from the concentration-time profiles from pairs of application sites in each subject was evaluated in order to assess...

  15. Sampling times and genotyping concerns in bioequivalence evaluation of branded and generic formulations

    Directory of Open Access Journals (Sweden)

    Zhao XY

    2013-11-01

    Full Text Available Xiao-Ying Zhao,1 Hui-Min Xu,2 Quan Zhou2 1The Medical Ethics Committee, 2Department of Pharmacy, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People's Republic of ChinaWe read with great interest the study by Del Tacca et al,1 who performed a comparative pharmacokinetic (PK and pharmacodynamic (PD evaluation of branded and generic formulations of meloxicam in healthy male subjects, and concluded that the two products can be used interchangeably in clinical practice. We especially appreciate their exploratory study on the PD/PK relationship which provides an important reference for bioequivalence studies of analgesics. However, we found two points worthy of discussion and we would like to share our perspectives in the following paragraphs.View original paper by Del Tacca and colleagues.

  16. Current Challenges in Bioequivalence, Quality, and Novel Assessment Technologies for Topical Products

    DEFF Research Database (Denmark)

    Yacobi, Avraham; Shah, Vinod P; Bashaw, Edward D;

    2014-01-01

    topical products. The methods currently available for assessment of BE were reviewed as well as alternatives and the advantages and disadvantages of each method were considered. Guidance on quality and performance of topical products was reviewed and a framework to categorise existing and alternative......This paper summarises the proceedings of a recent workshop which brought together pharmaceutical scientists and dermatologists from academia, industry and regulatory agencies to discuss current regulatory issues and industry practices for establishing therapeutic bioequivalence (BE) of dermatologic...... of topical bioavailability. The discussion on the BE and clinical equivalence of topical products revealed considerable concerns about the variability present in the current methodologies utilized by the industry and regulatory agencies. It was proposed that academicians, researchers, the pharmaceutical...

  17. Search and Recommendation

    DEFF Research Database (Denmark)

    Bogers, Toine

    2014-01-01

    -scale application by companies like Amazon, Facebook, and Netflix. But are search and recommendation really two different fields of research that address different problems with different sets of algorithms in papers published at distinct conferences? In my talk, I want to argue that search and recommendation......In just a little over half a century, the field of information retrieval has experienced spectacular growth and success, with IR applications such as search engines becoming a billion-dollar industry in the past decades. Recommender systems have seen an even more meteoric rise to success with wide...... are more similar than they have been treated in the past decade. By looking more closely at the tasks and problems that search and recommendation try to solve, at the algorithms used to solve these problems and at the way their performance is evaluated, I want to show that there is no clear black and white...

  18. Management recommendations: Tewaukon Complex

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — This document is a review of land management practices at the Tewaukon Complex, by a land use specialist. Recommendations, time frame and additional comments are...

  19. Recommended Textbooks (Booksearch).

    Science.gov (United States)

    English Journal, 1988

    1988-01-01

    Evaluates four textbooks recommended by junior high and high school teachers for teaching writing and literature: "Enjoying Literature" (published by Macmillan, 1985); "Exposition: Critical Writing and Thinking" (Robert J. Gula); "Situational Writing" (Gene Krupa); and "Double Exposure: Composing through Writing…

  20. Bioequivalence of two formulations of montelukast sodium 4 mg oral granules in healthy adults.

    Science.gov (United States)

    Fey, Constanze; Thyroff-Friesinger, Ursula; Jones, Spencer

    2014-01-01

    Montelukast is an effective and well-tolerated treatment for the prophylaxis and chronic treatment of asthma, acute prevention of exercise-induced bronchoconstriction and symptomatic relief of seasonal allergic rhinitis and perennial allergic rhinitis. The aim of the study was to compare bioavailability, and characterise the pharmacokinetic profile and safety of Sandoz generic montelukast 4 mg oral granules relative to Singulair(®) mini (Merck, Sharp & Dohme). An open-label, randomised, single-dose, two-treatment, two-period, two-sequence, two-way crossover bioequivalence study was conducted in healthy male volunteers aged 18-55 years, under fasting conditions. The duration of the clinical part of the trial was ≈ 11 days. Montelukast levels in plasma were quantified using a validated liquid chromatography tandem mass spectrometry method, and pharmacokinetic parameters calculated from the drug concentration-time profile using a non-compartmental model. A total of 40 subjects completed both study periods. The ratio test/reference of geometric least squares means was calculated for both formulations of montelukast for the In-transformed pharmacokinetic parameters; the 90% confidence intervals (CIs) were within the pre-defined limits of 80.00-125.00%: 92.2% (90% CI: 87.42-97.30%) for Cmax, 98.1% (90% CI: 94.49-101.81%) for AUC0-t and 97.6% (90% CI: 94.14-101.27%) for AUC0-∞. Two study subjects each reported one mild adverse event: dyspepsia (possibly related to study medication) and throat pain (not considered related to study medication). Sandoz montelukast 4 mg oral granules are bioequivalent to Singulair(®) 4 mg mini oral granules, with a similar safety profile. This suggests that these two preparations can be considered interchangeable in clinical practice.

  1. Bioequivalence studies of tacrolimus capsule under fasting and fed conditions in healthy male and female subjects.

    Science.gov (United States)

    Lainesse, Audrey; Hussain, Saleh; Monif, Tausif; Reyar, Simrit; Tippabhotla, Sudhakar Koundinya; Madan, Ashish; Thudi, Nageshwar Rao

    2008-01-01

    The bioequivalence of tacrolimus (CAS 104987-11-3) 5 mg capsules was assessed in two single-dose, open-label, randomIzed 2-way crossover trials with a minimum washout period of 14 days; one trial was conducted under fasting condition (n = 44) and the other one under fed condition (n = 48). Blood samples were collected over a 120-h period and concentrations were assayed using a liquid chromatography tandem mass spectrometry (LCMS/MS) method. A non-compartmental method was used for calculation of pharmacokinetic parameters. Under fasting conditions, mean AUC(0-t), AUC(0-inf) and C(max) were comparable between the test (296 ng x h/mL, 318 ng x h/mL and 32 ng/ mL, respectively) and the reference formulations (289 ng x h/mL, 309 ng x h/mL and 33 ng/mL, respectively). T(max) was reached between 1.5 and 2 h post-dose. Mean AUC(0-t), AUC(0-inf) and C(max) were also comparable under fed conditions (154 ng x h/mL, 169 ng x h/mL and 7.6 ng/mL, respectively, for the test and 161 ng x h/mL, 176 ng x h/mL and 7.5 ng/mL, respectively, for the reference formulation). Under fed conditions, T(max) was reached between 5 and 6 h post-dose. 90% geometric confidence intervals were all within the acceptable 80-125% limit, suggesting bioequivalence between the generic product and the innovator product.

  2. Pharmacokinetics and bioequivalence studies of cefteram pivoxil in healthy Chinese volunteers.

    Science.gov (United States)

    Wei, Fangmi; Zhu, Rong; Zhao, Wenhui; Yang, Jing; Cai, Zheng; Hu, Qin

    2009-01-01

    A simple, sensitive and specific method has been developed for the determination of cefteram in human plasma. Sample preparation was accomplished through protein precipitation with 20% trichloroacetic acid (v/v) and chromatographic separation was performed on a C18 column at 25 degrees C. The mobile phase consisted of methanol-aqueous 20 mM ammonium acetate (18:82, v/v) at flow rate of 1.0 mL/min. Wavelength was set at 235 nm. The lower limit of quantification was 0.04 microg/mL and the assay exhibited a linear range of 0.04-3.2 microg/mL (r=0.9996). The relative recoveries of cefteram from human plasma at three different concentrations were more than 90%. The method was successfully applied to investigate the bioequivalence between two kinds of cefteram pivoxil preparations (test vs reference) in 24 healthy Chinese volunteers. After a single 100 mg dose for the test and reference product, the resulting means of major pharmacokinetic parameters such as AUC(0-t), AUC(0-infinity), Cmax and Tmax of cefteram pivoxil were 4.75 +/- 1.35 vs 4.76 +/- 1.29 microg h/mL, 4.89 +/- 1.36 vs 4.91 +/- 1.29 microg h/mL, 1.65 +/- 0.45 vs 1.73 +/- 0.45 microg/mL and 1.48 +/- 0.59 vs 1.73 +/- 0.45 h, respectively, indicating that these two kinds of preparations were bioequivalent.

  3. Estudo comparativo entre as metodologias preconizadas pelo CLSI e pelo EUCAST para avaliação da atividade antifúngica Comparative study of the recommended methodologies by CLSI and EUCAST for activity evaluation antifungal

    Directory of Open Access Journals (Sweden)

    Marcos Aurélio Stoppa

    2009-01-01

    Full Text Available The international organizations CLSI and EUCAST developed reference methodologies for activity evaluation antifungal. The aim of this work was to compare the recommended methodologies by the CLSI and EUCAST in the antifungal activity evaluation of crude extracts of Azadirachta indica and green propolis. The results showed that the MIC values determined by the EUCAST methodology were smaller than that determined by the CLSI. Nevertheless, both methodologies were satisfactory to detect and evaluate antifungal activity of the crude extracts and isolated compounds. The EUCAST methodology showed advantage by making possible to obtain results in less time.

  4. Probabilistic approaches to recommendations

    CERN Document Server

    Barbieri, Nicola; Ritacco, Ettore

    2014-01-01

    The importance of accurate recommender systems has been widely recognized by academia and industry, and recommendation is rapidly becoming one of the most successful applications of data mining and machine learning. Understanding and predicting the choices and preferences of users is a challenging task: real-world scenarios involve users behaving in complex situations, where prior beliefs, specific tendencies, and reciprocal influences jointly contribute to determining the preferences of users toward huge amounts of information, services, and products. Probabilistic modeling represents a robus

  5. Kernel based collaborative recommender system for -purchasing

    Indian Academy of Sciences (India)

    M K Kavitha Devi; P Venkatesh

    2010-10-01

    Recommender system a new marketing strategy plays an important role particularly in an electronic commerce environment. Among the various recommender systems, collaborative recommender system (CRS) is widely used in a number of different applications such as recommending web pages, movies, tapes and items. CRS suffers from scalability, sparsity, and cold start problems. An intelligent integrated recommendation approach using radial basis function network (RBFN) and collaborative filtering (CF), based on Cover’s theorem, is proposed in order to overcome the traditional problems of CRS. The proposed system predicts the trend by considering both likes and dislikes of the active user. The empirical evaluation results reveal that the proposed approach is more effective than other existing approaches in terms of accuracy and relevance measure of recommendations.

  6. New Insulin Delivery Recommendations.

    Science.gov (United States)

    Frid, Anders H; Kreugel, Gillian; Grassi, Giorgio; Halimi, Serge; Hicks, Debbie; Hirsch, Laurence J; Smith, Mike J; Wellhoener, Regine; Bode, Bruce W; Hirsch, Irl B; Kalra, Sanjay; Ji, Linong; Strauss, Kenneth W

    2016-09-01

    Many primary care professionals manage injection or infusion therapies in patients with diabetes. Few published guidelines have been available to help such professionals and their patients manage these therapies. Herein, we present new, practical, and comprehensive recommendations for diabetes injections and infusions. These recommendations were informed by a large international survey of current practice and were written and vetted by 183 diabetes experts from 54 countries at the Forum for Injection Technique and Therapy: Expert Recommendations (FITTER) workshop held in Rome, Italy, in 2015. Recommendations are organized around the themes of anatomy, physiology, pathology, psychology, and technology. Key among the recommendations are that the shortest needles (currently the 4-mm pen and 6-mm syringe needles) are safe, effective, and less painful and should be the first-line choice in all patient categories; intramuscular injections should be avoided, especially with long-acting insulins, because severe hypoglycemia may result; lipohypertrophy is a frequent complication of therapy that distorts insulin absorption, and, therefore, injections and infusions should not be given into these lesions and correct site rotation will help prevent them; effective long-term therapy with insulin is critically dependent on addressing psychological hurdles upstream, even before insulin has been started; inappropriate disposal of used sharps poses a risk of infection with blood-borne pathogens; and mitigation is possible with proper training, effective disposal strategies, and the use of safety devices. Adherence to these new recommendations should lead to more effective therapies, improved outcomes, and lower costs for patients with diabetes.

  7. An individual bioequivalence approach to compare the intrasubject variability of two ciclosporin formulations, SangCya and Neoral.

    Science.gov (United States)

    Canafax, D M; Irish, W D; Moran, H B; Squiers, E; Levy, R; Pouletty, P; First, M R; Christians, U

    1999-08-01

    A novel bioequivalence testing approach was used to determine intrasubject variability and switchability of two ciclosporin formulations, SangCya (test) and Neoral (reference). Twenty healthy volunteers were enrolled into a single-dose, randomized, open-label, 4-period, 2-sequence study with a crossover replicate design. Subject-by-formulation interaction variances were compared using a mixed effects linear model. Intrasubject variability for ln AUC(0-infinity) and ln C(max) of SangCya and Neoral were not significantly different. The 95% confidence intervals of the intrasubject variability of AUC(0-infinity) (0.94) and C(max) (1.28) as determined using the bootstrap nonparametric percentile method (n = 2,000) were below the individual bioequivalence limit estimated at 2.25. We concluded equivalent intrasubject variability of ciclosporin pharmacokinetics and switchability between SangCya and Neoral.

  8. A Bioequivalence Approach for Generic Narrow Therapeutic Index Drugs: Evaluation of the Reference-Scaled Approach and Variability Comparison Criterion

    OpenAIRE

    Jiang, Wenlei; Makhlouf, Fairouz; Schuirmann, Donald J.; Zhang, Xinyuan; Zheng, Nan; Conner, Dale; Yu, Lawrence X.; Lionberger, Robert

    2015-01-01

    Various health communities have expressed concerns regarding whether average bioequivalence (BE) limits (80.00–125.00%) for the 90% confidence interval of the test-to-reference geometric mean ratio are sufficient to ensure therapeutic equivalence between a generic narrow therapeutic index (NTI) drug and its reference listed drug (RLD). Simulations were conducted to investigate the impact of different BE approaches for NTI drugs on study power, including (1) direct tightening of average BE lim...

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

    Directory of Open Access Journals (Sweden)

    Bin Yang

    2017-01-01

    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.

  10. Bioavailability and bioequivalence studies in Turkey: A status report from the national registry of studies between 2008-2014

    OpenAIRE

    Toprak, Suheyla; Evirgen, Selen; Ilbars, Hilal

    2015-01-01

    Objective: To evaluate bioavailability (BA) and bioequivalence (BE) studies conducted in Turkey between January 2008 and the end of June 2014.Materials and Methods: Data on BA/BE studies collected from databases for 2008-2014 studies of Turkish Medicines and Medical Devices Agency were evaluated in terms of endpoint classification (BA/BE), allocation status (randomized/nonrandomized), blinding (open/single blind/double blind), dose (single/multiple dose), and interventional group (single grou...

  11. Dissolution efficiency and bioequivalence study using urine data from healthy volunteers: a comparison between two tablet formulations of cephalexin

    Directory of Open Access Journals (Sweden)

    Cristina Helena dos Reis Serra

    2015-06-01

    Full Text Available The aim of the present study was to assess the bioequivalence of two cephalexin tablet formulations available in the Brazilian market (product A as reference formulation and product B as test formulation. Dissolution efficiency (DE% was calculated for both formulations to evaluate their in vitrobiopharmaceutical features. The oral bioequivalence study was performed in twenty-four healthy volunteers in a crossover design. Single oral dose (tablet containing 500 mg of cephalexin of each product was administered with two weeks of washout period. Urinary concentrations of cephalexin were measured by high-performance liquid chromatography (HPLC method and pharmacokinetics parameters were estimated by urinary excretion data. The bioequivalence was determined by the following parameters: the cumulative amount of cephalexin excreted in the urine, the total amount of cephalexin excreted in the urine and the maximum urinary excretion rate of cephalexin. DE values of immediate-release cephalexin tablets (500 mg were 68.69±4.18% for product A and 71.03±6.63% for product B. Regarding the dissolution test of the two brands (A and B analysed, both were in compliance with the official pharmacopeial specifications, since the dissolution of both formulations was superior to 80% of the amount declared in the label after 45 minutes of test (A=92.09%±1.84; B=92.84%±1.08. The results obtained indicated that the products A and B are pharmaceutical equivalents. Confidence intervals for the pharmacokinetic parameters were in compliance with the international standards, indicating that products A and B can be considered bioequivalents and, therefore, interchangeable.

  12. Bioequivalence studies of film-coated tablet and chewable tablet generic formulations of montelukast in healthy volunteers.

    Science.gov (United States)

    Cánovas, Mercedes; Arcabell, Marta; Martínez, Gemma; Canals, Mirela; Cabré, Francesc

    2011-01-01

    Two studies were conducted in order to assess the bioequivalence of montelukast (CAS 151767-02-1) 10 mg film-coated tablet (FCT) and 5 mg chewable tablet (CT) test formulations in comparison with the original brands. Under fasting conditions, healthy male and female volunteers received one 10 mg FCT or 5 mg CT orally as a single dose of a test or reference formulation. Both studies were designed as open-label, randomized, two-period, two-sequence, crossover studies with a 7-day washout interval. Plasma samples were collected up to 24 h after drug administration and montelukast levels were determined by a validated LC/ MS/MS method. Pharmacokinetic parameters were calculated using non-compartmental analysis and were statistically compared by analysis of variance for test and reference formulation. Bioequivalence between products was determined by calculating 90% confidence interval of the ratio test/reference of least-square means of logarithmically transformed Cmax and AUC0-t parameters. AUC0-infinity was also analysed to obtain additional information. The calculated 90% confidence intervals for the ratios of Cmax and AUC0-t parameters were 89.33-110.52 and 92.06-109.46, respectively, in the FCT study, and 91.58-101.86 and 92.15-98.83, respectively, in the CT study, which are all within the bioequivalence acceptance range of 80-125%. Based on the results, it can be concluded that the evaluated test FCT and CT formulations are bioequivalent to their respective reference formulation in terms of rate and extent of absorption.

  13. 泛昔洛韦片在中国健康人体的生物等效性%Bioequivalence of famciclovir tablets in Chinese healthy volunteers

    Institute of Scientific and Technical Information of China (English)

    郭韶洁; 王淑民; 武峰; 李嘉静; 周辉; 赵秀丽

    2012-01-01

    目的 评价2种国产泛昔洛韦片在中国健康人体的生物等效性.方法 20名健康男性受试者随机交叉单剂量口服泛昔洛韦片试验药物或对照药物,各500 mg.用高效液相色谱法测定血浆中喷昔洛韦浓度;用DAS 2.0软件计算药代动力学参数,并对2种药物进行生物等效性评价.结果 试验药物和对照药物的药代动力学参数:Cmax分别为(2.60±0.53)和(3.50 ±0.84)mg·L-1;Tmax 分别为(0.99±0.45)和(2.50±0.23)h;t1/2分别为(2.52±0.32)和(2.50±0.23);AUC0-t分别为(9.10±1.61)和(9.61±1.70)mg·h·L-1.AUC0-t、AUC0-∞、Cmax的90%可信区间分别为90.7%~ 99.0%、90.9%~99.6%和70.4%~ 80.6%.试验药物相对于对照药物的生物利用度F为(95.29±9.85)%.结论 试验药物和对照药物生物等效.%Objective To evaluate the bioequivalent of test tablet and reference tablet of famciclovir in Chinese volunteers. Method In self -control and two - way crossover design, 20 healthy male volunteers were divided into two groups at random. Each subject was given 500 mg of the test tablet and reference tablet of famciclovir respectively at single dose. Plasma concentrations of penciclovir ( active metabolin) were determined by HPLC method. The pharmacokinetic parameters were calculated with DAS statistic software, the bioequivalent of famciclovir tablet evaluated as well. Results The main pharmacokinetic parameters of famciclovir test tablet and reference tablet were as follows: C^ ( 2. 60 ± 0. 53 ) , ( 3. 50 ±0.84) mg·L-1; Tmax,(0. 99 ±0.45), (2.50±0.23) h ; t1/2(2.52 ±0.32),(2. 50 ±0. 23) h; AUC0_t(9. 10 ±1.61), (9.61 ±1.70)mg ? H ? L~ , respectively. The relative bioavailability of famciclovir test tablet was (95. 29 ± 9. 85)% . Conclusion The test tablet and reference tablet of famciclovir were bioequivalent.

  14. A Bioequivalence Approach for Generic Narrow Therapeutic Index Drugs: Evaluation of the Reference-Scaled Approach and Variability Comparison Criterion.

    Science.gov (United States)

    Jiang, Wenlei; Makhlouf, Fairouz; Schuirmann, Donald J; Zhang, Xinyuan; Zheng, Nan; Conner, Dale; Yu, Lawrence X; Lionberger, Robert

    2015-07-01

    Various health communities have expressed concerns regarding whether average bioequivalence (BE) limits (80.00-125.00%) for the 90% confidence interval of the test-to-reference geometric mean ratio are sufficient to ensure therapeutic equivalence between a generic narrow therapeutic index (NTI) drug and its reference listed drug (RLD). Simulations were conducted to investigate the impact of different BE approaches for NTI drugs on study power, including (1) direct tightening of average BE limits and (2) a scaled average BE approach where BE limits are tightened based on the RLD's within-subject variability. Addition of a variability comparison (using a one-tailed F test) increased the difficulty for generic NTIs more variable than their corresponding RLDs to demonstrate bioequivalence. Based on these results, the authors evaluate the fully replicated, 2-sequence, 2-treatment, 4-period crossover study design for NTI drugs where the test product demonstrates BE based on a scaled average bioequivalence criterion and a within-subject variability comparison criterion.

  15. Pharmacokinetic and Bioequivalence Studies of a Newly Developed Branded Generic of Candesartan Cilexetil Tablets in Healthy Volunteers.

    Science.gov (United States)

    Patel, Rajesh; Palmer, Jonathan L; Joshi, Shashidhar; Di Ció Gimena, Alejandro; Esquivel, Florencia

    2016-10-18

    Two bioavailability/bioequivalence studies were carried out to evaluate the pharmacokinetics of candesartan cilexetil 16-mg tablet formulations. A pilot study was used to optimize the formulation and manufacturing process prior to conducting the definitive study. The pilot study was a single-dose, randomized, 2-period crossover, and the definitive study was a single-dose, randomized, 3-period, 6-sequence crossover study in healthy adults. In the pilot study the test formulation was 24% and 18% greater for Cmax and AUC, respectively, compared with the innovator product. Following optimization two 16-mg candesartan cilexetil tablet formulations were taken forward into the second bioavailability study.  Eighteen healthy fasted adult subjects were dosed with either the test formulations or the innovator. The pharmacokinetic parameters Cmax , AUC0-t , and AUC0-∞ of candesartan were investigated together with safety and tolerability. The geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for candesartan, Cmax , AUC0-t , and AUC0-∞ were within the boundary of 0.8-1.25 for one of the test formulations (formulation 2). For test formulation 3 the 90%CI of GMR for Cmax was above (133%) the upper limit of 125% for bioequivalence. Test formulation 2 was found to be bioequivalent and met internationally acceptable regulatory requirements.

  16. Fluorescence detection of tramadol in healthy Chinese volunteers by high-performance liquid chromatography and bioequivalence assessment.

    Science.gov (United States)

    Zhou, Xiao; Liu, Ji

    2015-01-01

    This study developed a revised high-performance liquid chromatography fluorescence method to determine plasma tramadol concentration, and thereby to examine the bioequivalence of two tramadol formulations among healthy male Chinese volunteers. The study used a double-blind, randomized, 2×2 crossover-design principle. Calculated pharmacokinetic parameters for both formulations were consistent with previous reports. According to the observation of vital signs and laboratory measurement, no subjects had any adverse reactions. The geometric mean ratios (90% confidence interval) of the test drug/reference drug for tramadol were 100.2% (95.3%-103.4%) for the area under the plasma concentration-time curve (AUC) from time zero to the last measurable concentration, 99.6% (94.2%-102.7%) for the AUC from administration to infinite time, and 100.8% (93.1%-106.4%) for maximum concentration. For the 90% confidence intervals of the test/reference AUC ratio and maximum concentration ratio of tramadol, both were in the acceptance range for bioequivalence. According to the two preparations by pharmacokinetic parameter statistics, the half-life, mean residence time, and clearance values showed no significant statistical differences. Therefore, the conclusion of this study was that the two tramadol formulations (tablets and capsules) were bioequivalent.

  17. Simple and Robust Analysis of Cefuroxime in Human Plasma by LC-MS/MS: Application to a Bioequivalence Study.

    Science.gov (United States)

    Hu, Xingjiang; Huang, Mingzhu; Liu, Jian; Chen, Junchun; Shentu, Jianzhong

    2014-01-01

    A simple, robust LC-MS/MS assay for quantifying cefuroxime in human plasma was developed. Cefuroxime and tazobactam, as internal standard (IS), were extracted from human plasma by methanol to precipitate protein. Separation was achieved on a Zorbax SB-Aq (4.6 × 250 mm, 5  μ m) column under isocratic conditions. The calibration curve was linear in the concentration range of 0.0525-21.0  μ g/mL (r = 0.9998). The accuracy was higher than 90.92%, while the intra- and interday precision were less than 6.26%. The extraction procedure provides recovery ranged from 89.44% to 92.32%, for both analyte and IS. Finally, the method was successfully applied to a bioequivalence study of a single 500 mg dose of cefuroxime axetil in 22 healthy Chinese male subjects under fasting condition. Bioequivalence was determined by calculating 90% Cls for the ratios of C max, AUC0-t , and AUC0-∞ values for the test and reference products, using logarithmic transformed data. The 90% Cls for the ratios of C max (91.4%~104.2%), AUC0-t (97.4%~110.9%), and AUC0-∞ (97.6%~111.1%) values were within the predetermined range. It was concluded that the two formulations (test for capsule, reference for tablet) analyzed were bioequivalent in terms of rate and extent of absorption and the method met the principle of quick and easy clinical analysis.

  18. Saliva vs. plasma bioequivalence of metformin in humans: validation of class II drugs of the salivary excretion classification system.

    Science.gov (United States)

    Idkaidek, N; Arafat, T

    2014-11-01

    To study saliva and plasma bioequivalence of metformin in humans, and to investigate the robustness of using saliva instead of plasma as surrogate for bioequivalence of class II drugs according to the salivary excretion classification system (SECS).Plasma and saliva samples were collected for 12 h after 500 mg oral dosing of metformin to 16 healthy humans. Plasma and saliva pharmacokinetic parameters, 90% confidence intervals and intra-subject variability values were calculated using Kinetica V5. Descriptive statistics and dimensional analysis were calculated by Excel. SimCYP program V13 was used for estimation of effective intestinal permeability.Metformin was subjected to salivary excretion since it falls into class II (Low permeability/High fraction unbound to plasma proteins), with correlation coefficients of 0.95-0.99 between plasma and saliva concentrations. Saliva/plasma concentration ratios were 0.29-0.39. The 90% confidence limits of all parameters failed in both saliva and plasma. Intra-subject variability values in saliva were higher than plasma leading to need for higher number of subjects to be used in saliva.Saliva instead of plasma can be used as surrogate for bioequivalence of class II drugs according to SECS when adequate sample size is used. Future work is planned to demonstrate SECS robustness in drugs that fall into class III.

  19. Distributed Deliberative Recommender Systems

    Science.gov (United States)

    Recio-García, Juan A.; Díaz-Agudo, Belén; González-Sanz, Sergio; Sanchez, Lara Quijano

    Case-Based Reasoning (CBR) is one of most successful applied AI technologies of recent years. Although many CBR systems reason locally on a previous experience base to solve new problems, in this paper we focus on distributed retrieval processes working on a network of collaborating CBR systems. In such systems, each node in a network of CBR agents collaborates, arguments and counterarguments its local results with other nodes to improve the performance of the system's global response. We describe D2ISCO: a framework to design and implement deliberative and collaborative CBR systems that is integrated as a part of jcolibritwo an established framework in the CBR community. We apply D2ISCO to one particular simplified type of CBR systems: recommender systems. We perform a first case study for a collaborative music recommender system and present the results of an experiment of the accuracy of the system results using a fuzzy version of the argumentation system AMAL and a network topology based on a social network. Besides individual recommendation we also discuss how D2ISCO can be used to improve recommendations to groups and we present a second case of study based on the movie recommendation domain with heterogeneous groups according to the group personality composition and a group topology based on a social network.

  20. Using a single tablet daily to treat latent tuberculosis infection in Brazil: bioequivalence of two different isoniazid formulations (300 mg and 100 mg demonstrated by a sensitive and rapid high-performance liquid chromatography-tandem mass spectrometry method in a randomised, crossover study

    Directory of Open Access Journals (Sweden)

    André Daher

    2015-06-01

    Full Text Available The recommended treatment for latent tuberculosis (TB infection in adults is a daily dose of isoniazid (INH 300 mg for six months. In Brazil, INH was formulated as 100 mg tablets. The treatment duration and the high pill burden compromised patient adherence to the treatment. The Brazilian National Programme for Tuberculosis requested a new 300 mg INH formulation. The aim of our study was to compare the bioavailability of the new INH 300 mg formulation and three 100 mg tablets of the reference formulation. We conducted a randomised, single dose, open label, two-phase crossover bioequivalence study in 28 healthy human volunteers. The 90% confidence interval for the INH maximum concentration of drug observed in plasma and area under the plasma concentration vs. time curve from time zero to the last measurable concentration “time t” was 89.61-115.92 and 94.82-119.44, respectively. The main limitation of our study was that neither adherence nor the safety profile of multiple doses was evaluated. To determine the level of INH in human plasma, we developed and validated a sensitive, simple and rapid high-performance liquid chromatography-tandem mass spectrometry method. Our results showed that the new formulation was bioequivalent to the 100 mg reference product. This finding supports the use of a single 300 mg tablet daily strategy to treat latent TB. This new formulation may increase patients’ adherence to the treatment and quality of life.

  1. Estimating Probabilities in Recommendation Systems

    OpenAIRE

    Sun, Mingxuan; Lebanon, Guy; Kidwell, Paul

    2010-01-01

    Recommendation systems are emerging as an important business application with significant economic impact. Currently popular systems include Amazon's book recommendations, Netflix's movie recommendations, and Pandora's music recommendations. In this paper we address the problem of estimating probabilities associated with recommendation system data using non-parametric kernel smoothing. In our estimation we interpret missing items as randomly censored observations and obtain efficient computat...

  2. Order Theoretical Semantic Recommendation

    Energy Technology Data Exchange (ETDEWEB)

    Joslyn, Cliff A.; Hogan, Emilie A.; Paulson, Patrick R.; Peterson, Elena S.; Stephan, Eric G.; Thomas, Dennis G.

    2013-07-23

    Mathematical concepts of order and ordering relations play multiple roles in semantic technologies. Discrete totally ordered data characterize both input streams and top-k rank-ordered recommendations and query output, while temporal attributes establish numerical total orders, either over time points or in the more complex case of startend temporal intervals. But also of note are the fully partially ordered data, including both lattices and non-lattices, which actually dominate the semantic strcuture of ontological systems. Scalar semantic similarities over partially-ordered semantic data are traditionally used to return rank-ordered recommendations, but these require complementation with true metrics available over partially ordered sets. In this paper we report on our work in the foundations of partial order measurement in ontologies, with application to top-k semantic recommendation in workflows.

  3. Archetypal Game Recommender Systems

    DEFF Research Database (Denmark)

    Sifa, Rafet; Bauckhage, C.; Drachen, Anders

    2014-01-01

    feedback are presented: factor- and neighborhood-oriented models. These form the rst application of rec- ommender systems to digital games. Both models are tested on a dataset of 500,000 users of the game distribution platform Steam, covering game ownership and playtime data across more than 3000 games....... Compared to four other recommender models (nearest neighbor, two popularity mod- els, random baseline), the archetype based models provide the highest recall rates showing that Archetypal Analysis can be successfully applied for Top-L recommendation purposes...

  4. A perspective for biowaivers of human bioequivalence studies on the basis of the combination of the ratio of AUC to the dose and the biopharmaceutics classification system.

    Science.gov (United States)

    Sakuma, Shinji; Tachiki, Hidehisa; Uchiyama, Hitoshi; Fukui, Yasunobu; Takeuchi, Naohiro; Kumamoto, Kazuo; Satoh, Tomonori; Yamamoto, Yoshinobu; Ishii, Emi; Sakai, Yoshiyuki; Takeuchi, Susumu; Sugita, Masaru; Yamashita, Shinji

    2011-08-01

    The ratio of AUC to the dose (AUC/dose) was previously found as a parameter that predicts a risk of bioinequivalence of oral drug products. On the basis of the combination of this parameter and the biopharmaceutics classification system (BCS), a perspective for biowaivers of human bioequivalence studies is discussed. Databases of bioequivalence studies using immediate-release solid oral dosage forms were disclosed by 6 Japanese generic pharmaceutical companies, and the number of subjects required for demonstrating bioequivalence between generic and reference products was plotted as a function of AUC/dose for each BCS category. A small variation in the number of subjects was constantly observed in bioequivalence studies using dosage forms containing an identical BCS class 1 or class 3 drug, even though formulations of the generic product differ between companies. The variation was extremely enlarged when the drugs were substituted with BCS class 2 drugs. Rate-determining steps in oral absorption of highly water-soluble BCS class 1 and class 3 drugs are independent of formulations when there is no significant difference in the in vitro dissolution profiles between formulations. The small variation observed for both BCS categories indicates that the number of subjects converges into one value for each drug. Our analysis indicates the appropriateness of biowaiver of bioequivalence studies for immediate-release solid oral dosage forms containing not only BCS class 1 drugs but also class 3 drugs.

  5. OARSI Clinical Trials Recommendations

    DEFF Research Database (Denmark)

    Emery, C. A.; Roos, Ewa M.; Verhagen, E.;

    2015-01-01

    The risk of post-traumatic osteoarthritis (PTOA) substantially increases following joint injury. Research efforts should focus on investigating the efficacy of preventative strategies in high quality randomized controlled trials (RCT). The objective of these OARSI RCT recommendations is to inform...

  6. Privacy in recommender systems

    NARCIS (Netherlands)

    Jeckmans, Arjan; Beye, Michael; Erkin, Zekeriya; Hartel, Pieter; Lagendijk, Reginald; Tang, Qiang; Ramzan, Naeem; Zwol, van Roelof; Lee, Jong-Seok; Clüver, Kai; Hua, Xian-Sheng

    2013-01-01

    In many online applications, the range of content that is offered to users is so wide that a need for automated recommender systems arises. Such systems can provide a personalized selection of relevant items to users. In practice, this can help people find entertaining movies, boost sales through ta

  7. Towards Geosocial Recommender Systems

    NARCIS (Netherlands)

    Graaff, de Victor; Keulen, van Maurice; By, de Rolf A.

    2012-01-01

    The usage of social networks sites (SNSs), such as Facebook, and geosocial networks (GSNs), such as Foursquare, has increased tremendously over the past years. The willingness of users to share their current locations and experiences facilitate the creation of geographical recommender systems based

  8. Analysis of Intra- and Intersubject Variability in Oral Drug Absorption in Human Bioequivalence Studies of 113 Generic Products.

    Science.gov (United States)

    Sugihara, Masahisa; Takeuchi, Susumu; Sugita, Masaru; Higaki, Kazutaka; Kataoka, Makoto; Yamashita, Shinji

    2015-12-07

    In this study, the data of 113 human bioequivalence (BE) studies of immediate release (IR) formulations of 74 active pharmaceutical ingredients (APIs) conducted at Sawai Pharmaceutical Co., Ltd., was analyzed to understand the factors affecting intra- and intersubject variabilities in oral drug absorption. The ANOVA CV (%) calculated from area under the time-concentration curve (AUC) in each BE study was used as an index of intrasubject variability (Vintra), and the relative standard deviation (%) in AUC was used as that of intersubject variability (Vinter). Although no significant correlation was observed between Vintra and Vinter of all drugs, Vintra of class 3 drugs was found to increase in association with a decrease in drug permeability (P(eff)). Since the absorption of class 3 drugs was rate-limited by the permeability, it was suggested that, for such drugs, the low P(eff) might be a risk factor to cause a large intrasubject variability. To consider the impact of poor water solubility on the variability in BE study, a parameter of P(eff)/Do (Do; dose number) was defined to discriminate the solubility-limited and dissolution-rate-limited absorption of class 2 drugs. It was found that the class 2 drugs with a solubility-limited absorption (P(eff)/Do < 0.149 × 10(-4) cm/s) showed high intrasubject variability. Furthermore, as a reason for high intra- or intersubject variability in AUC for class 1 drugs, effects of drug metabolizing enzymes were investigated. It was demonstrated that intrasubject variability was high for drugs metabolized by CYP3A4 while intersubject variability was high for drugs metabolized by CYP2D6. For CYP3A4 substrate drugs, the Km value showed the significant relation with Vintra, indicating that the affinity to the enzyme can be a parameter to predict the risk of high intrasubject variability. In conclusion, by analyzing the in house data of human BE study, low permeability, solubility-limited absorption, and high affinity to CYP3A4 are

  9. Quantitation of niflumic acid in human plasma by high-performance liquid chromatography with ultraviolet absorbance detection and its application to a bioequivalence study of talniflumate tablets.

    Science.gov (United States)

    Lee, H W; Won, K J; Cho, S H; Ha, Y H; Park, W S; Yim, H T; Baek, M; Rew, J H; Yoon, S H; Yim, S V; Chung, J H; Lee, K T

    2005-07-25

    A rapid and simple HPLC method with UV detection (288 nm) was developed and validated for quantitation of niflumic acid in human plasma, the active metabolite of talniflumate. After precipitation with 100% methanol containing the internal standard, indomethacin, the analysis of the niflumic acid level in the plasma samples was carried out using a reverse phase C18 CAPCELL PAK (5 microm, 4.6 mm x 250 mm) column. The chromatographic separation was accomplished with an isocratic mobile phase consisting of a mixture of 0.1M sodium acetate in water and acetonitrile (37:63, v/v), adjusted to pH 6.4. This HPLC method was validated by examining its precision and accuracy for inter- and intra-day runs in a linear concentration range of 0.02-5.00 microg/mL. Stability of niflumic acid in plasma was excellent, with no evidence of degradation during sample processing (autosampler) and 30 days storage in a freezer. This validated method was successfully applied to the bioequivalence study of talniflunate in healthy volunteers.

  10. Validated ion pair liquid chromatography/fluorescence detection method for assessing the variability of the loratadine metabolism occurring in bioequivalence studies.

    Science.gov (United States)

    Sora, Daniela Iuliana; Udrescu, Stefan; David, Victor; Medvedovici, Andrei

    2007-10-01

    Inter- and intra-individual variability of the loratadine (LOR) metabolism in Caucasian subjects was assessed during a bioequivalence study for two pharmaceutical formulations (solid oral dosage forms) containing 10 mg of the active substance. The analytical data were obtained by applying a reliable, low-cost and sensitive ion pair liquid chromatography/fluorescence (IPLC/FLD) method for determination of both loratadine and descarboethoxyloratadine (DCL) in human plasma samples. The sample preparation procedure is based on liquid-liquid extraction of the target analytes from alkalinized plasma using diethyl-ether. The separation of the analytes and 8-chloroazatadine as internal standard (IS) was achieved through an isocratic ion pair (IP) elution on a Purospher((R)) STAR RP-18 column. The mobile phase containing sodium dodecyl sulfate (SDS) as ion pairing agent was pumped at a flow rate of 1 mL/min. Fluorescence detection (FLD) was achieved at 280 nm (excitation) and 440 nm (emission) wavelengths. The increased sensitivity of the method is also based on a large sample injected volume (250 microL). Linear response was found over the 0.5-20 ng/mL concentration interval for both target compounds. Low limits of quantification (LLOQ) around 0.3 ng/mL were found for LOR and DCL. Method validation is presented.

  11. No time for the gym? Housework and other non-labor market time use patterns are associated with meeting physical activity recommendations among adults in full-time, sedentary jobs.

    Science.gov (United States)

    Smith, Lindsey P; Ng, Shu Wen; Popkin, Barry M

    2014-11-01

    Physical activity and inactivity have distinct cardio-metabolic consequences, suggesting that combinations of activities can impact health above and beyond the effects of a single activity. However, little work has examined patterns of non-labor market time activity in the US population, particularly among full-time employees in sedentary occupations, who are at increased risk of adverse health consequences associated with a sedentary lifestyle. Identification of these patterns, and how they are related to total physical activity levels, is important for developing effective, attainable physical activity recommendations among sedentary employees, who typically have less time available for exercise. This is especially the case for low-income employees who face the highest time and financial barriers to achieving physical activity goals. This study uses cluster analysis to examine patterns of non-labor market time use among full-time (≥40 h/week) employed adults in sedentary occupations (improve physical activity among similarly sedentary groups. Alternately, non-labor market time use patterns characterized by housework and caregiving represented feasible avenues for increasing overall physical activity levels, especially for those with low financial and time resources. Consideration of non-labor market time use patterns may improve strategies to increase physical activity and decrease inactivity among full-time employed adults in sedentary jobs.

  12. Bioequivalence study of a generic Risperidone (Iperdal® in healthy Thai male volunteers

    Directory of Open Access Journals (Sweden)

    Werawath Mahatthanatrakul

    2008-05-01

    Full Text Available The objective of this study was to compare the rate and extent of absorption of a generic risperidone (Iperdal® with a reference formulation (Risperdal® when given orally. The study was an open label, randomized, two-period, two-sequence,single dose cross-over design with a 2 weeks washout period in 16 healthy Thai male volunteers. Single oral dose of two 2-mg tablets of risperidone were administered and serial blood samples were collected from the antecubital vein before and at0.17, 0.33, 0.5, 0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 12, 24 and 48 hours post dose. Risperidone plasma concentrations were assayed using a validated High Performance Liquid Chromatographic (HPLC-UV method modified from Avenosoet al. (2000. Pharamcokinetic parameters i.e. Cmax, AUC0à48 and Tmax were analyzed by noncompartment analysis. Variations of the data were analyzed by “Two Way Analysis of Variance” (ANOVA. Statistics were tested as stated in USP 28 guidelinefor bioequivalence study. The maximum concentration (Cmax, ng/ml of risperidone for the innovator and the generic product were 31.11±17.24 (range 5.64-56.78 and 32.58±19.77 (range 5.29-84.56 ng/ml, respectively. The area under theplasma concentration-time curve (AUC0®48 of the innovator and the generic product were 160.64±152.89 (range 18.57- 550.32 and 144.03±127.37 (range 16.27-456.0 ng.hr/ml, respectively. The time to maximum concentration (Tmax of theinnovator and the generic product were 0.97±0.41(range 0.5-2 and 1.02±0.32 (range 0.5-1.5 hr, respectively. The 90% confidence interval of the ratio of the ln-transformed of Cmax and AUC0à48 of both preparations were 89.39-112.99% and80.02-107.28% respectively which were within the acceptance range of 80.00-125.00%. Therefore, it can be concluded that both preparations used in this study are bioequivalent in terms of both the rate and extent of absorption.

  13. Bioequivalence Study of Two Long-Acting Formulations of Oxytetracycline Following Intramuscular Administration in Bovines.

    Science.gov (United States)

    Mestorino, Nora; Marchetti, María Laura; Lucas, Mariana Florencia; Modamio, Pilar; Zeinsteger, Pedro; Fernández Lastra, Cecilia; Segarra, Ignacio; Mariño, Eduardo Luis

    2016-01-01

    The aim of this study was to evaluate the bioequivalence of two commercial long-acting formulations based on oxytetracycline (OTC) hydrochloride between the reference formulation (Terramycin LA, Pfizer) and a test formulation (Cyamicin LA, Fort Dodge Saude Animal). Both formulations were administered in a single intramuscular route at a dose of 20 mg OTC/kg of body weight in clinically healthy bovines. The study was carried out according to a one-period parallel design. Plasma samples were analyzed by high-pressure liquid chromatography. The limit of quantitation was 0.050 μg/mL with an accuracy of 101.67% with a coefficient of variation of 13.15%. Analysis of variance and 90% confidence interval tests were used to compare the bioavailability parameters (maximum plasma concentration, C max, and the area under the concentration-versus-time curve extrapolated to infinity, AUC0-∞) of both products. In the case of the time to maximum concentration (T max), non-parametric tests based on Wilcoxon's signed rank test were preferred. The comparison of the mean AUC0-∞ values did not reveal any significant differences (311.40 ± 93.05 μg h/mL and 287.71 ± 45.31 μg h/mL, respectively). The results were similar for the T max (3.58 ± 0.90 h versus 3.42 ± 0.51 h). However, when comparing the mean C max some significant differences were found (8.73 ± 3.66 μg/mL and 10.43 ± 3.84 μg/mL, respectively). The 90% confidence intervals for the ratio of AUC0-∞ and T max values for the reference and test product are within the interval 80-125%, but the 90% confidence intervals for the ratio of C max falls outside the proposed interval. It was concluded that C max of test product are not within the 20% of those of the reference, thus suggesting that test OTC is not bioequivalent to the reference formulation.

  14. Bioequivalence Study of Two Long-Acting Formulations of Oxytetracycline Following Intramuscular Administration in Bovines

    Science.gov (United States)

    Mestorino, Nora; Marchetti, María Laura; Lucas, Mariana Florencia; Modamio, Pilar; Zeinsteger, Pedro; Fernández Lastra, Cecilia; Segarra, Ignacio; Mariño, Eduardo Luis

    2016-01-01

    The aim of this study was to evaluate the bioequivalence of two commercial long-acting formulations based on oxytetracycline (OTC) hydrochloride between the reference formulation (Terramycin LA, Pfizer) and a test formulation (Cyamicin LA, Fort Dodge Saude Animal). Both formulations were administered in a single intramuscular route at a dose of 20 mg OTC/kg of body weight in clinically healthy bovines. The study was carried out according to a one-period parallel design. Plasma samples were analyzed by high-pressure liquid chromatography. The limit of quantitation was 0.050 μg/mL with an accuracy of 101.67% with a coefficient of variation of 13.15%. Analysis of variance and 90% confidence interval tests were used to compare the bioavailability parameters (maximum plasma concentration, Cmax, and the area under the concentration-versus-time curve extrapolated to infinity, AUC0–∞) of both products. In the case of the time to maximum concentration (Tmax), non-parametric tests based on Wilcoxon’s signed rank test were preferred. The comparison of the mean AUC0–∞ values did not reveal any significant differences (311.40 ± 93.05 μg h/mL and 287.71 ± 45.31 μg h/mL, respectively). The results were similar for the Tmax (3.58 ± 0.90 h versus 3.42 ± 0.51 h). However, when comparing the mean Cmax some significant differences were found (8.73 ± 3.66 μg/mL and 10.43 ± 3.84 μg/mL, respectively). The 90% confidence intervals for the ratio of AUC0–∞ and Tmax values for the reference and test product are within the interval 80–125%, but the 90% confidence intervals for the ratio of Cmax falls outside the proposed interval. It was concluded that Cmax of test product are not within the 20% of those of the reference, thus suggesting that test OTC is not bioequivalent to the reference formulation. PMID:27446938

  15. Implementation of a reference-scaled average bioequivalence approach for highly variable generic drug products by the US Food and Drug Administration.

    Science.gov (United States)

    Davit, Barbara M; Chen, Mei-Ling; Conner, Dale P; Haidar, Sam H; Kim, Stephanie; Lee, Christina H; Lionberger, Robert A; Makhlouf, Fairouz T; Nwakama, Patrick E; Patel, Devvrat T; Schuirmann, Donald J; Yu, Lawrence X

    2012-12-01

    Highly variable (HV) drugs are defined as those for which within-subject variability (%CV) in bioequivalence (BE) measures is 30% or greater. Because of this high variability, studies designed to show whether generic HV drugs are bioequivalent to their corresponding HV reference drugs may need to enroll large numbers of subjects even when the products have no significant mean differences. To avoid unnecessary human testing, the US Food and Drug Administration's Office of Generic Drugs developed a reference-scaled average bioequivalence (RSABE) approach, whereby the BE acceptance limits are scaled to the variability of the reference product. For an acceptable RSABE study, an HV generic drug product must meet the scaled BE limit and a point estimate constraint. The approach has been implemented successfully. To date, the RSABE approach has supported four full approvals and one tentative approval of HV generic drug products.

  16. Rheumatologic rehabilitation: towards recommendations

    Directory of Open Access Journals (Sweden)

    S. Maddali Bongi

    2014-11-01

    Full Text Available Rheumatic patients are highly complex and often affected by chronic diseases. Rehabilitation is generally needed for proper management of the underlying disease. This article describes the characteristics of an effective rheumatologic rehabilitation, takes into account data published in international literature, suggests recommendations based on scientific evidence to develop a correct rehabilitation plan for rheumatic patients and proposes the basis to draw up guidelines in the field of rheumatologic rehabilitation.

  17. Australians are not Meeting the Recommended Intakes for Omega-3 Long Chain Polyunsaturated Fatty Acids: Results of an Analysis from the 2011–2012 National Nutrition and Physical Activity Survey

    Directory of Open Access Journals (Sweden)

    Barbara J. Meyer

    2016-02-01

    Full Text Available Health benefits have been attributed to omega-3 long chain polyunsaturated fatty acids (n-3 LCPUFA. Therefore it is important to know if Australians are currently meeting the recommended intake for n-3 LCPUFA and if they have increased since the last National Nutrition Survey in 1995 (NNS 1995. Dietary intake data was obtained from the recent 2011–2012 National Nutrition and Physical Activity Survey (2011–2012 NNPAS. Linoleic acid (LA intakes have decreased whilst alpha-linolenic acid (LNA and n-3 LCPUFA intakes have increased primarily due to n-3 LCPUFA supplements. The median n-3 LCPUFA intakes are less than 50% of the mean n-3 LCPUFA intakes which highlights the highly-skewed n-3 LCPUFA intakes, which shows that there are some people consuming high amounts of n-3 LCPUFA, but the vast majority of the population are consuming much lower amounts. Only 20% of the population meets the recommended n-3 LCPUFA intakes and only 10% of women of childbearing age meet the recommended docosahexaenoic acid (DHA intake. Fish and seafood is by far the richest source of n-3 LCPUFA including DHA.

  18. Australians are not Meeting the Recommended Intakes for Omega-3 Long Chain Polyunsaturated Fatty Acids: Results of an Analysis from the 2011-2012 National Nutrition and Physical Activity Survey.

    Science.gov (United States)

    Meyer, Barbara J

    2016-02-24

    Health benefits have been attributed to omega-3 long chain polyunsaturated fatty acids (n-3 LCPUFA). Therefore it is important to know if Australians are currently meeting the recommended intake for n-3 LCPUFA and if they have increased since the last National Nutrition Survey in 1995 (NNS 1995). Dietary intake data was obtained from the recent 2011-2012 National Nutrition and Physical Activity Survey (2011-2012 NNPAS). Linoleic acid (LA) intakes have decreased whilst alpha-linolenic acid (LNA) and n-3 LCPUFA intakes have increased primarily due to n-3 LCPUFA supplements. The median n-3 LCPUFA intakes are less than 50% of the mean n-3 LCPUFA intakes which highlights the highly-skewed n-3 LCPUFA intakes, which shows that there are some people consuming high amounts of n-3 LCPUFA, but the vast majority of the population are consuming much lower amounts. Only 20% of the population meets the recommended n-3 LCPUFA intakes and only 10% of women of childbearing age meet the recommended docosahexaenoic acid (DHA) intake. Fish and seafood is by far the richest source of n-3 LCPUFA including DHA.

  19. Recommending Given Names

    CERN Document Server

    Mitzlaff, Folke

    2013-01-01

    All over the world, future parents are facing the task of finding a suitable given name for their child. This choice is influenced by different factors, such as the social context, language, cultural background and especially personal taste. Although this task is omnipresent, little research has been conducted on the analysis and application of interrelations among given names from a data mining perspective. The present work tackles the problem of recommending given names, by firstly mining for inter-name relatedness in data from the Social Web. Based on these results, the name search engine "Nameling" was built, which attracted more than 35,000 users within less than six months, underpinning the relevance of the underlying recommendation task. The accruing usage data is then used for evaluating different state-of-the-art recommendation systems, as well our new \\NR algorithm which we adopted from our previous work on folksonomies and which yields the best results, considering the trade-off between prediction ...

  20. Helping Clinicians Prevent Pregnancy among Sexually Active Adolescents: U.S. Medical Eligibility Criteria for Contraceptive Use and U.S. Selected Practice Recommendations for Contraceptive Use.

    Science.gov (United States)

    Godfrey, Emily M

    2015-08-01

    The United States has made substantial progress in reducing teenage birth rates in recent decades, but rates remain high. Teen pregnancy can increase the risk of poor health outcomes and lead to decreased educational attainment, increased poverty, and welfare use, as well as increased cost to taxpayers. One of the most effective ways to prevent teenage pregnancy is through the use of effective birth control methods. The Centers for Disease Control (CDC) and Prevention has made the prevention of teenage pregnancy 1 of its 10 winnable battles. The CDC has released 2 evidence-based clinical guideline documents regarding contraceptive use for adolescents and adults. The first guideline, US Medical Eligibility Criteria for Contraceptive Use, 2010, helps clinicians recognize when a contraceptive method may not be safe to use for a particular adolescent but also when not to withhold a contraceptive method that is safe to use. The second document, US Selected Practice Recommendations for Contraceptive Use, 2013, provides guidance for how to use contraceptive methods safely and effectively once they are deemed safe. Health care providers are encouraged to use these documents to provide safe and effective contraceptive care to patients seeking family planning, including adolescents.

  1. Estimating Probabilities in Recommendation Systems

    CERN Document Server

    Sun, Mingxuan; Kidwell, Paul

    2010-01-01

    Recommendation systems are emerging as an important business application with significant economic impact. Currently popular systems include Amazon's book recommendations, Netflix's movie recommendations, and Pandora's music recommendations. In this paper we address the problem of estimating probabilities associated with recommendation system data using non-parametric kernel smoothing. In our estimation we interpret missing items as randomly censored observations and obtain efficient computation schemes using combinatorial properties of generating functions. We demonstrate our approach with several case studies involving real world movie recommendation data. The results are comparable with state-of-the-art techniques while also providing probabilistic preference estimates outside the scope of traditional recommender systems.

  2. Rapid LC-MS/MS method for determination of drotaverine in a bioequivalence study.

    Science.gov (United States)

    Vancea, Szende; Gáll, Zsolt; Donáth-Nagy, Gabriella; Borka-Balás, Réka

    2014-09-01

    A liquid chromatography coupled with tandem mass spectrometry method for the quantification of the antispasmodic drug drotaverine in human plasma was developed and validated according to the current bioanalytical guidelines. The internal standard used was imipramine. The separation was performed on a Kinetex C18 50×3mm, 2.6μm column under isocratic conditions using a mobile phase of 65:35 (v/v) formic acid 0.2% (v/v) in water and acetonitrile at 40°C with a flow rate of 0.4ml/min. The detection of drotaverine and the internal standard was performed in multiple reaction monitoring (MRM) mode using an ion trap mass spectrometer with electrospray ionization, operating in positive mode. The human plasma samples (0.24ml) were deproteinized with methanol and aliquots of 4μl from supernatants obtained after centrifugation were directly injected into the chromatographic system. The method shows a good linearity (r(2)>0.997), precision (CVdrotaverine in plasma. The recovery was between 91 and 98%. The limit of quantification was 2.24ng/ml. The analysis required only a 3.0min run. The developed and validated method for the determination of drotaverine in human plasma was successfully applied in a bioequivalence study, for analyzing approximately 1000 subject's samples.

  3. Application of liquid chromatography method with electrochemical detection for bioequivalence study of trimetazidine in human plasma.

    Science.gov (United States)

    Grabowski, Tomasz; Swierczewska, Anna; Borucka, Beata; Sawicka, Renata; Sasinowska-Motyl, Małgorzata; Gumułka, Stanisław Witold

    2012-01-01

    A method to estimate trimetazidine (CAS: 13171-25-0) levels in human plasma by means of HPLC with electrochemical detection was developed. Trimethoprim (CAS: 26807-65-8) was used as an internal standard. This method of analysis was fully validated according to the guidelines of the United States Food and Drug Administration, European Medicines Agency and Organization for Economic Co-operation and Development and Good Laboratory Practice rules. The accuracy and precision of the developed method were found to be satisfactory and stability studies showed acceptable variation (below 15%) of trimetazidine concentrations when samples were stored frozen at -75 degrees C for 54 days. The developed method was successfully used for a comparative 2 x 2 period, crossover bioequivalence study of two extended-release preparations of trimetazidine performed on 24 healthy volunteers at the steady state after multiple dosing of 35 mg twice daily for 4 days and a single 35 mg dose on the 5th day and after a single dose of 35 mg under fasting or postprandial conditions.

  4. Theoretical Investigation of Dissolution Test Criteria for Waiver of Clinical Bioequivalence Study.

    Science.gov (United States)

    Sugano, Kiyohiko

    2016-06-01

    The purpose of the present study was to provide a theoretical basis for the dissolution test criteria of a biowaiver scheme. The critical dissolution number (Dncrit) was defined as a value to show bioequivalence of AUC and Cmax against infinitely rapid dissolution (Dn = ∞). The gastrointestinal tract was represented by the one-compartment model. The dissolution of a drug was expressed by the Noyes-Whitney equation. The permeation of a drug was expressed by the first-order equation. The approximate analytical solutions of Dncrit were derived from the analytical solution for the fraction of a dose absorbed [Fa = 1 - exp(-1/(1/Dn + Do/Pn)]; Do, the dose number; Pn, the permeation number). Numerical integration was also performed to calculate Dncrit more accurately. Dncrit was found to become smaller as Pn and Do became smaller. Dncrit for Cmax was found to be dependent on the elimination half-life of a drug as well as Pn and Do. The Fa equation can be an appropriate theoretical basis for a biowaiver scheme.

  5. A bioequivalency study of two trifluoperazine tablet formulations using RIA and GC-MS.

    Science.gov (United States)

    Midha, K K; Hawes, E M; Korchinski, E D; Hubbard, J W; McKay, G; Cooper, J K; Roscoe, R M

    1984-01-01

    Two sensitive analytical procedures, a radioimmunoassay (RIA) and a mass fragmentographic (GC-MS) method, were used to quantitate plasma trifluoperazine concentrations over 24 h in five healthy male volunteers following single 5 mg doses of two trifluoperazine tablet formulations (A and B) in a two-way cross-over design. Bioavailability in terms of area under the plasma concentration versus time curve to 24h or extrapolated to infinity, maximum plasma concentration and time to maximum plasma concentration using either RIA or GC-MS was not statistically significantly different from one formulation to the other. Also, there were no statistically significant differences between GC-MS and RIA values for AUC24(0) and Cmax for each of the two formulations examined. However, the mean AUC24(0) RIA/GC-MS ratios for formulations A and B were 3.1 and 3.4, respectively, while the mean Cmax RIA/GC-MS ratios were 1.7 and 2.1, respectively. These differences in AUC and Cmax are probably mainly due to the relative non-specificity of the RIA antiserum. Thus, where GC-MS is preferred for pharmacokinetic studies, both analytical procedures can be used for comparative single-dose bioequivalence studies of trifluoperazine. However, both the methods should be tested in patients in order to establish the suitability of one procedure over the other for the study of plasma level versus clinical response correlations.

  6. Clinical Recommendation: Vulvovaginitis.

    Science.gov (United States)

    Zuckerman, Andrea; Romano, Mary

    2016-12-01

    Vulvovaginitis is a commonly encountered condition among prepubertal and adolescent females. The objective of this report is to provide the latest evidence regarding the diagnosis and management of vulvovaginitis in prepubertal and adolescent females. In this systematic review we used the Grading of Recommendations Assessment, Development and Evaluation evidence system. Vulvovaginal complaints are common in the pediatric and adolescent age group. The patient's age in conjunction with history and associated complaints will guide evaluation, diagnosis, and treatment. Treatment should include counseling on hygiene and voiding techniques as well as therapy for any specific pathogens identified.

  7. Personalized professional content recommendation

    Science.gov (United States)

    Xu, Songhua

    2015-10-27

    A personalized content recommendation system includes a client interface configured to automatically monitor a user's information data stream transmitted on the Internet. A hybrid contextual behavioral and collaborative personal interest inference engine resident to a non-transient media generates automatic predictions about the interests of individual users of the system. A database server retains the user's personal interest profile based on a plurality of monitored information. The system also includes a server programmed to filter items in an incoming information stream with the personal interest profile and is further programmed to identify only those items of the incoming information stream that substantially match the personal interest profile.

  8. Saliva versus plasma bioequivalence of rusovastatin in humans: validation of class III drugs of the salivary excretion classification system.

    Science.gov (United States)

    Idkaidek, Nasir; Arafat, Tawfiq

    2015-03-01

    Bioequivalence of rusovastatin in healthy human volunteers was done using saliva and plasma matrices in order to investigate the robustness of using saliva instead of plasma as a surrogate for bioequivalence of class III drugs according to the salivary excretion classification system (SECS). Saliva and plasma samples were collected for 72 h after oral administration of rusovastatin 40 mg to 12 healthy humans. Saliva and plasma pharmacokinetic parameters were calculated by non-compartmental analysis. Analysis of variance, 90 % confidence intervals, and intra-subject and inter-subject variability values of pharmacokinetic parameters were calculated using Kinetica program V5. Human effective intestinal permeability was also calculated by SimCYP program V13. Rusovastatin falls into class III (high permeability/low fraction unbound to plasma proteins) and hence was subjected to salivary excretion. A correlation coefficient of 0.99 between saliva and plasma concentrations, and a saliva/plasma concentration ratio of 0.175 were observed. The 90 % confidence limits of area under the curve (AUClast) and maximum concentration (C max) showed similar trends in both saliva and plasma. On the other hand, inter- and intra-subject variability values in saliva were higher than in plasma, leading to the need for a slightly higher number of subjects to be used in saliva studies. Non-invasive saliva sampling instead of the invasive plasma sampling method can be used as a surrogate for bioequivalence of SECS class III drugs when an adequate sample size is used.

  9. Simple and Robust Analysis of Cefuroxime in Human Plasma by LC-MS/MS: Application to a Bioequivalence Study

    Directory of Open Access Journals (Sweden)

    Xingjiang Hu

    2014-01-01

    Full Text Available A simple, robust LC-MS/MS assay for quantifying cefuroxime in human plasma was developed. Cefuroxime and tazobactam, as internal standard (IS, were extracted from human plasma by methanol to precipitate protein. Separation was achieved on a Zorbax SB-Aq (4.6×250 mm, 5 μm column under isocratic conditions. The calibration curve was linear in the concentration range of 0.0525–21.0 μg/mL (r=0.9998. The accuracy was higher than 90.92%, while the intra- and interday precision were less than 6.26%. The extraction procedure provides recovery ranged from 89.44% to 92.32%, for both analyte and IS. Finally, the method was successfully applied to a bioequivalence study of a single 500 mg dose of cefuroxime axetil in 22 healthy Chinese male subjects under fasting condition. Bioequivalence was determined by calculating 90% Cls for the ratios of Cmax, AUC0-t, and AUC0-∞ values for the test and reference products, using logarithmic transformed data. The 90% Cls for the ratios of Cmax (91.4%~104.2%, AUC0-t (97.4%~110.9%, and AUC0-∞ (97.6%~111.1% values were within the predetermined range. It was concluded that the two formulations (test for capsule, reference for tablet analyzed were bioequivalent in terms of rate and extent of absorption and the method met the principle of quick and easy clinical analysis.

  10. School Health Guidelines to Promote Healthy Eating and Physical Activity. Morbidity and Mortality Weekly Report. Recommendations and Reports. Volume 60, Number 5

    Science.gov (United States)

    Rutledge, Teresa F., Ed.

    2011-01-01

    During the last 3 decades, the prevalence of obesity has tripled among persons aged 6-19 years. Multiple chronic disease risk factors, such as high blood pressure, high cholesterol levels, and high blood glucose levels are related to obesity. Schools have a responsibility to help prevent obesity and promote physical activity and healthy eating…

  11. Maximizing profit using recommender systems

    CERN Document Server

    Das, Aparna; Ricketts, Daniel

    2009-01-01

    Traditional recommendation systems make recommendations based solely on the customer's past purchases, product ratings and demographic data without considering the profitability the items being recommended. In this work we study the question of how a vendor can directly incorporate the profitability of items into its recommender so as to maximize its expected profit while still providing accurate recommendations. Our approach uses the output of any traditional recommender system and adjust them according to item profitabilities. Our approach is parameterized so the vendor can control how much the recommendation incorporating profits can deviate from the traditional recommendation. We study our approach under two settings and show that it achieves approximately 22% more profit than traditional recommendations.

  12. On the leveling-off properties of the new bioequivalence limits for highly variable drugs of the EMA guideline.

    Science.gov (United States)

    Karalis, Vangelis; Symillides, Mira; Macheras, Panos

    2011-11-20

    Recently, the European Medicines Agency (EMA) issued a new guideline on the investigation of bioequivalence (BE). In case of highly variable drugs, this guideline proposes that the acceptance limits for C(max) can gradually be expanded as a function of within-subject variability (CV(wR)). Actually, these BE limits exhibit leveling-off properties since they are not allowed to scale continuously, but only up to CV(wR)=50%. To avoid the risk of accepting two drug products which may differ significantly, this EMA guideline also proposes the use of a secondary constraint criterion on the geometric mean ratio (GMR) of the two products under comparison. Aim of this study was to explore the leveling-off properties of the new EMA limits in comparison to other approaches, as well as to assess the impact of the complementary GMR criterion on the ability to declare bioequivalence. Simulated bioequivalence studies and extreme GMR plots were used to assess the performance of the EMA limits. Three sequence, three period (3×3) crossover studies with two treatments (T and R) were simulated. The R product was considered to be administered twice, while the T only once (i.e., TRR/RTR/RRT). Among others, this study revealed the leveling-off properties of the new EMA limits. It was also shown that the complementary GMR-constraint is only effective when a large sample size is used and at regions of CV(wR) close to 50%. This GMR-criterion begins to be effective at sample sizes around 60 and becomes more prominent as the number of subjects participating in the BE study increases. For CV(wR) values lower than 50%, the GMR-constraint has no role. In case of within-subject variabilities greater than 50%, the impact of the GMR-constraint diminishes due to the leveling-off properties of the EMA limits. Compared to the classic 0.80-1.25 or the extended 0.75-1.33 criteria, the new EMA limits are more liberal at high CV(wR) values and allow greater differences between the two drug products to be

  13. High-Performance Liquid Chromatographic-Tandem Mass Spectrometric Determination of Itraconazole in Human Plasma for Bioavailability and Bioequivalence Studies

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Young Wook; Nam, Dae Young; Kang, Kyoung Hoon; Ha, Kyung Wook; Han, In Hee; Chang, Byung Kon; Yoon, Mi Kyeong; Lee, Jae Hwi [Chung-Ang University, Seoul (Korea, Republic of)

    2006-02-15

    A highly sensitive high-performance liquid chromatographic-tandem mass spectrometric method (HPLC-MSMS) has been developed to quantify itraconazole in human plasma for the purpose of pharmacokinetic studies. Sample preparation was carried out by liquid-liquid extraction using loratadine as an internal standard. Chromatographic separation used a YMC C{sub 18} column, giving an extremely fast total run time of 3 min. The method was validated and used for the bioequivalence study of itraconazole tablets in healthy male volunteers (n = 31). The lower limit of detection proved to be 0.2 ng /mL for itraconazole.

  14. Common reasons for "for-cause" inspections in bioequivalence studies submitted to the Food and Drug Administration.

    Science.gov (United States)

    Li, Bing V; Davit, Barbara M; Lee, Christina H; Pabba, Santhosh K; Mahadevan, Chitra; Caramenico, Hoainhon T; Haidar, Sam H; Sanchez, Aida L; Sigler, Aaron W; Stier, Ethan M; Conner, Dale P

    2013-01-01

    "For-cause" inspections are initiated during the review of bioequivalence (BE) data submitted to Abbreviated New Drug Applications when possible scientific misconduct and study irregularities are discovered. We investigated the common reasons for initiating "for-cause" inspections related to the clinical, analytical, and dissolution study sites associated with BE studies. This information may help the pharmaceutical industry to understand the root causes of compliance failures in BE studies and help them to improve compliance with FDA's regulations, thereby facilitating more rapid approval of safe and effective generic drugs.

  15. Bioequivalence between two commercial formulations of gliclazide in Colombia Bioequivalencia entre dos formulaciones comerciales de gliclazida en Colombia

    Directory of Open Access Journals (Sweden)

    Ignacio Rodríguez

    2001-01-01

    Full Text Available Two commercial formulations of Gliclazide 80 mg tablets were studied in order to evaluate both pharmaceutical and biological equivalence, Glidiab® Tecnoquímicas Laboratories and Diamicron® Euroetika-Elsevier Laboratories. After proving the pharmaceutical equivalence, a bioequivalence was tested in 14 healthy volunteers and the determination of gliclazide in plasma was carried out by high-performance liquid chromatography (HPLC. The evaluated pharmacokinetic parameters were: area under the curve (AUC from 0 to 60 hours, maximum concentration (Cmax and time to maximum concentration (Tmax. In statistical analysis the 90.0% confidence intervals for AUC, Cmax and Tmax, and acceptance range for bioequivalence of 80.0%-125.0% to AUC and Cmax and acceptance range of 80:0%-120.0% to Tmax, were applied. Both formulations presented inter and intra subject high variability and it was found that they are bioequivalent in relation to AUC but they are not bioequivalent in relation to Cmax and Tmax. Los formulaciones comerciales de Gliclazida de 80 mg – tabletas, los productos Glidiab® de Tecnoquímicas y Diamicron® de Euroetika-Elsevier, fueron sometidos a estudio para evaluar la equivalencia farmacéutica y la equivalencia biológica. Después de comprobar la equivalencia farmacéutica se llevó a cabo el estudio de la equivalencia biológica en 14 voluntarios sanos; la cuantificación de Gliclazida en plasma se realizó por la técnica de cromatografía líquida de alta resolución (HPLC. Los parámetros farmacocinéticos evaluados fueron: área bajo la curva (AUC de 0-60 horas, concentración máxima (Cmáx y el tiempo máximo (tmáx los cuales se analizaron estadísticamente con intervalos de confianza del 90.0% y un rango de aceptación para bioequivalencia del 80.0% al 125.0% para AUC y Cmáx y del 80.0% al 120.0% para el tmáx. Ambas formulaciones presentaron alta variabilidad inter e intrasujeto y se encontró que son bioequivalentes con

  16. Ebola virus: recommendations

    CERN Multimedia

    CERN Medical Service

    2014-01-01

    The CERN Medical Service has been closely following, in particular via the WHO, the development of the Ebola virus outbreak currently affecting some African countries. This infectious disease may be passed on through direct contact with the bodily fluids of a sick person.   Based on the recommendations of the WHO and the two Host States, Switzerland and France, as updated on their respective websites, so far there has been no ban on travel to the countries concerned. However, unless it is absolutely essential, you are advised not to visit any of the countries affected by Ebola (Guinea, Republic of Sierra Leone, Liberia, Nigeria). The two Host States have established an alert system, and a check is carried out on departure from the airports of those countries. It is strongly recommended that you contact the Medical Service if you are travelling to those countries. We remind you to observe the basic rules of hygiene such as frequent hand washing, whatever your destination. The Medical Service is...

  17. Preventing Recommendation Attack in Trust-Based Recommender Systems

    Institute of Scientific and Technical Information of China (English)

    Fu-Guo Zhang

    2011-01-01

    Despite its success,similarity-based collaborative filtering suffers from some limitations,such as scalability,sparsity and recommendation attack.Prior work has shown incorporating trust mechanism into traditional collaborative filtering recommender systems can improve these limitations.We argue that trust-based recommender systems are facing novel recommendation attack which is different from the profile injection attacks in traditional recommender system.To the best of our knowledge,there has not any prior study on recommendation attack in a trust-based recommender system.We analyze the attack problem,and find that "victim" nodes play a significant role in the attack.Furthermore,we propose a data provenance method to trace malicious users and identify the "victim" nodes as distrust users of recommender system.Feasibility study of the defend method is done with the dataset crawled from Epinions website.

  18. Recommendations for the management of individuals with acquired valvular heart diseases who are involved in leisure-time physical activities or competitive sports.

    Science.gov (United States)

    Mellwig, Klaus Peter; van Buuren, Frank; Gohlke-Baerwolf, Christa; Bjørnstad, Hans Halvor

    2008-02-01

    Physical check-ups among athletes with valvular heart disease are of significant relevance. In athletes with mitral valve stenosis the extent of allowed physical activity is dependant on the size of the left atrium and the severity of the valve defect. Patients with mild-to-moderate mitral valve regurgitation can participate in all types of sport associated with low and moderate isometric stress and moderate dynamic stress. Patients under anticoagulation should not participate in any type of contact sport. Asymptomatic athletes with mild aortic valve stenosis can take part in all types of sport, as long as left ventricular function and size are normal, a normal response to exercise at the level performed during athletic activities is present and there are no arrhythmias. Asymptomatic athletes with moderate aortic valve stenosis should only take part in sports with low dynamic and static stress. Aortic valve regurgitation is often present due to connective tissue disease of a bicuspid valve. Athletes with mild aortic valve regurgitation, with normal end diastolic left ventricular size and systolic function can participate in all types of sport. A mitral valve prolapse is often associated with structural diseases of the myocardium and endocardium. In patients with mitral valve prolapse Holter-ECG monitoring should also be performed to detect significant arrhythmias. All athletes with known valvular heart disease, a previous history of infective endocarditis and valve surgery should receive endocarditis prophylaxis before dental, oral, respiratory, intestinal and genitourinary procedures associated with bacteraemia. Sport activities have to be avoided during active infection with fever.

  19. Recommendation Process in SR1 Web Document Recommender System

    OpenAIRE

    Munteanu, Dan

    2008-01-01

    This paper presents a recommender system for web documents (given as bookmarks). The system uses for classification a combination of content, event and collaborative filters and for recommendation a modified Pearson-r algorithm. The algorithm for recommendation is using not only the correlation between users but also the similarity between classes. Some experimental results that support this approach are also presented.

  20. Recommendation in evolving online networks

    Science.gov (United States)

    Hu, Xiao; Zeng, An; Shang, Ming-Sheng

    2016-02-01

    Recommender system is an effective tool to find the most relevant information for online users. By analyzing the historical selection records of users, recommender system predicts the most likely future links in the user-item network and accordingly constructs a personalized recommendation list for each user. So far, the recommendation process is mostly investigated in static user-item networks. In this paper, we propose a model which allows us to examine the performance of the state-of-the-art recommendation algorithms in evolving networks. We find that the recommendation accuracy in general decreases with time if the evolution of the online network fully depends on the recommendation. Interestingly, some randomness in users' choice can significantly improve the long-term accuracy of the recommendation algorithm. When a hybrid recommendation algorithm is applied, we find that the optimal parameter gradually shifts towards the diversity-favoring recommendation algorithm, indicating that recommendation diversity is essential to keep a high long-term recommendation accuracy. Finally, we confirm our conclusions by studying the recommendation on networks with the real evolution data.

  1. On Imprecise Investment Recommendations

    Directory of Open Access Journals (Sweden)

    Piasecki Krzysztof

    2014-08-01

    Full Text Available The return rate is considered here as a fuzzy probabilistic set. Then the expected return is obtained as a fuzzy subset in the real line. This result is a theoretical foundation for new investment strategies. All considered strategies result of comparison profit fuzzy index and limit value. In this way we obtain an imprecise investment recommendation. Financial equilibrium criteria are a special case of comparison of the profit index and the limit value. The following criteria are generalized here: the Sharpe's Ratio, the Jensen's Alpha and the Treynor's Ratio. Moreover, the safety-first criteria are generalized here for the fuzzy case. The Roy Criterion, the Kataoka Criterion and the Telser Criterion are also generalized. Obtained results show that proposed theory is useful for the investment applications.

  2. Personalized professional content recommendation

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Songhua

    2015-10-27

    A personalized content recommendation system includes a client interface configured to automatically monitor a user's information data stream transmitted on the Internet. A hybrid contextual behavioral and collaborative personal interest inference engine resident to a non-transient media generates automatic predictions about the interests of individual users of the system. A database server retains the user's personal interest profile based on a plurality of monitored information. The system also includes a server programmed to filter items in an incoming information stream with the personal interest profile and is further programmed to identify only those items of the incoming information stream that substantially match the personal interest profile.

  3. OARSI Clinical Trials Recommendations

    DEFF Research Database (Denmark)

    Kraus, V B; Blanco, F J; Englund, M

    2015-01-01

    The objective of this work was to describe requirements for inclusion of soluble biomarkers in osteoarthritis (OA) clinical trials and progress toward OA-related biomarker qualification. The Guidelines for Biomarkers Working Group, representing experts in the field of OA biomarker research from...... of reasons but in particular, to determine whether biomarkers are useful in identifying those individuals most likely to receive clinically important benefits from an intervention; and to determine whether biomarkers are useful for identifying individuals at earlier stages of OA in order to institute...... both academia and industry, convened to discuss issues related to soluble biomarkers and to make recommendations for their use in OA clinical trials based on current knowledge and anticipated benefits. This document summarizes current guidance on use of biomarkers in OA clinical trials...

  4. National Recommended Water Quality Criteria

    Data.gov (United States)

    U.S. Environmental Protection Agency — The National Recommended Water Quality Criteria is a compilation of national recommended water quality criteria for the protection of aquatic life and human health...

  5. A comparative analysis of biopharmaceutics classification system and biopharmaceutics drug disposition classification system: a cross-sectional survey with 500 bioequivalence studies.

    Science.gov (United States)

    Cristofoletti, Rodrigo; Chiann, Chang; Dressman, Jennifer B; Storpirtis, Silvia

    2013-09-01

    Although policies of waiving bioequivalence studies are part of the legal framework of various regulatory agencies, there is no harmonization with regard to extension of the biowaiver to drugs other than those with high solubility and high permeability, nor is there any consensus or official endorsement of the biopharmaceutics drug disposition classification system (BDDCS). To better understand the applicability of the biowaiver, we carried out a cross-sectional survey to estimate the relative risk of obtaining nonbioequivalent (non-BE) or bioinequivalent (BIE) results for drug products containing drugs belonging to each of the biopharmaceutics classification system (BCS) and BDDCS classes. Five hundred bioequivalence studies were randomly sampled from a database of the Brazilian Health Surveillance Agency (ANVISA). The drugs were classified according to the BCS and BDDCS, to evaluate how characteristics related to drug and dosage form influence the outcome of bioequivalence studies. The relative risk of obtaining a non-BE result was approximately four times lower for drugs in classes 1 and 3 of BCS or BDDCS when compared with class 2 drugs. Thus, it seems that the final outcome of a bioequivalence study is strongly influenced by the solubility of the drug, but not by its intestinal permeability or extent of metabolism.

  6. Classification of Recommender Expertise in the Wikipedia Recommender System

    DEFF Research Database (Denmark)

    Jensen, Christian D.; Pilkauskas, Povilas; Lefévre, Thomas

    2011-01-01

    feedback from recommenders that the user has agreed with in the past. This exposes the problem that most recommenders are not equally competent in all subject areas. The first WRS prototype did not include an evaluation of the areas of expertise of recommenders, so the trust metric used in the article...... ratings reflected the average competence of recommenders across all subject areas. We have now developed a new version of the WRS, which evaluates the expertise of recommenders within different subject areas. In order to do this, we need to identify a way to classify the subject area of all the articles...

  7. Determination of captopril by hplctandem mass spectrometry: application in a bioequivalence study

    Directory of Open Access Journals (Sweden)

    Aline Kércia Alves Soares

    2012-03-01

    Full Text Available Objective: To assess three different captopril tablet formulations of 25mg for their bioavailability (Capoten® as the reference formulation and Captopril from FURP and Farmanguinhos as the test formulations in 24 healthy volunteers of both sexes. Methods: The volunteers were free from serious disease, as assessed by physical and psychiatricexamination, EKG, and laboratory tests. The study was open, with a three-period crossover design and a five-day washout period. Plasma samples were obtained over a 24-hour interval.Captopril concentrations were determined by reversed phase liquid chromatography tandem mass spectrometry (LC-MS-MS. Results: The geometric mean for Capoten® /Captopril- FURP 25 mg was 96.9 % for AUC0-24, 95.58 % for AUC0-∞, and 98.17% for Cmax. The 90% confidence intervals (CI were 84.8-100.65%, 88.5-109.42% and 82.52-116.8%, respectively. The geometric mean for Capoten®/Captopril-Farmanguinhos 25 mg was 99.63 % for AUClast, 98.52% for AUC0-∞, and 95.52 for Cmax. The 90% CI were 87.23-113.8%, 86.06-112.79% and 80.29-113.64%, respectively. Therefore, the 90% CI for Cmax, AUClast, AUC0-∞ were within the 80-125% interval proposed by the Food and Drug Administration. Conclusion: Captopril- FURP and Captopril-Farmanguinhos 25 mg tablets were bioequivalent to Capoten® 25 mg,according to both the rate and extent of absorption.

  8. Pharmacokinetics and bioequivalence study of ranitidine film tablets in healthy male subjects.

    Science.gov (United States)

    Gschwend, Michael H; Guserle, Richard; Erenmemişoglu, Aydin; Martin, Wolfgang; Tamur, Uygur; Kanzik, Ilker; Hincal, A Atilla

    2007-01-01

    The aim of the present study was to compare the bioavailability of ranitidine (CAS 66357-35-5) from two different ranitidine hydrochloride (CAS 66357-59-3) film tablets (Ranitab 150 mg film tablets as test preparation and 150 mg film tablets of the originator product as reference preparation). The study was conducted according to an open-label, randomised two-period cross-over design with a wash-out phase of 9 days. Blood samples for pharmacokinetic profiling were taken up to 24 h post-dose, and ranitidine plasma concentrations were determined with a validated HPLC method with UV-detection. Maximum plasma concentrations (Cmax) of 461.8 ng/ml (test) and 450.6 ng/ ml (reference) were achieved. Areas under the plasma concentration-time curve (AUC (0-infinity) of 2,488.6 ng . h/ml (test) and 2,528.8 ng . h/ml (reference) were calculated. The median tmax was 2.83 h (test) and 3.04 h (reference). Plasma elimination half-lives (t1/2) of 2.78 h (test) and 2.89 h (reference) were determined. Both primary target parameters AUC(0-infinity) and Cmax were tested parametrically by analysis of variance (ANOVA) and the 90% confidence intervals were between 91.93 %-106.98 % (AUC (0-infinity) and 92.34%-118.85% (Cmax). Bioequivalence between test and reference preparation was demonstrated since for both parameters AUC and Cmax the 90 % confidence intervals of the T/R ratios of logarithmically transformed data were in the generally accepted range of 80 %-125 %.

  9. Pharmacokinetics and bioequivalence studies of galantamine hydrobromide dispersible tablet in healthy male Chinese volunteers.

    Science.gov (United States)

    Zhang, Li-jun; Fang, Xiao-ling; Li, Xue-ning; Wang, Qing-song; Han, Li-mei; Zhang, Zhi-wen; Sha, Xian-yi

    2007-03-01

    A randomized, two-way, crossover study was conducted in 18 healthy male Chinese volunteers to compare pharmacokinetics profiles of galantamine hydrobromide dispersible tablet with that of conventional tablet. A single oral dose of 10 mg galantamine was administrated to each volunteer. Plasma concentrations of galantamine were determined by a validated high-performance liquid chromatography (HPLC) method with fluorescence detection, which allowed 1 ng/mL to be assayed as the lowest quantifiable concentration. From plasma concentrations, AUC(0-->t) (the area under the plasma concentration-time curve from time 0 to the last sampling time, 32 hr), AUC(0-->infinity) (the area under the plasma concentration-time curve from time 0 to infinity), t((1/2)) (elimination of half-life of the terminal log linear phase), C(max) (maximum plasma drug concentration) and T(max) (time to reach C(max)) were evaluated through noncompartmental pharmacokinetic analysis. AUC(0-->t) and AUC(0-->infinity) were calculated by the linear-log trapezoidal rule method. C(max) and T(max) were obtained directly from the plasma concentration-time curve. Analysis of variance was carried out using logarithmically transformed AUC(0-->t), AUC(0-->infinity) and C(max). As far as AUC(0-->t), AUC(0-->infinity) and C(max) were concerned, there was no statistically significant difference between the test and reference formulations. Ninety percent confidence intervals (90% CI) for the ratio of AUC(0-->t), AUC(0-->infinity) and C(max) values for the test and reference formulations were 100.4-107.8%, 99.0-107.2% and 87.5-111.3%, respectively. As the 90% CIs of AUC(0-->t), AUC(0-->infinity) and C(max) were entirely within 80-125%, two formulations were considered bioequivalent.

  10. Application of a Stable Isotope Technique for the Bioequivalency Study of Two Transdermal Nitroglycerin Systems.

    Science.gov (United States)

    Sun, Jim X.; Piraino, Anthony J.; Morgan, John M.; Joshi, Jill C.; Chan, Keith; John, Vivian A.; Good, William R.

    1994-06-01

    A bioequivalency study of an experimental transdermal nitroglycerin system relative to the commercial Transderm-Nitro 0.4 mg/h system was performed on eight healthy volunteers by using an innovative stable isotope technique. Plasma clearance changes for nitroglycerin (NTG) during patch application were corrected with simultaneously administered intravenous infusion of (15)N-labeled nitroglycerin ((15)N-NTG) solution. The total amount of NTG transdermally absorbed (AUC x CL) during a 22-h application for the experimental system was not statistically different from that for the commercial system (9.7 plus minus 3.3 versus 8.1 plus minus 2.6 mg; p = 0.41). The analysis of residual drug content in the used system revealed that the difference in amounts of NTG delivered from the experimental and commercial systems were not significant (12.2 plus minus 3.1 versus 10.8 plus minus 3.1 mg; p = 0.29). With the isotope-labeled method, the absorption rate was evaluated at each time interval during the system application. The peak concentration values were 0.52 plus minus 0.21 mg h(minus sign1) at 1 h for the experimental system and 0.41 plus minus 0.15 mg h(minus sign1) at 2 h for commercial systems. After the peak concentrations, the absorption rates remained constant for both systems over the 16-h period. There was no statistical difference in absorption between the two systems at any sampling time. In this study, substantial fluctuations in the plasma concentrations of both NTG and (15)N-NTG were observed within and between subjects. In addition, the variability in plasma concentrations of NTG correlated well with that of (15)N-NTG for all participating subjects. The momentary changes of clearance, estimated from (15)N-NTG plasma data, were found to be responsible for the fluctuation of NTG in plasma.

  11. 78 FR 65338 - Agency Information Collection Activities; Submission for Office of Management and Budget Review...

    Science.gov (United States)

    2013-10-31

    ... Bioequivalence Studies in Humans AGENCY: Food and Drug Administration, HHS. ACTION: Notice. SUMMARY: The Food and... Drug and Biological Products and Safety Reporting Requirements for Bioavailability and Bioequivalence... Bioequivalence Studies in Humans.'' The document clarified the Agency's expectations for timely...

  12. BIOEQUIVALENCE BETWEEN rhGH FOR RECONSTITUTION AND READY-TO-USE rhGH IN TWO LIQUID FORMULATIONS

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    Objective To evaluate the bioequivalence between recombinant human growth hormone ( rhGH) for reconstitution, and two dosages of liquid formulation of rhGH [ (15IU)5mg or ( 30IU) l0mg per 3ml].Methods The study drugs were tested in a randomized, single-blind and three-period crossover studies in 24 healthy male subjects. The three drugs were administered by subcutaneous injection at a dose of 0. 2IU/kg body weight. A continuous somatostatin infusion was given in order to suppress the secretion of endogenous GH. The venous blood samples were drawn at different time points to test the serum concentration of GH. The pharmacokinetic parameters were analyzed by statistical methods. Results 90% confidence intervals (CI) of AUC0-24h among three products were all within 80% -125% interval (103.4% -116. 5%, 105. 7% -119. 6% and 91.9% -103. 7%,respectively), and the CIs of Cmax among three products were all within 70%-143% interval ( 91.9%-114. 0%,103. 7%-127. 2% and 81.6%-97. 4%, respectively). There was no statisitical difference of tmax among all the three products. Conclusion These data demonstrate that there is bioequivalence between rhGH for reconstitution and two liquid formulations of rhGH.

  13. A simplified HPLC method for quantification of torsemide from human plasma and its application to a bioequivalence study

    Directory of Open Access Journals (Sweden)

    Khan I

    2008-01-01

    Full Text Available A simple, rapid and selective method was developed. The method was validated and found to be linear in the range of 100-4000 ng/ml. Chromatographic peaks were separated by means of a 5 µm, C18 silica column using acetonitrile and phosphate buffer (0.05 M in proportion of 40:60 (pH 4.0 as a mobile phase. The retention time of torsemide was 5.00±0.20 min. The chromatograms showed good resolution and no interference from plasma. The mean recovery from human plasma was found to be above 82%. Both inter-day and intra-day accuracy and precision data showed good reproducibility. This method was applied to a single dose bioequivalence study. Log transformed values were compared by ANOVA followed by classical 90% confidence interval. Confidence limits for C max , AUC 0-t and AUC 0-inf ranged from 98.6 to 102.8, 101.8 to 105.3 and 102.4 to 105.5 respectively. These results suggested that the analytical method was linear, precise and accurate. Test and reference product were found to be bioequivalent.

  14. A Novel Approach to Testing for Average Bioequivalence Based on Modeling the Within-Period Dependence Structure.

    Science.gov (United States)

    Chandrasekhar, Rameela; Shi, Yi; Hutson, Alan D; Wilding, Gregory E

    2015-01-01

    Bioequivalence trials are commonly conducted to assess therapeutic equivalence between a generic and an innovator brand formulations. In such trials, drug concentrations are obtained repeatedly over time and are summarized using a metric such as the area under the concentration vs. time curve (AUC) for each subject. The usual practice is to then conduct two one-sided tests using these areas to evaluate for average bioequivalence. A major disadvantage of this approach is the loss of information encountered when ignoring the correlation structure between repeated measurements in the computation of areas. In this article, we propose a general linear model approach that incorporates the within-subject covariance structure for making inferences on mean areas. The model-based method can be seen to arise naturally from the reparameterization of the AUC as a linear combination of outcome means. We investigate and compare the inferential properties of our proposed method with the traditional two one-sided tests approach using Monte Carlo simulation studies. We also examine the properties of the method in the event of missing data. Simulations show that the proposed approach is a cost-effective, viable alternative to the traditional method with superior inferential properties. Inferential advantages are particularly apparent in the presence of missing data. To illustrate our approach, a real working example from an asthma study is utilized.

  15. Pharmacokinetics and steady-state bioequivalence of treprostinil sodium (Remodulin) administered by the intravenous and subcutaneous route to normal volunteers.

    Science.gov (United States)

    Laliberte, Kevin; Arneson, Carl; Jeffs, Roger; Hunt, Thomas; Wade, Michael

    2004-08-01

    Treprostinil sodium is a chemically stable analogue of prostacyclin administered as a chronic, continuous subcutaneous infusion for the treatment of pulmonary arterial hypertension (PAH). There has been significant clinical interest in determining the feasibility of delivering treprostinil by intravenous infusion. Therefore, a bioequivalence and comparative pharmacokinetics study of the two routes of administration was conducted in normal volunteers. A randomized, two-period, crossover study design was employed. Each subject was dosed at 10 ng/kg/min for 72 hours by each route, with the infusions separated by a 4-day wash-out period. In the 51 subjects who received at least 24 hours of treprostinil administered subcutaneously and intravenously, the steady-state ratios of the geometric means (i.v./s.c.) and 90% confidence intervals for AUCss and Cmaxss were 92.9% (89.8-96.1%) and 106% (99.4-113%), respectively. Secondary pharmacokinetic assessments confirmed the comparability of the two routes of administration at steady state, and also demonstrated that the elimination half-life of treprostinil was 4.4 and 4.6 hours following intravenous and subcutaneous administration, respectively. Based on these findings it was concluded that intravenously and subcutaneously administered treprostinil are bioequivalent at steady state.

  16. Bioequivalence evaluation of two roxithromycin formulations in healthy human volunteers by high performance liquid cromatography coupled to tandem mass spectrometry.

    Science.gov (United States)

    Motta, M; Ribeiro, W; Ifa, D R; Moares, M E; Moraes, M O; Corrado, A P; De Nucci, G

    1999-01-01

    The bioequivalence of two different formulations containing roxithromycin (SPE-712-1). Oral suspension 300 mg/15 mL as test formulation and Rotram, tablets 300 mg as reference formulation, both by Schering Plough S.A., Brazil) was evaluated in 24 healthy volunteers of both sexes (12 male and 12 female). The study was conducted open with randomized two-period crossover design and a 14-day washout period. Each subject received 300 mg of each roxithromycin formulation. Plasma samples were obtained over a 72-hour interval and roxithromycin concentrations were analyzed by combined LC-MS/MS with positive ion electrospray ionization using selected ion monitoring method. From the plasma roxithromycin concentration vs time curves the following pharmacokinetic parameters were obtained: AUC(0-72 h), AUC(0-infinity), Cmax, t1/2 ratios and tmax individual differences. The 90% for confidence interval (CI) of geometric mean SPE-712-L/Rotram individual percent ratio were 105.0-128.3% for AUC(0-72 h), and 78.4-96.9 for Cmax. Although this 90% CI were marginally outside the interval proposed by the Food and Drug Administration, the probability assessed by the two-one sided West for ratios was included in the 0.8-1.25 interval, as we concluded that SPE-712-L oral suspension formulation was bioequivalent to Rotram tablet formulation for the extent and rate of absorption.

  17. Semi-physiologic model validation and bioequivalence trials simulation to select the best analyte for acetylsalicylic acid.

    Science.gov (United States)

    Cuesta-Gragera, Ana; Navarro-Fontestad, Carmen; Mangas-Sanjuan, Victor; González-Álvarez, Isabel; García-Arieta, Alfredo; Trocóniz, Iñaki F; Casabó, Vicente G; Bermejo, Marival

    2015-07-10

    The objective of this paper is to apply a previously developed semi-physiologic pharmacokinetic model implemented in NONMEM to simulate bioequivalence trials (BE) of acetyl salicylic acid (ASA) in order to validate the model performance against ASA human experimental data. ASA is a drug with first-pass hepatic and intestinal metabolism following Michaelis-Menten kinetics that leads to the formation of two main metabolites in two generations (first and second generation metabolites). The first aim was to adapt the semi-physiological model for ASA in NOMMEN using ASA pharmacokinetic parameters from literature, showing its sequential metabolism. The second aim was to validate this model by comparing the results obtained in NONMEM simulations with published experimental data at a dose of 1000 mg. The validated model was used to simulate bioequivalence trials at 3 dose schemes (100, 1000 and 3000 mg) and with 6 test formulations with decreasing in vivo dissolution rate constants versus the reference formulation (kD 8-0.25 h (-1)). Finally, the third aim was to determine which analyte (parent drug, first generation or second generation metabolite) was more sensitive to changes in formulation performance. The validation results showed that the concentration-time curves obtained with the simulations reproduced closely the published experimental data, confirming model performance. The parent drug (ASA) was the analyte that showed to be more sensitive to the decrease in pharmaceutical quality, with the highest decrease in Cmax and AUC ratio between test and reference formulations.

  18. Improving an Hybrid Literary Book Recommendation System through Author Ranking

    CERN Document Server

    Vaz, Paula Cristina; Martins, Bruno; Calado, Pavel

    2012-01-01

    Literary reading is an important activity for individuals and choosing to read a book can be a long time commitment, making book choice an important task for book lovers and public library users. In this paper we present an hybrid recommendation system to help readers decide which book to read next. We study book and author recommendation in an hybrid recommendation setting and test our approach in the LitRec data set. Our hybrid book recommendation approach purposed combines two item-based collaborative filtering algorithms to predict books and authors that the user will like. Author predictions are expanded in to a book list that is subsequently aggregated with the former list generated through the initial collaborative recommender. Finally, the resulting book list is used to yield the top-n book recommendations. By means of various experiments, we demonstrate that author recommendation can improve overall book recommendation.

  19. Effect of Truncating AUC at 12, 24 and 48 hr When Evaluating the Bioequivalence of Drugs with a Long Half-Life.

    Science.gov (United States)

    Moreno, Isabel; Ochoa, Dolores; Román, Manuel; Cabaleiro, Teresa; Abad-Santos, Francisco

    2016-01-01

    Bioequivalence studies of drugs with a long half-life require long periods of time for pharmacokinetic sampling. The latest update of the European guideline allows the area under the curve (AUC) truncated at 72 hr to be used as an alternative to AUC0-t as the primary parameter. The objective of this study was to evaluate the effect of truncating the AUC at 48, 24 and 12 hr on the acceptance of the bioequivalence criterion as compared with truncation at 72 hr in bioequivalence trials. The effect of truncated AUC on the within-individual coefficient of variation (CVw) and on the ratio of the formulations was also analysed. Twenty-eight drugs were selected from bioequivalence trials. Pharmacokinetic data were analysed using WinNonLin 2.0 based on the trapezoidal method. Analysis of variance (ANOVA) was performed to obtain the ratios and 90% confidence intervals for AUC at different time-points. The degree of agreement of AUC0-72 in relation to AUC0-48 and AUC0-24, according to the Landis and Koch classification, was 'almost perfect'. Statistically significant differences were observed when the CVw of AUC truncated at 72, 48 and 24 hr was compared with the CVw of AUC0-12. There were no statistically significant differences in the AUC ratio at any time-point. Compared to AUC0-72, Pearson's correlation coefficient for mean AUC, AUC ratio and AUC CVw was worse for AUC0-12 than AUC0-24 or AUC0-48. These preliminary results could suggest that AUC truncation at 24 or 48 hr is adequate to determine whether two formulations are bioequivalent.

  20. Urgent recommendation. Interim report

    Energy Technology Data Exchange (ETDEWEB)

    Nakano, Masayuki [International Affairs and Safeguards Division, Atomic Energy Bureau, Science and Technology Agency, Tokyo (Japan)

    2000-12-01

    The Investigation Committee for Critical Accident at Uranium Processing Plant was founded immediately after the accident to investigate the cause of the accident and to establish measures to prevent the similar accident. On September 30, 1999 around 10:35, the Japan's first criticality accident occurred at JCO Co. Ltd. Uranium processing plant (auxiliary conversion plant) located at Tokai-mura Ibaraki-ken. The criticality continued on and off for approximately 20 hours after the first instantaneous criticality. The accident led the recommendation of tentative evacuation and sheltering indoors for residents living in the neighborhood. The serious exposure to neutrons happened to three workers. The dominant effect is dose due to neutrons and gamma rays from the precipitation tank. When the accident took place, three workers dissolved sequentially about 2.4 kg uranium powder with 18.8 % enrichment in the 10-litter bucket with nitric acid. The procedure of homogenization of uranium nitrate was supposed to be controlled using the shape-limited narrow storage column. Actually, however, the thick and large precipitation tank was used. As a result, about 16.6 kg of uranium was fed into the tank, which presumably caused criticality. The first notification by JCO was delayed and the following communication was not smooth. This led to the delay of correct understanding of the situation and made the initial proper response difficult, then followed by insufficient communication between the nation, prefecture, and local authority. Urgent recommendations were made on the following items; (1) Safety measures to be taken at the accident site, (2) health cares for residents and others, (3) Comprehensive safety securing at nuclear operators such as Establishment of the effective audit system, Safety education for employees and Qualification and licensing system, Safety related documents, etc. (4) Reconstruction of the government's safety regulations such as How safety

  1. Do recommender systems benefit users?

    CERN Document Server

    Yeung, Chi Ho

    2015-01-01

    Recommender systems are present in many web applications to guide our choices. They increase sales and benefit sellers, but whether they benefit customers by providing relevant products is questionable. Here we introduce a model to examine the benefit of recommender systems for users, and found that recommendations from the system can be equivalent to random draws if one relies too strongly on the system. Nevertheless, with sufficient information about user preferences, recommendations become accurate and an abrupt transition to this accurate regime is observed for some algorithms. On the other hand, we found that a high accuracy evaluated by common accuracy metrics does not necessarily correspond to a high real accuracy nor a benefit for users, which serves as an alarm for operators and researchers of recommender systems. We tested our model with a real dataset and observed similar behaviors. Finally, a recommendation approach with improved accuracy is suggested. These results imply that recommender systems ...

  2. Classification of Recommender Expertise in the Wikipedia Recommender System

    DEFF Research Database (Denmark)

    Jensen, Christian D.; Pilkauskas, Povilas; Lefevre, Thomas

    2011-01-01

    to the quality of articles. The Wikipedia Recommender System (WRS) was developed to help users determine the credibility of articles based on feedback from other Wikipedia users. The WRS implements a collaborative filtering system with trust metrics, i.e., it provides a rating of articles "which emphasizes...... feedback from recommenders that the user has agreed with in the past. This exposes the problem that most recommenders are not equally competent in all subject areas. The first WRS prototype did not include an evaluation of the areas of expertise of recommenders, so the trust metric used in the article...... ratings reflected the average competence of recommenders across all subject areas. We have now developed a new version of the WRS, which evaluates the expertise of recommenders within different subject areas. In order to do this, we need to identify a way to classify the subject area of all the articles...

  3. Recommendation Process in SR1 Web Document Recommender System

    Directory of Open Access Journals (Sweden)

    Dan MUNTEANU

    2008-12-01

    Full Text Available This paper presents a recommender system for web documents (given as bookmarks. The system uses for classification a combination of content, event and collaborative filters and for recommendation a modified Pearson-r algorithm. The algorithm for recommendation is using not only the correlation between users but also the similarity between classes. Some experimental results that support this approach are also presented.

  4. [Recommendations for neonatal transport].

    Science.gov (United States)

    Moreno Hernando, J; Thió Lluch, M; Salguero García, E; Rite Gracia, S; Fernández Lorenzo, J R; Echaniz Urcelay, I; Botet Mussons, F; Herranz Carrillo, G; Sánchez Luna, M

    2013-08-01

    During pregnancy, it is not always possible to identify maternal or foetal risk factors. Infants requiring specialised medical care are not always born in centres providing intensive care and will need to be transferred to a referral centre where intensive care can be provided. Therefore Neonatal Transport needs to be considered as part of the organisation of perinatal health care. The aim of Neonatal Transport is to transfer a newborn infant requiring intensive care to a centre where specialised resources and experience can be provided for the appropriate assessment and continuing treatment of a sick newborn infant. Intrauterine transfer is the ideal mode of transport when the birth of an infant with risk factors is diagnosed. Unfortunately, not all problems can be detected in advance with enough time to safely transfer a pregnant woman. Around 30- 50% of risk factors will be diagnosed during labour or soon after birth. Therefore, it is important to have the knowledge and resources to resuscitate and stabilise a newborn infant, as well as a specialised neonatal transport system. With this specialised transport it is possible to transfer newly born infants with the same level of care that they would receive if they had been born in a referral hospital, without increasing their risks or affecting the wellbeing of the newborn. The Standards Committee of the Spanish Society of Neonatology reviewed and updated recommendations for intrauterine transport and indications for neonatal transfer. They also reviewed organisational and logistic factors involved with performing neonatal transport. The Committee review included the type of personnel who should be involved; communication between referral and receiving hospitals; documentation; mode of transport; equipment to stabilise newly born infants; management during transfer, and admission at the referral hospital.

  5. Bioequivalence of two metformin formulations: 850 mg tablets in healthy colombian volunteers Bioequivalencia de dos formulaciones de metformina, tabletas de 850 mg, en voluntarios sanos colombianos

    Directory of Open Access Journals (Sweden)

    Ómar de Jesús Correa Cano

    2005-03-01

    Full Text Available Introduction: Metformin is an orally active antidiabetic agent used to treat type II diabetes; it is found in the Colombian market in both the innovator brand and the generic formulations. The latter have to prove some biopharmaceutical quality outcomes to guarantee interchangeable proprieties. Objective: To determine whether the drug Dimefor®/Metformina MK is bioequivalent to the reference product Glucophage®, when the products are administrated, at the same dose, to a group of healthy volunteers. Method: The study was made with 24 healthy volunteers who met the inclusion criteria and spontaneously decided to participate after being thoroughly informed. We used a two-sequence threeperiod randomized, crossed and double-blind study. The volunteers took an 850 mg dose of each medicine; then, blood samples were taken throughout 24 hours and the metformin quantification in plasma was determined by High Performance Liquid Chromatography with UV detection (HPLC/UV. For statistical analysis, Schuirmann’s test was used. Results: The study showed that both preparations are bioequivalent; confidence intervals for ln AUC0-∞, ln Cmax, ln AUC0-Tmax and Tmax were [84.6-100.0%], [89.1-109.0%], [83.4–01.4%] and [85.1-109.8% ], respectively. Introducción: la metformina es un antihiperglicemiante útil en el manejo de la diabetes mellitus tipo II, del que se encuentran en el mercado colombiano tanto el producto innovador como diferentes formulaciones genéricas. Para garantizar la seguridad y eficacia de estas últimas, es necesario demostrar su bioequivalencia con respecto al producto innovador. Objetivo: determinar si el producto Dimefor®/Metformina MK es bioequivalente con el producto Glucophage® (referencia cuando se administran en dosis iguales a un grupo de voluntarios sanos. Método: el estudio se realizó sobre veinticuatro voluntarios que cumplieron con los requisitos de inclusión y decidieron participar espontáneamente después de ser

  6. Bioequivalence of nicergoline dispersible tablets in healthy volunteers%尼麦角林分散片在人体的生物等效性

    Institute of Scientific and Technical Information of China (English)

    王晓波; 袭荣刚; 刘丹; 岳宏; 郑慧敏

    2011-01-01

    目的 建立人血浆中尼麦角林分散片代谢产物的LC-MS/MS测定方法,并研究尼麦角林分散片在健康中国志愿者体内的药动学及相对生物利用度.方法 20名男性健康志愿者采用双周期随机交叉给药方案,分别单剂量口服30㎎的尼麦角林试验制剂与参比制剂,采用LC-MS/MS法测定不同时刻血浆样本中尼麦角林代谢产物10α-甲氧基-9,10-二氢麦角醇(MDL)的浓度.应用DAS 2.1软件处理数据,计算2组的药动学参数及相对生物利用度.结果 口服尼麦角林试验制剂或参比制剂后,MDL的ρmax分别为(126.7+44.6)和(128.0±43.0)μg·-1;tmax分别为(3.3±1.7)和(2.4±0.5)h;t1/2分别为(11.0±7.6)和(10.1±7.2)h;AUC0→t分别为(877.9±267.0)和(862.6±268.6)μg·h·L-1.试验制剂中MDL的相对生物利用度为(106.0±28.3)%.结论 试验制剂与参比制剂具有生物等效性.%AIM To determine nicergoline dispersible tablets in human plasma by LC-MS/MS and to evaluate the pharmacokinetics and relative bioavailability of nicergoline dispersible tablets in healthy volunteers.METHODS A single oral dose of 30 mg nicergoline dispersible tablets, test drug or reference drug, was given to 20 healthy male volunteers according to an open randomized crossover study.The plasma concenwation of 10α-methoxy-9,10-dihydroergotamine alcohol(MDL), the active metabolite nicergoline, was determined by LC-MS/MS in different times.The data of pharmacokinetic parameters and relative bioailability were processed by DAS 2.1 software.RESULTS The main pharmacokinetic parameters of MDL in test preparation and reference preparation were obtained as follows: pmax was ( 126.7 ± 44.6) and (128.0±43.0) μg·L-1;tmax was(3.3±1.7) and(2.4±0.5)h;t1/2 was (11.0±7.6) and(10.1 ± 7.2) h;AUC0→t was (877.9 ± 267.0) and (862.6 ± 268.6) μg· h· L- 1, respectively.The average relative bioequivalence of test preparation MDL was ( 106.0 ± 28.3) %.CONCLUSION The results of statistical

  7. SYNTHETIC SLING FAILURE - EVALUATIONS & RECOMMENDATIONS

    Energy Technology Data Exchange (ETDEWEB)

    MACKEY TC; HENDERSON CS

    2009-10-26

    The information and evaluations provided in this report were compiled to address the recurring problem of synthetic sling failure. As safety is the number one priority in all work aspects, a solution must be devised to prevent accidents from occurring. A total of thirteen cases regarding synthetic sling failure were evaluated in order to determine their causes, effects, and preventative measures. From the collected data, it was found that all cases in which the synthetic sling contacted the edge of its load resulted in sling failure. It is required that adequate synthetic sling protection devices be used to protect slings in any lift where the sling comes in direct contact with the edge or corner of its load. However, there are no consensus codes or standards stating the type, material, or purpose of the type of protective device used to protect the sling from being cut. Numerous industry standards and codes provide vague descriptions on how to protect synthetic slings. Without a clear, concise statement of how to protect synthetic slings, it is common for inadequate materials and sling protection devices to be used in an attempt to meet the intent of these requirements. The use of an inadequate sling protection device is the main cause of synthetic sling failure in all researched cases. Commercial sling protection devices come in many shapes and sizes, and have a variety of names, as well as advertised uses. 'Abrasion pads' and 'wear protectors' are two different names for products with the same intended purpose. There is no distinguishable way to determine the extent of sling protection which these devices will provide, or what specific scenarios they are made for. This creates room for error in a field where error is unacceptable. This report provides a recommended action for hoisting and rigging activities which require synthetic slings to contact a load, as well as recommended changes to industry standards which will benefit overall

  8. Recommendation systems in software engineering

    CERN Document Server

    Robillard, Martin P; Walker, Robert J; Zimmermann, Thomas

    2014-01-01

    With the growth of public and private data stores and the emergence of off-the-shelf data-mining technology, recommendation systems have emerged that specifically address the unique challenges of navigating and interpreting software engineering data.This book collects, structures and formalizes knowledge on recommendation systems in software engineering. It adopts a pragmatic approach with an explicit focus on system design, implementation, and evaluation. The book is divided into three parts: "Part I - Techniques" introduces basics for building recommenders in software engineering, including techniques for collecting and processing software engineering data, but also for presenting recommendations to users as part of their workflow.?"Part II - Evaluation" summarizes methods and experimental designs for evaluating recommendations in software engineering.?"Part III - Applications" describes needs, issues and solution concepts involved in entire recommendation systems for specific software engineering tasks, fo...

  9. Economic assessment of nutritional recommendations.

    Science.gov (United States)

    Irz, Xavier; Leroy, Pascal; Réquillart, Vincent; Soler, Louis-Georges

    2015-01-01

    The effect of consumers' compliance with nutritional recommendations is uncertain because of potentially complex substitutions. To lift this uncertainty, we adapt a model of consumer behaviour under rationing to the case of linear nutritional constraints. Dietary adjustments are derived from information on consumer preferences, consumption levels, and nutritional contents of foods. A calibration exercise simulates, for different income groups, how the French diet would respond to various nutrition recommendations, and those behavioural adjustments are translated into health outcomes through the DIETRON epidemiological model. This allows for the ex-ante comparison of the efficiency, equity and health effects of ten nutritional recommendations. Although most recommendations impose significant taste costs on consumers, they are highly cost-effective, with the recommendations targeting salt, saturated fat, and fruits and vegetables (F&V) ranking highest in terms of efficiency. Most recommendations are also economically progressive, with the exception of that targeting F&V.

  10. Recommender systems in industrial contexts

    CERN Document Server

    Meyer, Frank

    2012-01-01

    This thesis consists of four parts: - An analysis of the core functions and the prerequisites for recommender systems in an industrial context: we identify four core functions for recommendation systems: Help do Decide, Help to Compare, Help to Explore, Help to Discover. The implementation of these functions has implications for the choices at the heart of algorithmic recommender systems. - A state of the art, which deals with the main techniques used in automated recommendation system: the two most commonly used algorithmic methods, the K-Nearest-Neighbor methods (KNN) and the fast factorization methods are detailed. The state of the art presents also purely content-based methods, hybridization techniques, and the classical performance metrics used to evaluate the recommender systems. This state of the art then gives an overview of several systems, both from academia and industry (Amazon, Google ...). - An analysis of the performances and implications of a recommendation system developed during this thesis: ...

  11. Bioequivalence study of two imatinib formulations after single-dose administration in healthy Korean male volunteers.

    Science.gov (United States)

    Jung, J A; Kim, N; Yang, J-S; Kim, T-e; Kim, J-R; Song, G-S; Kim, H; Ko, J W; Huh, W

    2014-12-01

    Imatinib mesylate is effective for chronic myeloid leukaemia and gastrointestinal tumours. We aimed to evaluate the pharmacokinetics of a 200-mg imatinib tablet compared to 2×100-mg imatinib tablets in order to meet the regulatory requirements for marketing in Korea.An open-label, randomized, single-dose, 2-period, 2-treatment cross-over study was conducted in 28 healthy Korean male volunteers. Subjects were administered a 200-mg imatinib tablet and 2×100-mg imatinib tablets under a fasting state according to a randomly assigned order with a 2-week wash-out period. Serial blood samples were collected up to 72 h post-dose. The pharmacokinetic parameters were calculated using non-compartmental methods.A total of 28 subjects were enrolled and 23 subjects completed the study. There were no serious adverse events during the study. 23 mild to moderate adverse events were reported (11 events with 200-mg imatinib vs. 12 events with 2×100-mg imatinib) and subjects recovered without sequelae. The Cmax value was 922.8±318.8 μg/L at 3.15 h for 200-mg imatinib tablet, and 986.3±266.0 μg/L at 2.91 h for the 2×100-mg imatinib tablet. The AUClast of 200-mg and 2×100-mg tablets were 13 084.3±39.1 and 14 131.7±3 826.2 h · μg/L, respectively. The geometric mean ratios (90% confidence intervals) for Cmax and AUClast were 0.9121 (0.8188, 1.0161) and 0.9558 (0.8685, 1.0519), respectively.A newly developed 200-mg imatinib tablet was bioequivalent to 2×100-mg imatinib tablets in healthy Korean subjects. A single-dose of either of the 2 formulations was generally well tolerated.

  12. Bioequivalence studies for three formulations of a recombinant human growth hormone: challenges and lessons learned.

    Science.gov (United States)

    Dao, Le; Jacobs, Joan; Kuebler, Peter; Bakker, Bert; Lippe, Barbara

    2010-10-01

    Two bioequivalence (BE) studies in healthy volunteers comparing new formulations of the recombinant human growth hormone (rhGH) Nutropin AQ (somatropin [rDNA origin] injection; Genentech, Inc., South San Francisco, CA) with the currently marketed formulation (5 mg/mL) were conducted to extend available dosing options. All formulations were administered by subcutaneous (SC) injection ranging in volume from 0.25 to 1.0 mL depending on the formulation concentration. Study A was a 2-period crossover design to assess the BE of 5 and 10 mg/mL. The estimate for relative bioavailability (AUC(0-24 h)) was within the prespecified BE interval (0.80-1.25). However, while the C(max) estimate (1.17) was contained within the range for BE, the 90% CI (0.986-1.38) extended beyond the prespecified BE interval. As a result, Study A failed to show BE between the 5 and 10mg/mL formulations. Review of the data showed unexpected increased variability in the observed C(max). Further review of individual data suggested that in 4 subjects, the GH concentration profile of 1 of the 2 injections closely resembled the absorption kinetics of an intramuscular injection rather than an SC injection. Because study conduct may have contributed to these results, we performed a second study, Study B. This study incorporated injection technique training, a defined injection site, and a larger sample size to accommodate variability. It also included a third formulation, creating a 3-period crossover design to assess the BE of 2.5, 5, and 10 mg/mL. Study B results demonstrated BE of the new 2.5- and 10-mg/mL formulations to the reference 5-mg/mL formulation, and BE to each other, with all 90% CIs within the BE range of 0.80 to 1.25. Thus the challenge of recognizing that design issues could affect outcomes gave us the tools to perform a second study, and the positive results taught us that demonstrating BE is an issue not only of pharmacology, but also of study methodology and execution.

  13. Recommendation Sets and Choice Queries

    DEFF Research Database (Denmark)

    Viappiani, Paolo Renato; Boutilier, Craig

    2011-01-01

    Utility elicitation is an important component of many applications, such as decision support systems and recommender systems. Such systems query users about their preferences and offer recommendations based on the system's belief about the user's utility function. We analyze the connection between...... the problem of generating optimal recommendation sets and the problem of generating optimal choice queries, considering both Bayesian and regret-based elicitation. Our results show that, somewhat surprisingly, under very general circumstances, the optimal recommendation set coincides with the optimal query....

  14. The advantages of combination therapy on hypertension: development of immediate release perindopril-indapamide tablet and assessment of bioequivalence studies.

    Science.gov (United States)

    Ölçer, A; Ölçer, M; İnce, I; Karasulu, E

    2016-03-01

    Hypertension has a major associated risk for organ damage and mortality, which is further heightened in patients with prior cardiovascular events, comorbid diabetes mellitus, microalbuminuria and renal impairment. Convers Plus tablet including perindopril erbumine (PE), which is an angiotensin converting enzyme (ACE) inhibitor, and indapamide, which is diuretic, was designed as a combined tablet to succes in the treatment of hypertension. Physico-pharmaceutical properties and characterization studies were evaluated in vitro conditions. Later on in vivo study was planned as a cross-designed, randomized, open-labeled, single-dose, single-center study via peroral route in 24 healthy male subjects. In this study, bioequivalence with primary pharmacokinetical target parameters reference (Bipreterax 4/1.25 mg Tablet-S.A.Servier Benelux N.V.) and test (Convers Plus 4/1.25 mg Tablet-ARGESAN Pharmaceutical Company) tablets have been found bioequivalent. The results of pharmacokinetic parameters for perindopril, perindoprilat and indapamide were found as Cmax = 23.179 µg/mL, tmax = 0.729 h, t1/2 = 1.429 h; AUC0-t = 26.998 µgs/mL, AUC0-inf = 27.117 µgs/mL; Cmax = 1.834 µg/mL, tmax = 8.792 h, t1/2 = 40.699 h; AUC0-t = 54.828 µgs/mL, AUC0-inf = 77.113 µgs/mL; Cmax = 18.994 µg/mL, tmax = 3.417 h, t1/2 = 16.626 h and AUC0-t = 385.829 µgs/mL, AUC0-inf = 410.728 µgs/mL respectively. In conclusion, physico-pharmaceutical properties and results of clinical trials show that Convers Plus tablets have been found as bioequivalent for perindopril, perindoprilat and indapamide in terms of AUC and Cmax, in 90% confidence limits.

  15. Pharmacokinetic and bioequivalence studies of trospium chloride after a single-dose administration in healthy Chinese volunteers.

    Science.gov (United States)

    Zhang, R; Yuan, G; Li, R; Liu, X; Wei, C; Wang, B; Gao, H; Guo, R

    2012-05-01

    The study aimed to compare and evaluate the bioequivalence of a new generic preparation of trospium chloride (CAS NO:10405-02-4) capsule (20 mg, test) and the available import tablet (20 mg , reference) for the requirement of state regulatory criteria in China. A randomized- sequence, 2-period crossover study was conducted in 20 healthy Chinese male volunteers in the fasted state. Blood samples were collected before and 1, 2, 3, 4, 5, 6, 7, 8, 12, 24, 36, 48, 60 h after administration of a single oral dose of 40 mg trospium chloride capsules or tablets, followed by a 7-day washout period. The concentration of trospium chloride was determined by a LC-MS/MS method. Drug And Statistical-Version 2.0 was used to calculate the pharmacokinetics parameters and assess bioequivalence of the two preparations. It was considered bioequivalent if the 90% CIs of the mean ratios (test: reference) for Cmax, AUC0-t and AUC0-∞ were within the range from 80% to 125%, respectively. The main pharmacokinetics parameters of test and reference were as follows: t1/2 was (15.11 ± 3.24) h and (16.00 ± 3.96) h; Tmax was (4.0 ± 1.2) h and (4.1 ± 0.9) h; Cmax was (3.76 ± 1.87) ng·mL - 1 and (3.70 ± 1.89) ng·mL - 1; AUC0-t was (33.51 ± 14.39) ng·mL - 1·h and (33.33 ± 14.88) ng·mL - 1·h, and the AUC0-∞ was (35.20 ± 14.88) ng·mL - 1·h and (35.16±15.17) ng·mL - 1·h. The ratios (test: reference) for Cmax, AUC0-t, and AUC0-∞ were 94.0%~111.7%, 96.4%~106.8%, and 96.1%~105.3%, respectively. No significant differences in pharmacokinetic parameters were found between preparations and periods (p>0.05). No obvious adverse events were monitored throughout the study based on clinical parameters and patient reports.

  16. Bioequivalence studies of two different film-coated tablet formulations of valacyclovir of two different strengths in healthy volunteers.

    Science.gov (United States)

    Neves, Rita; Almeida, Susana; Filipe, Augusto; Spinola, Ana Cristina Franco; Abolfathi, Zohreh; Lévesque, Ann; Ortuño, Jordi; Torns, Alex

    2010-01-01

    These studies were conducted in order to assess the bioequivalence of two film-coated formulations containing 250 mg and 1000 mg of valacyclovir (INN: valaciclovir; CAS 124832-26-4), which is the L-valyl ester and a pro-drug of the antiviral drug acyclovir (INN: aciclovir). In the study with valacyclovir 250 mg, 36 healthy subjects were enrolled in a randomized, single-dose, open-label, 2-way crossover study, with a washout period of 10 days. In the study with valacyclovir 1000 mg, 46 healthy subjects were enrolled in a randomized, single-dose, open-label, 2-way crossover study, with a washout period of 7 days. Plasma samples were collected up to 36 h postdose for both studies. Valacyclovir levels were determined by liquid chromatography with tandem mass detection (ie, the LC/MS/MS method) (lower limit of quantification: 0.50 ng/ mL for valacyclovir and 9.93 ng/mL for acyclovir for the 250 mg study and 1.00 ng/mL for valacyclovir and 20.00 ng/ mL for acyclovir for the 1000 mg study). Pharmacokinetic parameters used for bioequivalence assessment were the area under the concentration-time curve from time zero to time of last non-zero concentration (AUC(0-t)) and from time zero to infinity (AUC(0-inf) and maximum observed concentration (C(max)). These parameters were determined from the valacyclovir concentration data using non-compartmental analysis. In the tained by analysis of variance (ANOVA) for valacyclovir were 107.54-124.26% for C(max), 95.45-103.46% for AUC(0-Inf) and 95.53-103.63% for AUC(0-t) whereas for acyclovir the 90% confidence intervals obtained were 103.19-117.02% for C(max), 99.61-106.92% for AUC(0-Inf) and 99.58-106.94% for AUC(0-t). In the study with valacyclovir 1000 mg formulations, the 90% confidence intervals obtained for valacyclovir were 93.20-107.35% for C(max), 90.87-96.27% for AUC(0-inf) and 90.87-96.27% for AUC(0-t) whereas for acyclovir the 90% CIs obtained were 95.98-104.94% for C(max), 97.13-103.94% for AUC(0-inf) and 97

  17. Feature Analysis of Recommender Techniques Employed in the Recommendation Engines

    Directory of Open Access Journals (Sweden)

    Gopinath Ganapathy

    2010-01-01

    Full Text Available Problem statement: Recommender Systems (RS have become a widely researched area as it is extensively used in web usage mining and E-commerce platforms. Approach: There were a number of recommender systems available to suggest the web pages for the web users. Results: A recommender system acted as an intelligent intermediary that automatically generates and predicts information and web pages, which suit the users’ behavior and users’ needs. Conclusion: The various recommender models and analyzing the key features of those models and analyzing the features of portal sites that employ recommender systems to help the research community are the key features of this study and survey.

  18. QEIP Evaluation - Results & Recommendations

    OpenAIRE

    2014-01-01

    In 2010 War Child Holland (WCH) started a program aimed at improving the quality of education in governmental primary schools in Northern Uganda and Karamoja sub-region - Quality Education Improvement Plan (QEIP). QEIP uses a community based approach, involving all school stakeholders, with the aim to increase relevance and sustainability by putting the ownership of the activity with the children, school, community, local leaders and district. Through improving the quality of education and en...

  19. Esthesioneuroblastomas: Reservations and Recommendations

    Science.gov (United States)

    Nayal, Bhavna; Kumar, Vinod; Jaiprakash, Padmapriya

    2016-01-01

    Neuroectodermal tumour has a wide range of biological activity that ranges from an indolent course to local recurrence and rapid widespread metastasis. We describe, herewith, 2 patients with Esthesioneuroblastomas (ENB) who had varied atypical clinical presentation. The first case presented with Intracranial Pressure (ICP) headache and acute visual deterioration with radiology revealing an extra axial lesion with extension into the nasal cavity while the second case presented with nasal congestion and progressive headache of long duration. We review the unusual characteristics that may uncommonly occur in ENBs and elaborate regarding which of these must be considered when evaluating patients with this malignancy. PMID:27630897

  20. Promoting cold-start items in recommender systems

    CERN Document Server

    Liu, Jin-Hu; Zhang, Zi-Ke; Yang, Zimo; Liu, Chuang; Li, Wei-Min

    2014-01-01

    As one of major challenges, cold-start problem plagues nearly all recommender systems. In particular, new items will be overlooked, impeding the development of new products online. Given limited resources, how to utilize the knowledge of recommender systems and design efficient marketing strategy for new items is extremely important. In this paper, we convert this ticklish issue into a clear mathematical problem based on a bipartite network representation. Under the most widely used algorithm in real e-commerce recommender systems, so-called the item-based collaborative filtering, we show that to simply push new items to active users is not a good strategy. To our surprise, experiments on real recommender systems indicate that to connect new items with some less active users will statistically yield better performance, namely these new items will have more chance to appear in other users' recommendation lists. Further analysis suggests that the disassortative nature of recommender systems contributes to such ...

  1. Context-Aware Recommender Systems

    Science.gov (United States)

    Adomavicius, Gediminas; Tuzhilin, Alexander

    The importance of contextual information has been recognized by researchers and practitioners in many disciplines, including e-commerce personalization, information retrieval, ubiquitous and mobile computing, data mining, marketing, and management. While a substantial amount of research has already been performed in the area of recommender systems, most existing approaches focus on recommending the most relevant items to users without taking into account any additional contextual information, such as time, location, or the company of other people (e.g., for watching movies or dining out). In this chapter we argue that relevant contextual information does matter in recommender systems and that it is important to take this information into account when providing recommendations. We discuss the general notion of context and how it can be modeled in recommender systems. Furthermore, we introduce three different algorithmic paradigms - contextual prefiltering, post-filtering, and modeling - for incorporating contextual information into the recommendation process, discuss the possibilities of combining several contextaware recommendation techniques into a single unifying approach, and provide a case study of one such combined approach. Finally, we present additional capabilities for context-aware recommenders and discuss important and promising directions for future research.

  2. Quantification of Lumefantrine in Human Plasma Using LC-MS/MS and Its Application to a Bioequivalence Study.

    Science.gov (United States)

    Pingale, Satish G; Mangaonkar, Kiran V

    2013-01-01

    An analytical method based on protein precipitation has been developed and validated for analysis of lumefantrine in human plasma. Artesunate was used as an internal standard for lumefantrine. Inertsil ODS column provided chromatographic separation of analytes followed by detection with mass spectrometry. The method involves simple isocratic chromatographic condition and mass spectrometric detection in the positive ionization mode using an API-3000 system. The total run time was 2.5 minutes. The proposed method has been validated with linear range of 200-20000 ng/mL for lumefantrine. The intrarun and interrun precision values are within 6.66% and 5.56%, respectively, for lumefantrine at the lower limit of quantification level. The overall recovery for lumefantrine and artesunate was 93.16% and 91.05%, respectively. This validated method was used successfully for analysis of plasma samples from a bioequivalence study.

  3. Quantification of Lumefantrine in Human Plasma Using LC-MS/MS and Its Application to a Bioequivalence Study

    Directory of Open Access Journals (Sweden)

    Satish G. Pingale

    2013-01-01

    Full Text Available An analytical method based on protein precipitation has been developed and validated for analysis of lumefantrine in human plasma. Artesunate was used as an internal standard for lumefantrine. Inertsil ODS column provided chromatographic separation of analytes followed by detection with mass spectrometry. The method involves simple isocratic chromatographic condition and mass spectrometric detection in the positive ionization mode using an API-3000 system. The total run time was 2.5 minutes. The proposed method has been validated with linear range of 200–20000 ng/mL for lumefantrine. The intrarun and interrun precision values are within 6.66% and 5.56%, respectively, for lumefantrine at the lower limit of quantification level. The overall recovery for lumefantrine and artesunate was 93.16% and 91.05%, respectively. This validated method was used successfully for analysis of plasma samples from a bioequivalence study.

  4. Determination of phenobarbital in human plasma by a specific liquid chromatography method: application to a bioequivalence study

    Directory of Open Access Journals (Sweden)

    Sérgio Luiz Dalmora

    2010-01-01

    Full Text Available A liquid chromatography method was developed and validated for the determination of phenobarbital in human plasma using phenytoin as internal standard. The drugs were extracted from plasma by liquid-liquid extraction and separated isocratically on a C12 analytical column, maintained at 35 ºC, with water:acetonitrile:methanol (58.8:15.2:26, v/v/v as mobile phase, run at a flow rate of 1.2 mL/min with detection at 205 nm. The method was linear in the range of 0.1-4 μg/mL (r²=0.9999 and demonstrated acceptable results for the precision, accuracy and stability studies. The method was successfully applied for the bioequivalence study of two tablet formulations (test and reference of phenobarbital 100 mg after single oral dose administration to healthy human volunteers.

  5. From micronutrient recommendations to policy

    DEFF Research Database (Denmark)

    Timotijevic, Lada; Raats, Monique M.; Barnett, Julie

    2010-01-01

    Background/Objectives: To achieve the nutritional goals stipulated by micronutrient recommendations, greater attention must be paid to the behavioural routes to such nutritional outcomes. Coopting stakeholders and consumers into decisions regarding micronutrient recommendations is an important step...... towards achieving a greater link between micronutrient recommendations and behaviour. This study aims to examine the rationale and processes associated with consumer and stakeholder involvement in setting micronutrient recommendations across Europe. Subjects/Methods: Using the contacts established through...... the Eurreca network of excellence (commissioned by the European Commission), the research involved in-depth desk research of key documents and communication channels linked to the process of setting micronutrient recommendations across seven countries: the United Kingdom, Norway, Denmark, Germany, Spain...

  6. Bioequivalence of ondansetron oral soluble film 8 mg (ZUPLENZ) and ondansetron orally disintegrating tablets 8 mg (ZOFRAN) in healthy adults.

    Science.gov (United States)

    Dadey, Eric

    2015-01-01

    Oral formulations of ondansetron are used to prevent nausea and vomiting associated with chemotherapy, radiotherapy, and surgery. An oral soluble film formulation of ondansetron (OND OSF) was developed using MonoSol Rx's proprietary PharmFilm technology and was formulated to dissolve rapidly on the tongue, without the need for water. This product provides an oral antiemetic treatment option for patients who experience difficulty swallowing. The purpose of this study was to compare the bioequivalence of OND OSF 8 mg (ZUPLENZ, Monosol Rx, Warren, NJ) with ondansetron orally disintegrating tablets (OND ODT) 8 mg (ZOFRAN, GlaxoSmithKline, Research Triangle Park). In 3 individual open-label, randomized studies, healthy adult subjects received a single dose of OND OSF 8 mg and a single dose of OND ODT 8 mg, under fasted conditions (study 1, n = 48), fed conditions (study 2, n = 48), and fasted with and without water (study 3, n = 18). Each dosing period was followed by a 3- or 7-day washout period. Ondansetron pharmacokinetics were assessed predose to 24 hours postdose for the single 8-mg doses of OND OSF and OND ODT. All analyses were conducted on natural log-transformed pharmacokinetic parameters for OND OSF and OND ODT. Under both fasted and fed conditions, the 90% confidence interval for the comparisons of OND OSF and OND ODT plasma ondansetron area under the curve from time 0 to the last measured concentration (AUC0-t), area under the concentration vs. time curve from time 0 to infinity (AUC0-∞), and maximum plasma concentration (Cmax) were within the 80%-125% range, indicating bioequivalence between the formulations. With features designed to make it portable and easy to take, OND OSF 8 mg provides an alternative treatment option, particularly for patients with dysphagia and others who find it difficult to take oral tablets.

  7. Pharmacokinetics of fixed-dose combination of tenofovir disoproxil fumarate, lamivudine, and efavirenz: results of a randomized, crossover, bioequivalence study.

    Science.gov (United States)

    Abhyankar, Dhiraj; Shedage, Ashish; Gole, Milind; Raut, Preeti

    2016-06-17

    The objective of this study was to assess the bioequivalence between a fixed-dose combination of tenofovir disoproxil fumarate/lamivudine/efavirenz 300/300/600 mg and the individual innovator products. A randomized, balanced, open-label, two-sequence, two-treatment, two-period, single dose, crossover study in 48 healthy adults was conducted. Dosing was separated by a washout period of 32 days. Twenty-seven blood samples were collected in each period from pre-dose to 72 h post-dose. The data of 45 subjects were analyzed for pharmacokinetics and safety. Ninety percent CIs of geometric mean ratio on Cmax, AUC0-t, and AUC0-inf for tenofovir and lamivudine and on Cmax and AUC0-72 for efavirenz were within the acceptance criteria (80-125%). For tenofovir disoproxil fumarate, the Tmax, Kel, and t1/2 values for the test and reference products were 1.02 versus 0.91 h, 0.04 versus 0.04/h, 18.67 versus 18.46 h, respectively. For lamivudine, the Tmax, Kel, and t1/2 values were: 1.38 versus 1.30 h, 0.21 versus 0.19/h, 3.44 versus 3.91 h, respectively. For efavirenz, the Tmax values for the test and reference products were 3.71 and 3.65 h, respectively. Both the treatments were well tolerated. Our findings suggest that the tested formulation is bioequivalent to the innovators' formulations, and both treatments were well tolerated.

  8. An improved LC-MS/MS method for quantitation of indapamide in whole blood: application for a bioequivalence study.

    Science.gov (United States)

    Pinto, Guilherme Araújo; Pastre, Kátia Isabel Fercondini; Bellorio, Karini Bruno; de Souza Teixeira, Leonardo; de Souza, Weidson Carlo; de Abreu, Fernanda Crunivel; de Santana E Silva Cardoso, Fabiana Fernandes; Pianetti, Gerson Antônio; César, Isabela Costa

    2014-09-01

    An improved LC-MS/MS method for the quantitation of indapamide in human whole blood was developed and validated. Indapamide-d3 was used as internal standard (IS) and liquid-liquid extraction was employed for sample preparation. LC separation was performed on Synergi Polar RP-column (50 × 4.6 mm i.d.; 4 µm) and mobile phase composed of methanol and 5 mm aqueous ammonium acetate containing 1 mm formic acid (60:40), at flow rate of 1 mL/min. The run time was 3.0 min and the injection volume was 20 μL. Mass spectrometric detection was performed using electrospray ion source in negative ionization mode, using the transitions m/z 364.0 → m/z 188.9 and m/z 367.0 → m/z 188.9 for indapamide and IS, respectively. Calibration curve was constructed over the range 0.25-50 ng/mL. The method was precise and accurate, and provided recovery rates >80% for indapamide and IS. The method was applied to determine blood concentrations of indapamide in a bioequivalence study with two sustained release tablet formulations. The 90% confidence interval for the geometric mean ratios for maximum concentration was 95.78% and for the area under the concentration-time curve it was 97.91%. The tested indapamide tablets (Eurofarma Laboratórios S.A.) were bioequivalent to Natrilix®, according to the rate and extent of absorption.

  9. Determination of plasma topiramate concentration using LC-MS/MS for pharmacokinetic and bioequivalence studies in healthy Korean volunteers.

    Science.gov (United States)

    Park, Jin-Hee; Park, Yoo-Sin; Lee, Min-Ho; Rhim, Si-Youn; Song, Jae-Chul; Lee, Soo-Jin; Kim, Jung-Mogg; Shaw, Leslie M; Kang, Ju-Seop

    2008-08-01

    A rapid, simple and validated liquid chromatography coupled to tandem mass spectrometric method (LC-MS/MS) for topiramate analysis in human plasma has been applied to pharmacokinetic and bioequivalence studies in 24 healthy male Korean volunteers. The procedure involves a simple liquid extraction of topiramate and prednisone (internal standard) with acetonitrile and separation by HPLC equipped with a Capcell Pak C18 column using acetonitrile-0.1% triethylamine (80:20, v/v) as a mobile phase. Detection was carried out on an API 2000 MS system by multiple reactions monitoring mode. The ionization was optimized using ESI(-) and selectivity was achieved by MS/MS analysis, m/z 338.0 --> 77.5 and m/z 357.1 --> 327.2 for topiramate and prednisone, respectively. The method had a total run time of 2.5 min and showed good linearity over a working range of 20-5000 ng/mL in human plasma with a lower limit of quantification of 20 ng/mL. No metabolic compounds were found to interfere with the analysis. The inter-day and intra-day accuracy were in the ranges of 99.24-116.63 and 93.45-108.68%, respectively, and inter-day and intra-day precisions were below 6.24 and 5.25%, respectively. This method was successfully applied for pharmacokinetic and bioequivalence studies by analysis of blood samples taken up to 96 h after an oral administration of 100 mg of topiramate in 24 healthy Korean volunteers.

  10. Determination of paroxetine in plasma by liquid chromatography coupled to tandem mass spectrometry for pharmacokinetic and bioequivalence studies.

    Science.gov (United States)

    Jhee, Ok Hwa; Seo, Hee Kyoung; Lee, Min Ho; Jeon, Yong Cheol; Shaw, Leslie M; Lee, Seung Hoon; Hur, Yeon; Kim, Kwang-Hyun; Lee, Heon-Soo; Lee, Seo Eun; Kang, Ju Seop

    2007-01-01

    A rapid and validated liquid chromatography coupled to tandem mass spectrometric method (LC-MS-MS) has been developed and applied to pharmacokinetic and bioequivalence studies in 24 healthy male Korean volunteers. The procedure involves a liquid-liquid extraction of paroxetine (CAS 61869-08-7) and fluoxetine (internal standard, CAS 54910-89-3) with ether/methyl chloride (7:3, v/v) and separated by LC equipped with C18 column using acetonitrile: 5 mmol/L ammonium formate (4:3, v/v) as mobile phase. Detection is carried out on an API 2000 MS system by multiple reactions monitoring mode. The ionization was optimized using ESI(+) and selectivity was achieved by MS-MS analysis, mlz 330.0-->192.0 and m/ z 310-->148 for paroxetine and fluoxetine, respectively. The method has a total run time of 1.5 min and was linear over a working range of 0.05-20 ng/mL and the lower limit of quantification was 0.05 ng/ mL. No endogenous compounds were found to interfere with the analysis. The inter-day and intra-day accuracy was in the ranges of 102.69-107.79% and 102.07-109.57%, respectively and precision of inter-day and intra-day expressed as relative standard deviation were 1.86-9.99% and 1.52-6.28%, respectively. The validation of this method on linearity, specificity, accuracy, precision as well as applicability to pharmacokinetic and bioequivalence studies by analysis of blood samples taken up to 72 h after oral administration of 20 mg of paroxetine in 24 healthy volunteers were found to be good performance.

  11. Efectos del envejecimiento en las capacidades físicas: implicaciones en las recomendaciones de ejercicio físico en personas mayores. (Effects of aging on physical fitness: implications in the recommendations of physical activity for older adults.

    Directory of Open Access Journals (Sweden)

    Ana Carbonell Baeza

    2009-10-01

    showed to be an useful tool for decelerating the aging process; however, benefits only occur when the physical activity is practiced at the appropriate volume and intensity. Different recommendations for frequency, intensity and duration of physical exercise have been published. The current recommendations for elderly people, determine the minimal criteria for volume and intensity, and they must be taken into consideration when prescribing physical exercise in old people.

  12. 美国“积极生活研究”计划解读及启示%A interpretation of and inspirations from the“Active Life Research”program recommended by the United States

    Institute of Scientific and Technical Information of China (English)

    吴薇; 何晓龙; 陈佩杰

    2014-01-01

    环境和政策的策略,对体力活动的影响是近年来公共卫生领域的热点。美国推介“积极生活研究”计划作为该领域研究的一个典范,以美国突出的公共健康问题——儿童、青少年体力活动不足和肥胖为核心内容,围绕有关环境和政策策略,在促进儿童及其家庭成员日常体力活动中的作用展开研究。“积极生活研究”计划是“积极生活”计划体系的开端和重要组成部分,它提供了儿童肥胖和缺乏身体活动关系的可靠依据,并形成以行动为向导的研究成果,为此类问题的后续研究奠定了基础。%The influence of environment and policy strategies is a hot topic in the public health area in recent years. As a model of research in this area, the“Active Life Research”program recommended by the United States makes a study of boosting the functions of children and their family members in daily physical activities by basing its core contents on children and teenager physical activity insufficiency and obesity–prominent public health issues faced by the United States, and by sticking to environment and policy related strategies. The“Active Life Research”pro-gram is the initial and an important constituent part of the“Active Life”program system;it has provided a reliable criterion for the relationship between children obesity and lack of physical activities, and formed action oriented re-search achievements, which laid a foundation for follow-up researches on such a type of issues.

  13. 76 FR 81 - Adoption of Recommendation

    Science.gov (United States)

    2011-01-03

    ...; ] ADMINISTRATIVE CONFERENCE OF THE UNITED STATES Adoption of Recommendation AGENCY: Administrative Conference of... the attached recommendation at its Fifty-third Plenary Session. The recommendation addresses issues... makes recommendations for improvements to the agencies, collectively or individually, and to...

  14. 内源性物质药物生物等效性评价的探讨%Review on the methods assessing the bioequivalence of endogenous substances

    Institute of Scientific and Technical Information of China (English)

    曹国颖; 朱孔彩; 胡欣

    2012-01-01

    Assessment of the bioequivalence of drugs made of endogenous substances is complicated because it is difficult to distinguish the externally administered drugs with the endogenous ones following drug administration. A literature search of the PubMed and Wanfang databases was performed, and the commonly used bioequivalence assessment methods are reviewed in this article.%内源性物质是体内已有的物质,内源性物质药物生物等效性的评价因为体内自身物质的存在变得复杂化.文中以内源性物质和生物等效性为关键词,检索Pubmed和万方数据库,对常用的内源性物质药物的生物等效性评价方法进行了综述.

  15. Bioequivalence of two lansoprazole delayed release capsules 30 mg in healthy male volunteers under fasting, fed and fasting-applesauce conditions: a partial replicate crossover study design to estimate the pharmacokinetics of highly variable drugs.

    Science.gov (United States)

    Thota, S; Khan, S M; Tippabhotla, S K; Battula, R; Gadiko, C; Vobalaboina, V

    2013-11-01

    An open-label, 2-treatment, 3-sequence, 3-period, single-dose, partial replicate crossover studies under fasting (n=48), fed (n=60) and fasting-applesauce (n=48) (sprinkled on one table spoonful of applesauce) modalities were conducted in healthy adult male volunteers to evaluate bioequivalence between 2 formulations of lansoprazole delayed release capsules 30 mg. In all the 3 studies, as per randomization, either test or reference formulations were administered in a crossover manner with a required washout period of at least 7 days. Blood samples were collected adequately (0-24 h) to determine lansoprazole plasma concentrations using a validated LC-MS/MS analytical method. To characterize the pharmacokinetic parameters (Cmax, AUC0-t, AUC0-∞, Tmax, Kel and T1/2) of lansoprazole, non-compartmental analysis and ANOVA was applied on ln-transformed values. The bioequivalence was tested based on within-subject variability of the reference formulation. In fasting and fed studies (within-subject variability>30%) bioequivalence was evaluated with scaled average bioequivalence, hence for the pharmacokinetic parameters Cmax, AUC0-t and AUC0-∞, the 95% upper confidence bound for (μT-μR)2-θσ2 WR was ≤0, and the point estimates (test-to-reference ratio) were within the regulatory acceptance limit 80.00-125.00%. In fasting-applesauce study (within-subject variability<30%) bioequivalence was evaluated with average bioequivalence, the 90% CI of ln-transformed data of Cmax, AUC0-t and AUC0-∞ were within the regulatory acceptance limit 80.00-125.00%. Based on these aforesaid statistical inferences, it was concluded that the test formulation is bioequivalent to reference formulation.

  16. Bioequivalence evaluation of two amlodipine salts, besylate and orotate, each in a fixed-dose combination with olmesartan in healthy subjects

    Directory of Open Access Journals (Sweden)

    Lee SY

    2015-06-01

    Full Text Available Soo-Yun Lee,1 Jung-Ryul Kim,2,3 Jin Ah Jung,4 Wooseong Huh,2,5 Mi Young Bahng,6 Jae-Wook Ko1,2 1Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea; 2Department of Clinical Pharmacology and Therapeutics, Samsung Medical Center, Seoul, Republic of Korea; 3Department of Clinical Research Design and Evaluation, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea; 4Department of Clinical Pharmacology, Inje University, Busan Paik Hospital, Busan, Republic of Korea; 5Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; 6Dong-A ST Co., Ltd., Seoul, Republic of Korea Abstract: A fixed-dose combination of amlodipine and olmesartan is used to treat high blood pressure in patients whose hypertension is not sufficiently controlled with either drug alone. The objective of this study was to evaluate the bioequivalence of two fixed-dose combinations, ie, amlodipine orotate/olmesartan medoxomil 10/40 mg and amlodipine besylate/olmesartan medoxomil 10/40 mg, in healthy subjects. A randomized, open-label, single-dose, two-sequence, two-period, crossover study was conducted in 30 healthy adult volunteers. Blood samples were collected for up to 72 hours post-dose in each period. Safety data included the results of physical examinations, clinical laboratory tests, vital signs, an electrocardiogram, and adverse events. For both amlodipine and olmesartan, the 90% confidence intervals for the geometric mean ratios of AUClast and time to peak plasma concentration fell within the bioequivalence acceptance criteria. The two fixed-dose combinations showed similar safety profiles. Amlodipine orotate/olmesartan medoxomil 10/40 mg was bioequivalent to amlodipine besylate/olmesartan medoxomil 10/40 mg. Keywords: amlodipine orotate, amlodipine besylate, olmesartan medoxomil, fixed-dose combination, bioequivalence

  17. Development of a simple LC-MS/MS method for the determination of febuxostat in human plasma and its application to a bioequivalence study.

    Science.gov (United States)

    Shi, Zheng; Liu, Jian; Hu, Xing-Jiang; ShenTu, Jian-Zhong

    2013-06-01

    The purpose of this study was to design a simple, sensitive and rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for a febuxostat bioequivalence study in healthy Chinese male volunteers. In this method, febuxostat and etodolac (internal standard) were isolated from plasma samples by protein precipitation with acetonitrile. The supernatant was chromatographed on a Zorbax SB-C18 (150 x 3.0 mm, 3.5-microm particle size, Agilent) column with a SecurityGuard Inertsil Symmetry C18 column (12.5 x 4.6 mm, 5-microm particle size, Waters). The lower limit of quantification for febuxostat in 0.2 mL of human plasma was 13.40 ng x mL(-1), and the linearity was achieved over a concentration range from 13.40 to 21440 ng x mL(-1). Febuxostat tablets from Hengrui Medicine Co., Ltd (test, Jiangsu, China) and from Takeda pharmaceuticals america, Inc. (reference, Deerfield, IL) were evaluated following a single 80 mg oral dose to 18 healthy volunteers. Bioequivalence was determined by calculating 90% confidence intervals (90% CI) for the ratio of C(max), AUC(0-t), and AUC(0-infinity) values for the test and reference products, using logarithmic transformed data. The calculated 90% CIs for the ratio of C(max) (88.7-131.2%), AUC(0-t) (99.2-122.7%) and AUC(0-infinity) (99.5-123.1%) values for the test and reference products were all located within the bioequivalence criteria range (80-125% for AUC, and 70-143% for Ca(mzax)), proposed by State of Food and Drug Administration [SFDA, 2005. China]. It was concluded that the two febuxostat formulations (test and reference) analyzed were bioequivalent in terms of rate and extent of absorption and the method met the principle of quick and easy clinical analysis.

  18. Bioequivalence of Alendronate and Vitamin D3 in a Combination Tablet Versus Corresponding-Dose Individual Tablets in Healthy Taiwanese Volunteers, Determined Using a Novel Plasma Alendronate Assay

    Directory of Open Access Journals (Sweden)

    D. Hamish Wright, PhD

    2015-12-01

    Conclusions: The combination tablet was considered bioequivalent to coadministration based on ALN AUC0–∞ and unadjusted vitamin D3 parameters. Slight differences for ALN AUC0–last and Cmax (upper 90% CIs outside the bounds were not considered clinically significant. The combination tablet was well tolerated. No serious adverse experiences were reported. © 2015. The Authors. Published by Elsevier Inc. All rights reserved.

  19. Reverse-phase liquid chromatography with electrospray ionization/mass spectrometry for the quantification of pseudoephedrine in human plasma and application to a bioequivalence study.

    Science.gov (United States)

    Kim, Jin-Ki; Jee, Jun-Pil; Park, Jeong-Sook; Kim, Hyung Tae; Kim, Chong-Kook

    2011-01-01

    A sensitive and selective reverse-phase liquid chromatography electrospray ionization mass spectrometry (LC-ESI-MS) method was developed and validated to quantify pseudoephedrine (CAS 90-82-4) in human plasma. Phenacetin was used as the internal standard (I.S.). Sample preparation was performed with a deproteinization step using acetonitrile. Pseudoephedrine and I.S. were successfully separated using gradient elution with 0.5% trifluoroacetic acid (TFA) in water and 0.5% TFA in methanol at a flow-rate of 0.2 mL/min. Detection was performed on a single quadrupole mass spectrometer by a selected ion monitoring (SIM) mode via electrospray ionization (ESI) source. The ESI source was set at positive ionization mode. The ion signals of m/z 166.3 and 180.2 were measured for the protonated molecular ions of pseudoephedrine and I.S., respectively. The lower limit of quantification (LLOQ) of pseudoephedrine in human plasma was 10 ng/mL and good linearity was observed in the range of concentrations 10-500 ng/mL (R2 = 1). The intra-day accuracy of the drug containing plasma samples was more than 97.60% with a precision of 3.99-11.82%. The inter-day accuracy was 99.36% or more, with a precision of 7.65-18.42%. By using this analytical method, the bioequivalence study of the pseudoephedrine preparation was performed and evaluated by statistical analysis of the log transformed mean ratios of pharmacokinetic parameters. All the results fulfilled the standard criteria of bioequivalence, being within the 80-125% range which is required by the Korea FDA, US FDA, and EMEA to conclude bioequivalence. Consequently, the developed reverse-phase LC-ESI-MS method was successfully applied to bioequivalence studies of pseudoephedrine in healthy male volunteers.

  20. Comparison of liquid chromatography-ultraviolet and chromatography-tandem mass spectrometry for the determination of indapamide in human whole blood and their applications in bioequivalence studies.

    Science.gov (United States)

    Zhao, Libo; Gu, Shifen; Xu, Rong; Cui, Xiaoyu; Gan, Fangliang; Chen, Hui

    2010-01-01

    The aim of this study was to compare two methods which were based on liquid chromatography with ultraviolet detection (LC-UV) and liquid chromatography-tandem mass spectrometry (LC-MS/MS), respectively, to determine indapamide (CAS 26807-65-8) and to apply them to bioequivalence studies. The universal parameters, including selectivity, linearity, precision, and quantification limit, served as gold standard for the comparison of the two methods. As a result, the two methods were both very consistent and reliable. Furthermore, the LC-MS/MS method required only one-fifth the blood volume needed by the other method and was approximately 25 times more sensitive than the other method. The total run time of the LC-MS/MS method was 3.5 min per sample as opposed to 11 min for the other method. Forty healthy male Chinese volunteers were selected as subjects. One half were orally administrered 2.5 mg indapamide immediate release tablets while the other half were orally administered 1.5 mg indapamide sus-tained release coated tablets. The collected blood samples were determined with the two methods described above. The pharmacokinetic parameters were determined using a noncompartmental method. For the bioequivalence studies, the pharmacokinetic parameters acquired here were in line with the literature and parameters met the criteria set by the State Food and Drug Administration of China (SFDA) for bioequivalence study, indicating that generic drugs are bioequivalent to branded drugs. The present study suggests that the two methods based on LC-UV and LC-MS/MS were suitable for bioavailability studies of indapamide with different pharmaceutical formulations. Consequently, it can be believed that the criterion that each individual expected concentration range would need a given bioassay with the requested sensitivity is not absolutely right. In practice, most of the time, the highest sensitivity allows to bioassay concentrations in a higher range.

  1. 上海市18~69岁居民对推荐身体活动量的知晓现状%Awareness to recommended levels of physical activity among residents aged 18-69 years in Shanghai

    Institute of Scientific and Technical Information of China (English)

    李新建; 李光耀; 吕宁; 姜综敏; 姚海宏; 严青华; 徐继英; 仲伟鉴

    2015-01-01

    Objective To understand status of awareness to recommended level of physical activity and provide evi-dences for further promoting participation of physical activity among residents in Shanghai.Methods Stratified random sam-pling method was used to enroll samples in all 18 districts in Shanghai.A total of 8548 participants aged 18 -69 years were re-cruited and questionnaire survey was carried out by face-to-face interview.The unified questionnaire of evaluating national ac-tion for health lifestyle designed by China National Center for Disease Control and Prevention was used.The significances of rates were tested by Chi-square and associations with determinations were analyzed by logistic regression model.Results A-mong the residents in Shanghai,7544 (89.2%)and 3875 (45.8%)participants knew the recommended levels of “at least 6000 steps of physical activity of daily life,travel,and exercising everyday”and “at least 150 minutes of moderate intensity aerobic exercise every week”.Analysis results of logistic regression showed that gender (OR =1.184,95%CI:1.030 -1.361),age (OR =1.136,95% CI:1.020 -1.264),education level (OR =1.143,95% CI:1.046 -1.249),annual household income (OR =1.047,95% CI:1.009 -1.086)and area of residence (OR =0.796,95% CI:0.697 -0.922) for the former and education level (OR =1.241,95% CI:1.174 -1.313)and area of residence (OR =1.473,95% CI:1.345 -1.614)were influencing factors to awareness.Conclusion There was higher proportion of awareness to recommended level of “at least 6000 steps of physical activity of daily life,travel,and exercising everyday”compared with “at least 150 minutes of moderate intensity aerobic exercise every week”among Shanghai residents.After adjustment for age and gender,ed-ucation level and area of residence can influence awareness level of both recommended levels.%目的:了解上海市居民对推荐身体活动量的知晓情况,为进一步促进市民参加身体活动

  2. Pharmacokinetics and bioequivalence of sibutramine dripping pills in healthy volunteers%盐酸西布曲明滴丸人体药动学和生物等效性

    Institute of Scientific and Technical Information of China (English)

    董海军; 李见春; 赵明霞; 张俊东; 刘胜利; 高署

    2009-01-01

    OBJECTIVE To investigate the pharmacokinetics and relative bioavailability of sibutramine dripping pills and cap-sules in healthy volunteers and evaluate the bioequivalence. METHODS A single oral dose of 15 mg test and reference sibutra-mine dripping pills or capsules was given to 20 male healthy volunteers in a randomized, two-way crossover study. The concen-tration of one of active metabolite of sibutramine in plasma was determined by LC-MS/MS. The pharmacokinetics parameters and relative bioavailability were calculated with DAS 2. 0 software to evaluate the bioequivalence of the two preparations. RE-SULTS The main pharmacokinetics parameters of test and reference preparations were as follows: t1/2 (20. 8±6. 0) h and and reference granules were not significant. The relative bioavailability of F was(96. 4±18. 2)%. CONCLUSION The statisti-cal analysis of the results shows that the two preparations are bioequivalent.%目的:研究盐酸西布曲明滴丸在健康人体的药动学和相对生物利用度并求证其生物等效性.方法:男性健康志愿者20名,随机交叉单剂量口服受试制剂盐酸西布曲明滴丸和参比制剂盐酸西布曲明胶囊各15 mg,采用高效液相色谱-质谱联用法测定血浆中西布曲明的活性代谢产物之一双去甲基西布曲明的浓度.计算药动学参数和相对生物利用度,评价其生物等效性.结果:口服受试和参比制剂后的主要药动学参数经统计矩参数计算:试验制剂t1/2为(20.8±6.0)h和(21.2±6.2)h;tmax峨为(4.2±1.0)h和(4.8±1.2)h;Cmax为(7.3±2.1)μg·L-1和(7.6±2.0)μg·L-1;AUC0-96 h为(159.5±56.4)μg·h·L-1和(168.4±57.3)μg·h·L-1,受试制剂与参比制剂比较的相对生物利用度F为(96.4±18.2)%.结论:两制剂具有生物等效性.

  3. Development of a simple LC-MS/MS method for determination of rebamipide in human plasma and its application to a bioequivalence study.

    Science.gov (United States)

    Liu, Jian; Shen-Tu, Jianzhong; Wu, Lihua; Dou, Jing; Xu, Qiyang; Zhou, Huili; Wu, Guolan; Hu, Xingjiang

    2012-11-01

    The purpose of this study was to design a simple and rapid liquid chromatography-tandem mass spectrometric (LC-MS/MS) method for a rebamipide bioequivalence study in healthy Chinese male volunteers. In this method, sample pretreatment involved simple protein precipitation with venlafaxine as the internal standard. Analysis was achieved on a ZORBAX SB-C18 column with a concentration range of 6-1200 ng/mL. Rebamipide tablets from Yuanlijian (test, Hangzhou, China) and from Otsuka (reference, Hangzhou, China) were evaluated following a single 300 mg oral dose to 20 healthy volunteers. Bioequivalence was determined by calculating 90% confidence intervals (90% CI) for the ratio of Cmax, AUC(0-t) and AUC(0-infinity) values for the test and reference products, using logarithmic transformed data. The 90% confidence intervals for the ratio of Cmax (83.7-118.4%), AUC(0-t) (91.1-113.4%) and AUC(0-infinity) (90.6-113.2%) values for the test and reference products were within the interval (80.0-125.0% for AUC, and 70-143% for Cmax), proposed by State of Food and Drug Administration [SFDA, 2005. China]. It was concluded that the two rebamipide tablets were bioequivalent in their rate and extent of absorption and the method met the principle of quick and easy clinical analysis.

  4. Bioequivalence evaluation of two amlodipine salts, besylate and orotate, each in a fixed-dose combination with olmesartan in healthy subjects.

    Science.gov (United States)

    Lee, Soo-Yun; Kim, Jung-Ryul; Jung, Jin Ah; Huh, Wooseong; Bahng, Mi Young; Ko, Jae-Wook

    2015-01-01

    A fixed-dose combination of amlodipine and olmesartan is used to treat high blood pressure in patients whose hypertension is not sufficiently controlled with either drug alone. The objective of this study was to evaluate the bioequivalence of two fixed-dose combinations, ie, amlodipine orotate/olmesartan medoxomil 10/40 mg and amlodipine besylate/olmesartan medoxomil 10/40 mg, in healthy subjects. A randomized, open-label, single-dose, two-sequence, two-period, crossover study was conducted in 30 healthy adult volunteers. Blood samples were collected for up to 72 hours post-dose in each period. Safety data included the results of physical examinations, clinical laboratory tests, vital signs, an electrocardiogram, and adverse events. For both amlodipine and olmesartan, the 90% confidence intervals for the geometric mean ratios of AUClast and time to peak plasma concentration fell within the bioequivalence acceptance criteria. The two fixed-dose combinations showed similar safety profiles. Amlodipine orotate/olmesartan medoxomil 10/40 mg was bioequivalent to amlodipine besylate/olmesartan medoxomil 10/40 mg.

  5. Average bioequivalence of single 500 mg doses of two oral formulations of levofloxacin: a randomized, open-label, two-period crossover study in healthy adult Brazilian volunteers

    Directory of Open Access Journals (Sweden)

    Eunice Kazue Kano

    2015-03-01

    Full Text Available Average bioequivalence of two 500 mg levofloxacin formulations available in Brazil, Tavanic(c (Sanofi-Aventis Farmacêutica Ltda, Brazil, reference product and Levaquin(c (Janssen-Cilag Farmacêutica Ltda, Brazil, test product was evaluated by means of a randomized, open-label, 2-way crossover study performed in 26 healthy Brazilian volunteers under fasting conditions. A single dose of 500 mg levofloxacin tablets was orally administered, and blood samples were collected over a period of 48 hours. Levofloxacin plasmatic concentrations were determined using a validated HPLC method. Pharmacokinetic parameters Cmax, Tmax, Kel, T1/2el, AUC0-t and AUC0-inf were calculated using noncompartmental analysis. Bioequivalence was determined by calculating 90% confidence intervals (90% CI for the ratio of Cmax, AUC0-t and AUC0-inf values for test and reference products, using logarithmic transformed data. Tolerability was assessed by monitoring vital signs and laboratory analysis results, by subject interviews and by spontaneous report of adverse events. 90% CIs for Cmax, AUC0-t and AUC0-inf were 92.1% - 108.2%, 90.7% - 98.0%, and 94.8% - 100.0%, respectively. Observed adverse events were nausea and headache. It was concluded that Tavanic(c and Levaquin(c are bioequivalent, since 90% CIs are within the 80% - 125% interval proposed by regulatory agencies.

  6. 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.

    Science.gov (United States)

    Cristofoletti, Rodrigo; Dressman, Jennifer B

    2014-10-01

    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.

  7. Bioequivalence studies of omnitrope, the first biosimilar/rhGH follow-on protein: two comparative phase 1 randomized studies and population pharmacokinetic analysis.

    Science.gov (United States)

    Stanhope, Richard; Sörgel, Fritz; Gravel, Patricia; Pannatier Schuetz, Yannic B; Zabransky, Markus; Muenzberg, Michael

    2010-11-01

    This article discusses the bioequivalence of Omnitrope (Sandoz's rhGH biosimilar) and Genotropin (reference rhGH product), assessed in the first 2 clinical phase 1 studies conducted during the development of Omnitrope. Both of these phase 1 studies were randomized, double-blind, crossover studies, each involving 24 healthy volunteers who underwent pituitary somatrope cell down-regulation using octreotide. Three different formulations of recombinant human growth hormone (rhGH) were compared: Omnitrope lyophilisate, Omnitrope liquid and Genotropin (lyophilized powder for injection). Both pharmacokinetics (area under the curve [AUC], C(max), t(max) and t(1/2)) and pharmacodynamics (serum levels of insulin-like growth factor 1, insulin-like growth factor binding protein-3 and non-esterified fatty acid) were assessed after a single subcutaneous injection of 5 mg rhGH. The 3 formulations had comparable pharmacokinetics and pharmacodynamics. All the 90% confidence intervals of the ratios of the least squares means for the pharmacokinetic and pharmacodynamic parameters AUC and C(max) were within the predefined FDA and EMEA acceptance range of 80%-125% for bioequivalence. In addition, a comparative population pharmacokinetic analysis further supports that Omnitrope lyophilisate, Omnitrope liquid and Genotropin can be regarded as equivalent in terms of pharmacokinetics. Therefore, Omnitrope lyophilisate was demonstrated to be bioequivalent to both Genotropin and the Omnitrope liquid formulation.

  8. Strategic Arrivals Recommendation Tool Project

    Data.gov (United States)

    National Aeronautics and Space Administration — During the conduct of a NASA Research Announcement (NRA) in 2012 and 2013, the Mosaic ATM team first developed the Strategic Arrivals Recommendation Tool concept, or...

  9. Management recommendations: Benton Lake Complex

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — This document is a review of land management practices at the Benton Lake Complex, by a land use specialist. Recommendations, time frame and additional comments are...

  10. Management recommendations: Sand Lake Complex

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — This document is a review of land management practices at the Sand Lake National Wildlife Refuge, by a land use specialist. Recommendations, time frame and...

  11. Disability: recommendations for eye programmes

    Directory of Open Access Journals (Sweden)

    2013-05-01

    Full Text Available In 2012, CBM’s Medical Eye Care Advisory Working Group met in Hyderabad, India to discuss the inclusion of people with disabilities in eye care.As a result of these discussions, recommendations were made.

  12. RECOMMENDER SYSTEMS IN SOCIAL NETWORKS

    Directory of Open Access Journals (Sweden)

    Cleomar Valois Batista Jr

    2011-12-01

    Full Text Available The continued and diversified growth of social networks has changed the way in which users interact with them. With these changes, what once was limited to social contact is now used for exchanging ideas and opinions, creating the need for new features. Users have so much information at their fingertips that they are unable to process it by themselves; hence, the need to develop new tools. Recommender systems were developed to address this need and many techniques were used for different approaches to the problem. To make relevant recommendations, these systems use large sets of data, not taking the social network of the user into consideration. Developing a recommender system that takes into account the social network of the user is another way of tackling the problem. The purpose of this project is to use the theory of six degrees of separation (Watts 2003 amongst users of a social network to enhance existing recommender systems.

  13. Recommended Practices for Spreadsheet Testing

    CERN Document Server

    Panko, Raymond R

    2006-01-01

    This paper presents the authors recommended practices for spreadsheet testing. Documented spreadsheet error rates are unacceptable in corporations today. Although improvements are needed throughout the systems development life cycle, credible improvement programs must include comprehensive testing. Several forms of testing are possible, but logic inspection is recommended for module testing. Logic inspection appears to be feasible for spreadsheet developers to do, and logic inspection appears to be safe and effective.

  14. Tourism recommendation system: empirical investigation

    OpenAIRE

    Petrevska, Biljana; Saso KOCESKI

    2012-01-01

    The paper makes an attempt to justify the necessity of implementing recommendation system which will assist tourists in identification of their ideal holiday. The proposed recommendation system based on collaborative filtering notes positive impulses in the case of Macedonia. A software module is developed being capable to generate a personalized list of favorable and tailor-made items. The research outcomes indicate that the designed national tourism web portal can provide satisfactory perfo...

  15. User Profiling for Recommendation System

    OpenAIRE

    Kanoje, Sumitkumar; Girase, Sheetal; Mukhopadhyay, Debajyoti

    2015-01-01

    Recommendation system is a type of information filtering systems that recommend various objects from a vast variety and quantity of items which are of the user interest. This results in guiding an individual in personalized way to interesting or useful objects in a large space of possible options. Such systems also help many businesses to achieve more profits to sustain in their filed against their rivals. But looking at the amount of information which a business holds it becomes difficult to...

  16. A NEW HYBRID ALGORITHM FOR BUSINESS INTELLIGENCE RECOMMENDER SYSTEM

    Directory of Open Access Journals (Sweden)

    P.Prabhu

    2014-03-01

    Full Text Available Business Intelligence is a set of methods, process and technologies that transform raw data into meaningful and useful information. Recommender system is one of business intelligence system that is used to obtain knowledge to the active user for better decision making. Recommender systems apply data mining techniques to the problem of making personalized recommendations for information. Due to the growth in the number of information and the users in recent years offers challenges in recommender systems. Collaborative, content, demographic and knowledge-based are four different types of recommendations systems. In this paper, a new hybrid algorithm is proposed for recommender system which combines knowledge based, profile of the users and most frequent item mining technique to obtain intelligence.

  17. Introduction on health recommender systems.

    Science.gov (United States)

    Sanchez-Bocanegra, C L; Sanchez-Laguna, F; Sevillano, J L

    2015-01-01

    People are looking for appropriate health information which they are concerned about. The Internet is a great resource of this kind of information, but we have to be careful if we don't want to get harmful info. Health recommender systems are becoming a new wave for apt health information as systems suggest the best data according to the patients' needs.The main goals of health recommender systems are to retrieve trusted health information from the Internet, to analyse which is suitable for the user profile and select the best that can be recommended, to adapt their selection methods according to the knowledge domain and to learn from the best recommendations.A brief definition of recommender systems will be given and an explanation of how are they incorporated in the health sector. A description of the main elementary recommender methods as well as their most important problems will also be made. And, to finish, the state of the art will be described.

  18. Recommendation on mean molar activity coefficients and single ion activity coefficients of solutions for calibration of ion-selective electrodes for sodium, potassium and calcium determination (Reprinted from J Clin Chem Clin Biochem)

    NARCIS (Netherlands)

    Burnett, RW; Covington, AK; FoghAndersen, N; Kulpmann, WR; Maas, AHJ; MullerPlathe, O; SiggaardAndersen, O; VanKessel, A; Wimberley, PD; Zijlstra, WG

    1997-01-01

    In principle, flame photometry measures substance concentration, and ion-selective electrodes (ISEs) measure ion activity. However, the situation regarding the comparison of results from the two techniques when applied to blood plasma is complex. The problem can be approached experimentally from the

  19. Pharmacokinetics and bioequivalence evaluation of Gatifloxacin Capsules%加替沙星胶囊的药代动力学及生物等效性评价

    Institute of Scientific and Technical Information of China (English)

    苏冀红; 李奇矩

    2011-01-01

    Objective: To evaluate the pharmacokinetics and bioequivalence of Gatifloxacin Capsules in the healthy male.Methods: 40 healthy male were randomly divided into two groups, there were respectively given domestic and imported oral Gatifloxacin Capsules, used the high performance liquid chromatography method for detected the Catifloxacin concentrations in plasma, and analyzed the major drug pharmacokinetic parameters and evaluated the bioequivalence of two formulations. Results: The oral administration of domestic and imported in the two groups after gatifloxacin's half-life,peak time, peak concentration and the lag time had not significant different. Bioequivalence compared with the same time had no significant difference, so we thought thaL the two formulations were bioequivalent. Conclusion: Domestic and imported Catifloxacin Capsules preparation or reference test preparation in healthy volunteers are bioequivalent and similar pharmacokinetics.%目的:评价加替沙星胶囊在健康男性体内的药代动力学和生物等效性.方法:40例健康男性试验者随机平分为两组.分别口服国产与进口加替沙星胶囊试验制剂或参比制剂,采用高效液相色谱法测定血浆中加替沙星的浓度,计算主要药代动力学参数,评价两制剂的生物等效性.结果:口服国产和进口加替沙星后两组的半衰期、峰时间、峰浓度和滞后时间相比无显著性差异.同时生物等效性相比也无显著性差异,可认为两种制剂具有生物等效性.结论:国产与进口加替沙星胶囊试验制剂或参比制剂在健康志愿者体内具有生物等效性和类似的药代动力学.

  20. The biowaiver extension for BCS class III drugs: the effect of dissolution rate on the bioequivalence of BCS class III immediate-release drugs predicted by computer simulation.

    Science.gov (United States)

    Tsume, Yasuhiro; Amidon, Gordon L

    2010-08-02

    The Biopharmaceutical Classification System (BCS) guidance issued by the FDA allows waivers for in vivo bioavailability and bioequivalence studies for immediate-release (IR) solid oral dosage forms only for BCS class I drugs. However, a number of drugs within BCS class III have been proposed to be eligible for biowaivers. The World Health Organization (WHO) has shortened the requisite dissolution time of BCS class III drugs on their Essential Medicine List (EML) from 30 to 15 min for extended biowaivers; however, the impact of the shorter dissolution time on AUC(0-inf) and C(max) is unknown. The objectives of this investigation were to assess the ability of gastrointestinal simulation software to predict the oral absorption of the BCS class I drugs propranolol and metoprolol and the BCS class III drugs cimetidine, atenolol, and amoxicillin, and to perform in silico bioequivalence studies to assess the feasibility of extending biowaivers to BCS class III drugs. The drug absorption from the gastrointestinal tract was predicted using physicochemical and pharmacokinetic properties of test drugs provided by GastroPlus (version 6.0). Virtual trials with a 200 mL dose volume at different drug release rates (T(85%) = 15 to 180 min) were performed to predict the oral absorption (C(max) and AUC(0-inf)) of the above drugs. Both BCS class I drugs satisfied bioequivalence with regard to the release rates up to 120 min. The results with BCS class III drugs demonstrated bioequivalence using the prolonged release rate, T(85%) = 45 or 60 min, indicating that the dissolution standard for bioequivalence is dependent on the intestinal membrane permeability and permeability profile throughout the gastrointestinal tract. The results of GastroPlus simulations indicate that the dissolution rate of BCS class III drugs could be prolonged to the point where dissolution, rather than permeability, would control the overall absorption. For BCS class III drugs with intestinal absorption patterns

  1. Dynamic Recommendation: Disease Prediction and Prevention Using Recommender System

    Directory of Open Access Journals (Sweden)

    Mahdi Nasiri

    2016-06-01

    Full Text Available Background: In today’s world, chronic diseases are predominant health problems and cause heavy burden on society; therefore early diagnosis and even prediction of the disease is a way to reduce this burden. In this project, we tried to use recommender system to predict which other diseases a chronic patient is susceptible for. Methods: In this study, through a dynamic recommender system, we evaluated patients’ treatment destiny during the time. Results: It was shown that our method increased accuracy and reduced error compared with other recommendation methods in disease prediction. Conclusion: Compared to current usual methods, in our method we used previous patients’ characteristics as one of the factorization variables to predict destiny of future patients. Furthermore, using this method, we can predict which complication or disease the patient would suffer from first in future. Therefore, we can manage policies toward disease burden reduction by implementing prevention programs.

  2. Recommendations

    DEFF Research Database (Denmark)

    Baumeister, Ruth

    2016-01-01

    This article discusses three book publications: C. Kerez: Uncertain Certainty, Tokyo, 2013 H. Hertzberger: Lessons for students in architecture, Rotterdam, 2006, (1991) A. Jorn: Om Formen, Silkeborg, 2014, (1958)...

  3. Bioequivalence studies of tibolone in premenopausal women and effects on expression of the tibolone-metabolizing enzyme AKR1C (aldo-keto reductase) family caused by estradiol.

    Science.gov (United States)

    Kang, Keon W; Kim, Yoon G

    2008-12-01

    This study aimed to investigate the bioequivalence of a test formulation of tibolone with the marketed reference formulation in 24 young healthy female volunteers. Tibolone is a synthetic steroid hormone for menopausal women. Volunteers were treated with the 2 formulations of tibolone (total dose of active ingredient 2.5 mg) according to a 2 x 2 crossover design with a 1-week washout period. Plasma concentrations of 3alpha- and 3beta-hydroxytibolone, which are major metabolites of tibolone, were assayed in timed samples over a 24-hour period with a validated gas chromatography/mass spectrometry (GC/MS) method that had a lower limit of quantification of 0.5 ng/mL. The reference and test formulations gave a mean 3alpha-hydroxytibolone C(max) of 5.0 and 5.2 ng/mL, respectively, and a mean 3beta-hydroxytibolone C(max) of 16.4 and 16.5 ng/mL, respectively. The mean AUC(t) of 3alpha-hydroxytibolone was 24.7 and 24.3 ng h/mL, whereas the mean AUC(t) of 3beta-hydroxytibolone was 57.6 and 54.8 ng h/mL for the test and reference formulations, respectively. The authors did not find significant differences in pharmacokinetic parameters between the 2 formulations, but metabolite formation was different from reports in postmenopausal women. The authors therefore measured the effects of estradiol on the expression of the tibolone-metabolizing enzymes, from the aldo-keto reductase (AKR1C) family, using HepG2 cell (human hepatoma cells) and MCF-7 cell (human breast cancer cells). Estradiol increased mRNA levels of AKR1C1, AKR1C2, and AKR1C3 and protein levels of total AKR1C in HepG2 cells. Estradiol selectively enhanced levels of AKR1C2 mRNA in MCF-7 cells. Thus, changes in the major metabolites of tibolone might result from changes in AKR1C family expression by patient estrogen status.

  4. Challenging the Long Tail Recommendation

    CERN Document Server

    Yin, Hongzhi; Li, Jing; Yao, Junjie; Chen, Chen

    2012-01-01

    The success of "infinite-inventory" retailers such as Amazon.com and Netflix has been largely attributed to a "long tail" phenomenon. Although the majority of their inventory is not in high demand, these niche products, unavailable at limited-inventory competitors, generate a significant fraction of total revenue in aggregate. In addition, tail product availability can boost head sales by offering consumers the convenience of "one-stop shopping" for both their mainstream and niche tastes. However, most of existing recommender systems, especially collaborative filter based methods, can not recommend tail products due to the data sparsity issue. It has been widely acknowledged that to recommend popular products is easier yet more trivial while to recommend long tail products adds more novelty yet it is also a more challenging task. In this paper, we propose a novel suite of graph-based algorithms for the long tail recommendation. We first represent user-item information with undirected edge-weighted graph and i...

  5. Recommender Systems using Graph Theory

    Directory of Open Access Journals (Sweden)

    Vishal Venkatraman

    2013-08-01

    Full Text Available Recommender systems have become one of the important tools in E-Commerce. They combine the ratings of services or products by one user with the ratings from other users to answer similar interest queries with predictions and suggestions. The users thus receive anonymous recommendations from people similar interests. Even though this process seems unobjectionable, it aggregates user preferences, which can be tapped to recognise information about a particular user. Users who rate products or services across different types or domains in the systems are the major victims for this exploitation. We could determine the advantages and risks by performing a detailed analysis with a particular recommendation algorithm, but it would be difficult to draw general conclusions from this approach. In this paper, we aim for an algorithm independent analysis by applying a graph-theoretic model. By employing this model, we show that a user benefits most from recommendations based on similarity between the various products rated by the users. This paper tries to draw a graph through the various items rated by the users and finds the items that are most common among the user and his friends which is then recommended to him.

  6. Customization Using Fuzzy Recommender Systems

    Institute of Scientific and Technical Information of China (English)

    Ronald R. Yager

    2004-01-01

    We discuss some methods for constructing recommender systems. An important feature of the methods studied here is that we assume the availability of a description, representation, of the objects being considered for recommendation. The approaches studied here differ from collaborative filtering in that we only use pReferences information from the individual for whom we are providing the recommendation and make no use the preferences of other collaborators. We provide a detailed discussion of the construction of the representation schema used. We consider two sources of information about the users preferences. The first are direct statements about the type of objects the user likes. The second source of information comes from ratings of objects which the user has experienced.

  7. TDCCREC: AN EFFICIENT AND SCALABLE WEB-BASED RECOMMENDATION SYSTEM

    Directory of Open Access Journals (Sweden)

    K.Latha

    2010-10-01

    Full Text Available Web browsers are provided with complex information space where the volume of information available to them is huge. There comes the Recommender system which effectively recommends web pages that are related to the current webpage, to provide the user with further customized reading material. To enhance the performance of the recommender systems, we include an elegant proposed web based recommendation system; Truth Discovery based Content and Collaborative RECommender (TDCCREC which is capable of addressing scalability. Existing approaches such as Learning automata deals with usage and navigational patterns of users. On the other hand, Weighted Association Rule is applied for recommending web pages by assigning weights to each page in all the transactions. Both of them have their own disadvantages. The websites recommended by the search engines have no guarantee for information correctness and often delivers conflicting information. To solve them, content based filtering and collaborative filtering techniques are introduced for recommending web pages to the active user along with the trustworthiness of the website and confidence of facts which outperforms the existing methods. Our results show how the proposed recommender system performs better in predicting the next request of web users.

  8. TOURISM RECOMMENDATION SYSTEM: EMPIRICAL INVESTIGATION

    Directory of Open Access Journals (Sweden)

    Biljana PETREVSKA

    2012-12-01

    Full Text Available The paper makes an attempt to justify the necessity of implementing recommendation system which will assist tourists in identification of their ideal holiday. The proposed recommendation system based on collaborative filtering notes positive impulses in the case of Macedonia. A software module is developed being capable to generate a personalized list of favorable and tailor-made items. The research outcomes indicate that the designed national tourism web portal can provide satisfactory performance and may be of high importance to all key-tourism actors in the process of identifying measures necessary for creating competitive tourism product.

  9. An Improved Adaptive model for Information Recommending and Spreading

    Institute of Scientific and Technical Information of China (English)

    CHEN Duan-Bing; GAO Hui

    2012-01-01

    People in the Internet era have to cope with information overload and expend great effort on finding what they need.Recent experiments indicate that recommendations based on users' past activities are usually less favored than those based on social relationships,and thus many researchers have proposed adaptive algorithms on social recommendation.However,in those methods,quite a number of users have little chance to recommend information,which might prevent valuable information from spreading.We present an improved algorithm that allows more users to have enough followers to spread information.Experimental results demonstrate that both recommendation precision and spreading effectiveness of our method can be improved significantly.%People in the Internet era have to cope with information overload and expend great effort on finding what they need. Recent experiments indicate that recommendations based on users' past activities are usually less favored than those based on social relationships, and thus many researchers have proposed adaptive algorithms on social recommendation. However, in those methods, quite a number of users have little chance to recommend information, which might prevent valuable information from spreading. We present an improved algorithm that allows more users to have enough followers to spread information. Experimental results demonstrate that both recommendation precision and spreading effectiveness of our method can be improved significantly.

  10. Desidratação e recomendações para a reposição hídrica em crianças fisicamente ativas Dehydration and rehydration recommendations for physically active children

    Directory of Open Access Journals (Sweden)

    Luciana Rossi

    2010-09-01

    heat production. Most studies that address the risks of dehydration and provide recommendations for restoring water are directed to adults living in temperate climate regions, but little is known about the needs of restoring water to physically active children in tropical regions. This review discusses the recommendations for this population and the risks of sports practice in tropical climate areas. DATA SOURCE: Systematic analysis of the national (SciELO and international (Medline literature from 1972 to 2009, with the following keywords, alone or in combination, in Portuguese and English: hydration, children, dehydration and water replacement. DATA SYNTHESIS: There are risks related to dehydration and possible development of hyperthermia especially in adverse weather conditions without adequate fluid replacement. The main trigger for hyperthermia is that, compared to adults, children are less able of adapting to extremes of temperature due to their higher body surface area and lower capacity of thermoregulation by evaporation. Studies on this subject are scarce in face of the questions still open. CONCLUSIONS: Once dehydration factors are known, the best recommendation to aggressive climatic conditions is to establish a replacement program using flavored hydration beverage added with carbohydrates and sodium in order to avoid significant water losses and reduced performance, and to decrease health risks posed by hyperthermia and dehydration to physically active children.

  11. New Recommendations for Mefloquine Use in Pregnancy

    Science.gov (United States)

    ... CDC Malaria Branch clinician. malaria@cdc.gov Update: New Recommendations for Mefloquine Use in Pregnancy Recommend on Facebook Tweet Share Compartir Update: New Recommendations for Mefloquine Use in Pregnancy The Centers ...

  12. A Flexible Electronic Commerce Recommendation System

    Science.gov (United States)

    Gong, Songjie

    Recommendation systems have become very popular in E-commerce websites. Many of the largest commerce websites are already using recommender technologies to help their customers find products to purchase. An electronic commerce recommendation system learns from a customer and recommends products that the customer will find most valuable from among the available products. But most recommendation methods are hard-wired into the system and they support only fixed recommendations. This paper presented a framework of flexible electronic commerce recommendation system. The framework is composed by user model interface, recommendation engine, recommendation strategy model, recommendation technology group, user interest model and database interface. In the recommender strategy model, the method can be collaborative filtering, content-based filtering, mining associate rules method, knowledge-based filtering method or the mixed method. The system mapped the implementation and demand through strategy model, and the whole system would be design as standard parts to adapt to the change of the recommendation strategy.

  13. Ubiquitous Multicriteria Clinic Recommendation System.

    Science.gov (United States)

    Chen, Toly

    2016-05-01

    Advancements in information, communication, and sensor technologies have led to new opportunities in medical care and education. Patients in general prefer visiting the nearest clinic, attempt to avoid waiting for treatment, and have unequal preferences for different clinics and doctors. Therefore, to enable patients to compare multiple clinics, this study proposes a ubiquitous multicriteria clinic recommendation system. In this system, patients can send requests through their cell phones to the system server to obtain a clinic recommendation. Once the patient sends this information to the system, the system server first estimates the patient's speed according to the detection results of a global positioning system. It then applies a fuzzy integer nonlinear programming-ordered weighted average approach to assess four criteria and finally recommends a clinic with maximal utility to the patient. The proposed methodology was tested in a field experiment, and the experimental results showed that it is advantageous over two existing methods in elevating the utilities of recommendations. In addition, such an advantage was shown to be statistically significant.

  14. 生物等效性临床试验数据核查中常见问题与对策建议%Common Problems and Countermeasures for the Bioequivalence Trial Data Verification

    Institute of Scientific and Technical Information of China (English)

    朱玉先; 张军; 熊宁宁; 蒋萌; 居文政; 邹冲; 殷俊刚; 刘芳

    2016-01-01

    对生物等效性临床试验数据核查中存在的真实性、完整性、规范性等问题进行了梳理、归纳,分析其发生原因,提出相关对策,为生物等效性临床试验提供借鉴。%Problems revealed by verification of bioequivalence trial data for authenticity, integrity and standardability were sorted and summarized. By analyzing their causes, relevant countermeasures were put forward as reference for bioequivalence clinical trials.

  15. A Location-Based Business Information Recommendation Algorithm

    Directory of Open Access Journals (Sweden)

    Shudong Liu

    2015-01-01

    Full Text Available Recently, many researches on information (e.g., POI, ADs recommendation based on location have been done in both research and industry. In this paper, we firstly construct a region-based location graph (RLG, in which region node respectively connects with user node and business information node, and then we propose a location-based recommendation algorithm based on RLG, which can combine with user short-ranged mobility formed by daily activity and long-distance mobility formed by social network ties and sequentially can recommend local business information and long-distance business information to users. Moreover, it can combine user-based collaborative filtering with item-based collaborative filtering, and it can alleviate cold start problem which traditional recommender systems often suffer from. Empirical studies from large-scale real-world data from Yelp demonstrate that our method outperforms other methods on the aspect of recommendation accuracy.

  16. AN EFFECTIVE RECOMMENDATIONS BY DIFFUSION ALGORITHM FOR WEB GRAPH MINING

    Directory of Open Access Journals (Sweden)

    S. Vasukipriya

    2013-04-01

    Full Text Available The information on the World Wide Web grows in an explosive rate. Societies are relying more on the Web for their miscellaneous needs of information. Recommendation systems are active information filtering systems that attempt to present the information items like movies, music, images, books recommendations, tags recommendations, query suggestions, etc., to the users. Various kinds of data bases are used for the recommendations; fundamentally these data bases can be molded in the form of many types of graphs. Aiming at provided that a general framework on effective DR (Recommendations by Diffusion algorithm for web graphs mining. First introduce a novel graph diffusion model based on heat diffusion. This method can be applied to both undirected graphs and directed graphs. Then it shows how to convert different Web data sources into correct graphs in our models.

  17. Multimedia services in intelligent environments recommendation services

    CERN Document Server

    Virvou, Maria; Jain, Lakhmi

    2013-01-01

    Multimedia services are now commonly used in various activities in the daily lives of humans. Related application areas include services that allow access to large depositories of information, digital libraries, e-learning and e-education, e-government and e-governance, e-commerce and e-auctions, e-entertainment, e-health and e-medicine, and e-legal services, as well as their mobile counterparts (i.e., m-services). Despite the tremendous growth of multimedia services over the recent years, there is an increasing demand for their further development. This demand is driven by the ever-increasing desire of society for easy accessibility to information in friendly, personalized and adaptive environments. In this book at hand, we examine recent Recommendation Services. Recommendation services appear in the mobile environment, medicine/biology, tourism, education, and so on. The book includes ten chapters, which present various recently developed recommendation services. This research book is directed to professors...

  18. Virtual goods recommendations in virtual worlds.

    Science.gov (United States)

    Chen, Kuan-Yu; Liao, Hsiu-Yu; Chen, Jyun-Hung; Liu, Duen-Ren

    2015-01-01

    Virtual worlds (VWs) are computer-simulated environments which allow users to create their own virtual character as an avatar. With the rapidly growing user volume in VWs, platform providers launch virtual goods in haste and stampede users to increase sales revenue. However, the rapidity of development incurs virtual unrelated items which will be difficult to remarket. It not only wastes virtual global companies' intelligence resources, but also makes it difficult for users to find suitable virtual goods fit for their virtual home in daily virtual life. In the VWs, users decorate their houses, visit others' homes, create families, host parties, and so forth. Users establish their social life circles through these activities. This research proposes a novel virtual goods recommendation method based on these social interactions. The contact strength and contact influence result from interactions with social neighbors and influence users' buying intention. Our research highlights the importance of social interactions in virtual goods recommendation. The experiment's data were retrieved from an online VW platform, and the results show that the proposed method, considering social interactions and social life circle, has better performance than existing recommendation methods.

  19. Virtual Goods Recommendations in Virtual Worlds

    Directory of Open Access Journals (Sweden)

    Kuan-Yu Chen

    2015-01-01

    Full Text Available Virtual worlds (VWs are computer-simulated environments which allow users to create their own virtual character as an avatar. With the rapidly growing user volume in VWs, platform providers launch virtual goods in haste and stampede users to increase sales revenue. However, the rapidity of development incurs virtual unrelated items which will be difficult to remarket. It not only wastes virtual global companies’ intelligence resources, but also makes it difficult for users to find suitable virtual goods fit for their virtual home in daily virtual life. In the VWs, users decorate their houses, visit others’ homes, create families, host parties, and so forth. Users establish their social life circles through these activities. This research proposes a novel virtual goods recommendation method based on these social interactions. The contact strength and contact influence result from interactions with social neighbors and influence users’ buying intention. Our research highlights the importance of social interactions in virtual goods recommendation. The experiment’s data were retrieved from an online VW platform, and the results show that the proposed method, considering social interactions and social life circle, has better performance than existing recommendation methods.

  20. Estimation in AB/BA crossover trials with application to bioequivalence studies with incomplete and complete data designs.

    Science.gov (United States)

    Jaki, Thomas; Pallmann, Philip; Wolfsegger, Martin J

    2013-12-30

    Crossover studies are frequently used in clinical research as they allow within-subject comparisons instead of the between-subject evaluation of parallel group designs. Estimation of interesting parameters from such designs is, however, not trivial. We provide three methods for estimating treatment effects and associated standard errors from an AB/BA crossover trial. Assuming at least asymptotic normality, we can obtain the confidence intervals for single parameters as well as for differences or ratios of treatment effects. The latter is particularly useful in a pharmacokinetic context to establish bioequivalence using area under the concentration versus time curves (AUCs). In this work, we will illustrate how Fieller-type confidence intervals can be constructed for the ratio of AUCs estimated using a noncompartmental approach in a sparse sampling setting from a two-treatment, two-period, two-sequence crossover trial. In particular, we will discuss a flexible batch design, which includes traditional serial sampling and complete data designs as special cases. Via simulation, we show that the proposed intervals have nominal coverage and keep the type I error even for small sample sizes. Moreover, we illustrate the methodology in a real data example.