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Wang Z, Peng H, Zhang Y, Chen X, A J. Bioequivalence and safety assessment of sorafenib tosylate tablets in healthy Chinese subjects under fasting conditions. Front Pharmacol 2025; 16:1470095. [PMID: 40298089 PMCID: PMC12035729 DOI: 10.3389/fphar.2025.1470095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Accepted: 04/01/2025] [Indexed: 04/30/2025] Open
Abstract
Objective This study aimed to assess the bioequivalence and safety of two formulations of sorafenib in healthy Chinese subjects under fasting conditions. Methods A single-center, randomized, open, single-dose, two-formulation, four-period, crossover study was performed in 36 healthy Chinese subjects under fasting conditions. Blood samples were collected within 120 h after administration. The plasma concentrations of sorafenib were analyzed by a validated UPLC-MS/MS method, and pharmacokinetic parameters were analyzed using a non-compartmental method. Safety was assessed on the basis of the occurrence of adverse events and laboratory findings throughout the study period. Results The GMR point estimators of Cmax, AUC0-t, and AUC0-∞ for the two formulations were 88.97%, 81.67%, and 83.66%, respectively, which were within the bioequivalence criterion range of 80%-125%. The upper limits of the one-sided 95% confidence intervals of Cmax, AUC0-t, and AUC0-∞ after logarithmic transformation were -0.05, -0.04 and -0.03, respectively, which were less than 0. The difference in Tmax between these two formulations was not statistically significant according to the Wilcoxon signed-rank test (P = 0.3650 > 0.05). Therefore, the bioequivalence between the two formulations was established under fasting conditions. All adverse events were mild and transient. Conclusion The T formulation was bioequivalent and showed a similar safety profile to the R formulation Nexavar® (Bayer AG) in healthy Chinese subjects under fasting conditions. Clinical trial registration http://www.chinadrugtrials.org.cn/index.html, Identifier CTR20233578.
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Affiliation(s)
- Zhaoyu Wang
- Clinical Pharmacology Laboratory, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Hong Peng
- Clinical Pharmacology Laboratory, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Yun Zhang
- Clinical Pharmacology Laboratory, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Xijing Chen
- Clinical Pharmacology Laboratory, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Jiye A
- Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China
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Chow SC, Pariser A, Galson S. Use of alternative and confirmatory data in support of rare disease drug development. J Biopharm Stat 2025:1-15. [PMID: 40219600 DOI: 10.1080/10543406.2025.2489279] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/14/2025]
Abstract
Recently, the use of alternative and confirmatory data in support of rare disease drug development has received much attention (NASEM 2024). This article attempts to provide an overview regarding the limitations and major challenges of the use of ACD that are commonly encountered in rare disease drug (including biologics) product development. In addition, some innovative approaches using ACD under a novel two-stage hybrid adaptive trial design are proposed to assist the sponsors in rare disease drug development are proposed. Under the proposed hybrid adaptive trial design, statistical considerations regarding the implementation of ACD in support of the demonstration of the safety and efficacy in rare disease drug development are discussed.
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Affiliation(s)
- Shein-Chung Chow
- Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, North Carolina, USA
| | - Anne Pariser
- International Rare Diseases Research Consortium, Columbus, Ohio, USA
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Chow SC, Pariser A, Galson S. The role of regulatory flexibility in the review and approval process of rare disease drug development. J Biopharm Stat 2025:1-12. [PMID: 40219617 DOI: 10.1080/10543406.2025.2489290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/14/2025]
Abstract
The role of regulatory flexibility in the review and approval process of rare disease drug and biologics development was recently studied by a Consensus Committee of the National Academy of Sciences, Engineering and Medicine (NASEM 2024). In this article, regulatory flexibility is referred to as the exercise of scientific judgement by the regulatory agencies such as the United States Food and Drug Administration (FDA), in the review and oversight of a wide range of products, diseases and circumstances (see e.g. 21CFR Subpart E). This flexibility is intended to assist the sponsors in obtaining substantial evidence regarding safety and effectiveness of a test treatment under investigation. Applying general scientific principles, regulatory flexibility should be transparent, objective, and applied without undermining the integrity, quality and scientific validity of clinical investigation of the test treatment under study. This article attempts to provide an overview regarding the application of regulatory flexibility in rare disease drug and biologic development, which could also be applied to drug products for normal conditions. In addition, some innovative strategies and approaches which reflect regulatory flexibility and current thinking are proposed. Statistical considerations regarding the implementation of regulatory flexibility and/or current thinking in support of the demonstration of the safety and efficacy in drug development are discussed.
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Affiliation(s)
- Shein-Chung Chow
- Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, North Carolina, USA
| | - Anne Pariser
- International Rare Diseases Research Consortium, Columbus, Ohio, USA
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Leon S, Rantou E, Kim J, Choi S, Choi NH. Comparative Analyses of Bioequivalence Assessment Methods for In Vitro Permeation Test Data. Pharm Stat 2025; 24:e2434. [PMID: 39180456 DOI: 10.1002/pst.2434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 06/26/2024] [Accepted: 08/02/2024] [Indexed: 08/26/2024]
Abstract
For topical, dermatological drug products, an in vitro option to determine bioequivalence (BE) between test and reference products is recommended. In particular, in vitro permeation test (IVPT) data analysis uses a reference-scaled approach for two primary endpoints, cumulative penetration amount (AMT) and maximum flux (J max), which takes the within donor variability into consideration. In 2022, the Food and Drug Administration (FDA) published a draft IVPT guidance that includes statistical analysis methods for both balanced and unbalanced cases of IVPT study data. This work presents a comprehensive evaluation of various methodologies used to estimate critical parameters essential in assessing BE. Specifically, we investigate the performance of the FDA draft IVPT guidance approach alongside alternative empirical and model-based methods utilizing mixed-effects models. Our analyses include both simulated scenarios and real-world studies. In simulated scenarios, empirical formulas consistently demonstrate robustness in approximating the true model, particularly in effectively addressing treatment-donor interactions. Conversely, the effectiveness of model-based approaches heavily relies on precise model selection, which significantly influences their results. The research emphasizes the importance of accurate model selection in model-based BE assessment methodologies. It sheds light on the advantages of empirical formulas, highlighting their reliability compared to model-based approaches and offers valuable implications for BE assessments. Our findings underscore the significance of robust methodologies and provide essential insights to advance their understanding and application in the assessment of BE, employed in IVPT data analysis.
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Affiliation(s)
- Sami Leon
- Department of Biostatistics and Computational Biology, University of Rochester, Rochester, New York, USA
| | - Elena Rantou
- Office of Biostatistics, Office of Translational Science, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA
| | - Jessica Kim
- Office of Biostatistics, Office of Translational Science, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA
| | - Sungwoo Choi
- Office of Biostatistics, Office of Translational Science, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA
| | - Nam Hee Choi
- Office of Biostatistics, Office of Translational Science, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA
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Leong CW, Yee KM, Rani TA, Lau KJ, Ahmad S, Amran A, Mohd Hassan FW, Kumar N. Pharmacokinetics and Bioequivalence of Fixed-Dose Combination of Simvastatin and Ezetimibe Tablets: A Randomized, Crossover, Open-Label Study in Healthy Volunteers. Clin Pharmacol Drug Dev 2024; 13:938-946. [PMID: 38745538 DOI: 10.1002/cpdd.1411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Accepted: 04/08/2024] [Indexed: 05/16/2024]
Abstract
The current study aimed to evaluate the bioequivalence of a new generic combination of simvastatin and ezetimibe with the reference formulation. An open-label, randomized, 3-period, 3-sequence, crossover study, including 60 healthy volunteers, was implemented. Participants received the test and reference formulation, each containing 20 mg of simvastatin and 10 mg of ezetimibe as a single-dose tablet, separated by a minimum of 2-week washout periods. Blood samples were collected for 20 time points from predose to 72 hours after the dose. The total ezetimibe assay was carried out using a validated liquid chromatography-tandem mass spectrometry, while unconjugated ezetimibe, simvastatin, and simvastatin β-hydroxy acid determination was done via a validated ultra-performance liquid chromatography-tandem mass spectrometry. Each assay was preceded by a liquid-liquid extraction step. The pharmacokinetic parameters were derived using noncompartmental analysis and then compared between the reference and test formulations via a multivariate analysis of variance. No statistical difference was found in under the concentration-time curve from time 0 to the last quantifiable concentration and maximum concentration of unconjugated ezetimibe, total ezetimibe, and simvastatin between the reference and test formulations. The 90% confidence intervals of unconjugated ezetimibe, total ezetimibe, and simvastatin natural log-transformed under the concentration-time curve from time 0 to the last quantifiable concentration, and maximum concentration were in the range of 80%-125% as per the bioequivalence acceptance criteria. Therefore, the test formulation was bioequivalent to the reference formulation.
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Affiliation(s)
| | - Kar Ming Yee
- Duopharma Innovation Sdn. Bhd., Shah Alam, Selangor, Malaysia
| | - Tracy Ann Rani
- Duopharma Innovation Sdn. Bhd., Shah Alam, Selangor, Malaysia
| | - Kheng Jinm Lau
- Duopharma Innovation Sdn. Bhd., Shah Alam, Selangor, Malaysia
| | - Shahnun Ahmad
- Duopharma Innovation Sdn. Bhd., Shah Alam, Selangor, Malaysia
| | - Atiqah Amran
- Duopharma Innovation Sdn. Bhd., Shah Alam, Selangor, Malaysia
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Deng Y, Wang G, Jiang G, Song D, Xu X, Zhao D, Tan G, Tan Z, Chen J. Bioequivalence of Two 6-Mercaptopurine Tablet Formulations in Healthy Fasting Chinese Volunteers. Clin Pharmacol Drug Dev 2023; 12:1099-1103. [PMID: 37408364 DOI: 10.1002/cpdd.1298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 05/24/2023] [Indexed: 07/07/2023]
Abstract
The supply of branded 6-mercaptopurine (6-MP) is limited in China, necessitating the local production and clinical evaluation of generic alternatives. We evaluated the in vivo bioequivalence (BE) of a new generic mercaptopurine tablet (50 mg) formulation by comparing peak plasma concentration and area under the concentration-time curve (AUC) with a branded 6-MP formulation as the reference in 36 healthy fasting Chinese adults. The in vivo BE was evaluated by the average BE test. The safety parameters of the test and reference formulations were also evaluated. The geometric mean ratios for AUC over the dosing interval and AUC from time zero to infinity were 104% and 104%, respectively, of the reference values, while the point estimate of the geometric mean ratio for peak plasma concentration was 104% of the reference value. The test and reference formulations in this study were both deemed safe as only 23 Grade 1 adverse events were observed in 13 of 36 subjects. The test and reference formulations of 6-MP tablets meet the regulatory criteria for BE in healthy fasting Chinese adults.
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Affiliation(s)
- Yaping Deng
- Department of Clinical Pharmacology, Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Guohua Wang
- Zhejiang Zhebei Pharmaceutical Co., Ltd., Huzhou, Zhejiang, China
| | - Guojun Jiang
- Department of Clinical Pharmacology, Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Dandan Song
- Department of Clinical Pharmacology, Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou, Zhejiang, China
| | - Xian Xu
- Department of Clinical Pharmacology, Hangzhou Combak Hospital, Hangzhou, Zhejiang, China
| | - Dandan Zhao
- Department of Clinical Pharmacology, Hangzhou Combak Hospital, Hangzhou, Zhejiang, China
| | - Guojun Tan
- Zhejiang Zhebei Pharmaceutical Co., Ltd., Huzhou, Zhejiang, China
| | - Zijun Tan
- Zhejiang Zhebei Pharmaceutical Co., Ltd., Huzhou, Zhejiang, China
| | - Jian Chen
- Department of Clinical Pharmacology, Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou, Zhejiang, China
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Senemar S, Kuzma BA, Ramezanli T, Ghosh P, Raney SG, Rantou E, Stagni G. Bioequivalence Evaluation of Topical Metronidazole Products Using Dermal Microdialysis in New Zealand Rabbits. AAPS PharmSciTech 2023; 24:204. [PMID: 37789133 DOI: 10.1208/s12249-023-02660-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Accepted: 09/15/2023] [Indexed: 10/05/2023] Open
Abstract
Comparative assessment of cutaneous pharmacokinetics (cPK) by dermal microdialysis (dMD) appears to be suitable to evaluate the bioequivalence (BE) of topical dermatological drug products applied to the skin (TDDPs). Although dMD studies in the literature have reported inconclusive BE assessments, we have addressed several methodological deficiencies to improve dMD's capability to assess BE between reference (R) and approved generic (referred to as test (T)) gel and cream products of metronidazole (MTZ). The 90% confidence interval (CI) of the geometric mean ratios for the Ln(AUC0-24) and Ln(Cmax) endpoints was centered within the BE limits of 80-125%. The CIs extended outside this range as the proof-of-principle study was not statistically powered to demonstrate BE (N = 7 rabbits). A power analysis suggests that, with the variability observed in this study, 21 rabbits for the cream and 11 rabbits for the gel would be sufficient to support an evaluation of BE with the 2 probe replicates we used, and only 10 and 5 rabbits would be sufficient to power the study for the cream and gel, respectively, if 4 probe replicates are used for each treatment per rabbit. These results indicate that dMD when properly controlling variables can be used to support BE assessments for TDDPs.
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Affiliation(s)
- Sharareh Senemar
- Division of Pharmaceutical Sciences, Arnold and Marie Schwartz College of Pharmacy, Long Island University, 75 DeKalb Ave., Brooklyn, New York, 11201, USA
| | - Benjamin A Kuzma
- Division of Pharmaceutical Sciences, Arnold and Marie Schwartz College of Pharmacy, Long Island University, 75 DeKalb Ave., Brooklyn, New York, 11201, USA
- Drug Metabolism and Pharmacokinetics, Vertex Pharmaceuticals, Boston, Massachusetts, USA
| | - Tannaz Ramezanli
- Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA
| | - Priyanka Ghosh
- Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA
| | - Sam G Raney
- Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA
| | - Elena Rantou
- Division of Biometrics VIII, Office of Biostatistics, Office of Translational Sciences, Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, Maryland, USA
| | - Grazia Stagni
- Division of Pharmaceutical Sciences, Arnold and Marie Schwartz College of Pharmacy, Long Island University, 75 DeKalb Ave., Brooklyn, New York, 11201, USA.
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Qiu B, Song H, Ding C, Sun X, Du R, Yang H, Bai W, Dong Z. Pharmacokinetics and safety of highly variable valsartan in single-pill combination with amlodipine versus its generic formulation: a randomized, three-cycle, three-sequence, partially replicated crossover phase I bioequivalence clinical trial. Front Pharmacol 2023; 14:1264321. [PMID: 37745062 PMCID: PMC10512707 DOI: 10.3389/fphar.2023.1264321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Accepted: 08/23/2023] [Indexed: 09/26/2023] Open
Abstract
Valsartan/amlodipine (I) is a single-pill combination (SPC) of an angiotensin II receptor blocker (ARB) and a calcium channel blocker (CCB) for treating hypertension. A clinical trial was performed to demonstrate that the test and reference valsartan/amlodipine formulations were bioequivalent under fasting and postprandial conditions. Participants were randomly divided into three sequences at a ratio of 1:1:1 for three-cycle, reference formulation replicated, crossover administration. The average bioequivalence (ABE) and reference-scaled average bioequivalence (RSABE) methods were used to evaluate BE using the main pharmacokinetic (PK) parameters. Overall, 45 eligible participants were enrolled in the postprandial trial, which was consistent with the fasting trial. For valsartan, the RSABE method was used to evaluate the BE of Cmax, while the ABE method was applied to evaluate the BE of AUC0-t and AUC0-∞. Both point estimates and 95% upper confidence bound met the BE criteria. For amlodipine, the ABE method was performed, and the 90% confidence intervals of the geometric mean ratios (GMR) for Cmax and AUC0-72 h were all within 80%-125%, with the BE criteria being met. Therefore, the two formulations are bioequivalent and have similar safety profiles in healthy Chinese subjects. Clinical trial registration: [http://www.chinadrugtrials.org.cn/index.html], identifier [CTR20210214].
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Affiliation(s)
| | | | | | | | | | | | - Wanjun Bai
- Phase I Clinical Trial Laboratory, Hebei General Hospital, Shijiazhuang, China
| | - Zhanjun Dong
- Phase I Clinical Trial Laboratory, Hebei General Hospital, Shijiazhuang, China
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Krajcar D, Grabnar I, Jereb R, Legen I, Opara J. Predictive Potential of BCS and Pharmacokinetic Parameters on Study Outcome: Analysis of 198 In Vivo Bioequivalence Studies. Eur J Drug Metab Pharmacokinet 2023; 48:241-255. [PMID: 36872388 PMCID: PMC10175306 DOI: 10.1007/s13318-023-00821-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/12/2023] [Indexed: 03/07/2023]
Abstract
BACKGROUND AND OBJECTIVES Understanding predictive potential of parameters to perform early bioequivalence (BE) risk assessment is crucial for good planning and risk mitigation during product development. The objective of the present study was to evaluate predictive potential of various biopharmaceutical and pharmacokinetic parameters on the outcome of BE study. METHODS Retrospective analysis was performed on 198 Sandoz (Lek Pharmaceuticals d.d., A Sandoz Company, Verovskova 57, 1526 Ljubljana, Slovenia) sponsored BE studies [52 active pharmaceutical ingredients (API)] where characteristics of BE study and APIs were collected for immediate-release products and their predictive potential on the study outcome was assessed using univariate statistical analysis. RESULTS Biopharmaceutics Classification System (BCS) was confirmed to be highly predictive of BE success. BE studies with poorly soluble APIs were riskier (23% non-BE) than with highly soluble APIs (0.1% non-BE). APIs with either lower bioavailability (BA), presence of first-pass metabolism, and/or being substrate for P-glycoprotein substrate (P-gP) were associated with higher non-BE occurrence. In silico permeability and time at peak plasma concentrations (Tmax) were shown as potentially relevant features for predicting BE outcome. In addition, our analysis showed significantly higher occurrence of non-BE results for poorly soluble APIs with disposition described by multicompartment model. The conclusions for poorly soluble APIs were the same on a subset of fasting BE studies; for a subset of fed studies there were no significant differences between factors in BE and non-BE groups. CONCLUSION Understanding the association of parameters and BE outcome is important for further development of early BE risk assessment tools where focus should be first in finding additional parameters to differentiate BE risk within a group of poorly soluble APIs.
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Affiliation(s)
- Dejan Krajcar
- Lek Pharmaceuticals d.d., A Sandoz Company, Verovskova 57, 1526, Ljubljana, Slovenia.
- Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000, Ljubljana, Slovenia.
| | - Iztok Grabnar
- Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000, Ljubljana, Slovenia
| | - Rebeka Jereb
- Lek Pharmaceuticals d.d., A Sandoz Company, Verovskova 57, 1526, Ljubljana, Slovenia
| | - Igor Legen
- Lek Pharmaceuticals d.d., A Sandoz Company, Verovskova 57, 1526, Ljubljana, Slovenia
| | - Jerneja Opara
- Lek Pharmaceuticals d.d., A Sandoz Company, Verovskova 57, 1526, Ljubljana, Slovenia
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Wang Y, Xue J, Su Z, Cui Y, Liu G, Yang W, Liu Z, Chen J, Ren Q, Yu S, Cheng Y, Zhou Y, Wang W, Chen X, Qu D, Deng Q, Zhao Y, Yang H. Pharmacokinetics and safety of dasatinib and its generic: a phase I bioequivalence study in healthy Chinese subjects. Expert Opin Investig Drugs 2023; 32:263-270. [PMID: 36757390 DOI: 10.1080/13543784.2023.2179481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/10/2023]
Abstract
BACKGROUND Dasatinib (Sprycel®) is a tyrosine kinase inhibitor for treating chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. RESEARCH DESIGN & METHODS We designed a clinical study to demonstrate that the dasatinib tablet (YiNiShu®) (Chia Tai Tianqing Pharmaceutical Group Co., Ltd) and Dasatinib (Bristol Myers Squibb) were bioequivalent under fasting and fed conditions. The whole study was structured into the fasting trial and the postprandial trial. Each period, subjects were given 50 mg dasatinib or its generic. The RSABE (reference scale average bioequivalence) and ABE (average bioequivalence) methods were employed to assess bioequivalence by pharmacokinetics (PK) parameters for a highly variable drug. RESULTS 32 and 24 eligible volunteers were enrolled in the fasting and postprandial trials, respectively. In the fasting trial, the RSABE method was performed, and point estimates of Cmax, AUC0-t, and AUC0-∞ met the bioequivalence criteria. In the postprandial trial, the ABE method was performed, and the 90% CI of the geometric mean ratio (GMR) for PK parameters met the requirements of bioequivalence standards. CONCLUSION The results proved that the PK parameters of the two drugs were similar and bioequivalent, indicating that both drugs had a good safety profile. CLINICAL TRIAL REGISTRATION This trial was registered in ClinicalTrials.gov (Number: NCT05640804) and Drug Clinical Trial Registration and Information Disclosure Platform (Number: CTR20181708).
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Affiliation(s)
- Yanli Wang
- Phase I Clinical Trial Laboratory, Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, China
| | - Jinling Xue
- Department of clinical research center Clinical Research Center, Chia Tai Tianqing Pharmaceutical Group Co., Ltd, Nanjing, China
| | - Zhengjie Su
- Phase I Clinical Trial Laboratory, Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, China
| | - Yingzi Cui
- Phase I Clinical Trial Laboratory, Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, China
| | - Guangwen Liu
- Phase I Clinical Trial Laboratory, Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, China
| | - Wei Yang
- Phase I Clinical Trial Laboratory, Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, China
| | - Zhengzhi Liu
- Phase I Clinical Trial Laboratory, Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, China
| | - Jiahui Chen
- Phase I Clinical Trial Laboratory, Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, China
| | - Qing Ren
- Phase I Clinical Trial Laboratory, Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, China
| | - Shuang Yu
- Phase I Clinical Trial Laboratory, Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, China
| | - Yang Cheng
- Phase I Clinical Trial Laboratory, Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, China
| | - Yannan Zhou
- Phase I Clinical Trial Laboratory, Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, China
| | - Wanhua Wang
- Phase I Clinical Trial Laboratory, Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, China
| | - Xuesong Chen
- The Clinical Trial Quality Control Center, Ansiterui Medical Technology Consulting Co., Ltd, Changchun, China
| | - Dongmei Qu
- The Clinical Trial Quality Control Center, Ansiterui Medical Technology Consulting Co., Ltd, Changchun, China
| | - Qiaohuan Deng
- Phase I Clinical Trial Laboratory, Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, China
| | - Yicheng Zhao
- Puheng Technology Co., Ltd, Suzhou, China.,Clinical Medical College, Changchun University of Chinese Medicine, Changchun, China
| | - Haimiao Yang
- Phase I Clinical Trial Laboratory, Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, China
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Naqvi SMH, Gala MYN, Muchhala S, Arumugam A, Panigrahi D, Patil D, Rathod R, Mane A. Pharmacokinetics/Pharmacodynamics study of Fixtral SB as compared to supra bioavailable itraconazole and conventional itraconazole. World J Pharmacol 2023; 12:1-11. [DOI: 10.5497/wjp.v12.i1.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 11/11/2022] [Accepted: 02/07/2023] [Indexed: 02/17/2023] Open
Abstract
BACKGROUND Itraconazole is a broad-spectrum triazole antifungal inhibiting fungal growth by inhibiting ergosterol synthesis and exhibits a nonlinear pharmacokinetic profile. Erratic absorption pattern with wide fluctuations in blood levels causes inconsistent and unpredictable clinical behaviour of this drug despite its low minimum inhibitory concentration (MIC) as compared to other antifungal agents.
AIM To compare the oral bioavailability and bioequivalence of Fixtral SB (supra bioavailable itraconazole) with reference product R2 (supra bioavailable 2 × 50 mg itraconazole).
METHODS The study population consisted of 54 healthy volunteers, aged between 18-45 years and randomized to receive a single oral dose of either test [T; Fixtral SB (supra bioavailable itraconazole) 100 mg] or reference product (R1; Sporanox 100 mg × 2 capsules and R2; Lozanoc capsules 50 mg × 2 capsules). Blood samples were taken pre-dose and post-dose up to 96 h. The study evaluated bioequivalence by comparing the oral bioavailability of the test product with reference product R2. The pharmacodynamic characteristics of the drug were evaluated by comparing the test product with reference product R1. Pharmacokinetics (PK)-PD comparative analysis [area under the concentration-time curve (AUC)/ minimum inhibitory concentration (MIC) > 25] was performed for conventional itraconazole 100 mg and supra bioavailable itraconazole 50 mg. Adverse events (AEs) assessments were performed in each study period and post-study evaluation.
RESULTS Statistical analysis of primary PK variables revealed bioequivalence, with confidence intervals being completely inside the acceptance criteria of 80%-125%. The peak concentration levels of itraconazole were achieved at 10 h (T) and 8.5 h (R2), respectively. Pharmacodynamic parameter assessment showed that AUC/MIC for R1 are comparable to Fixtral SB 100mg for MIC levels up to 16mcg/mL (P > 0.05 and observed P = 0.3196). Six AEs were observed that were mild to moderate in severity and resolved. No severe AE was reported.
CONCLUSION Test product itraconazole Capsule 100 mg is bioequivalent with the reference product (R2) at 100 mg dose (2 capsules of Lozanoc® 50 mg) under fed conditions. Pharmacodynamics activity in terms of AUC/MIC is comparable between the test product at 100 mg dose and marketed itraconazole 200 mg. Fixtral SB is expected to have therapeutically similar efficacy at half the equivalent dose. Tested formulations were found to be safe and well tolerated.
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Affiliation(s)
| | | | - Snehal Muchhala
- Medical Affairs, Dr Reddy’s Laboratories, Hyderabad 500016, India
| | - Anand Arumugam
- Global Clinical Management, Dr Reddy’s Laboratories, Hyderabad 500016, India
| | | | - Dipak Patil
- Global Clinical Management, Dr Reddy’s Laboratories, Hyderabad 500016, India
| | - Rahul Rathod
- Medical Affairs, Dr Reddy’s Laboratories, Hyderabad 500016, India
| | - Amey Mane
- Medical Affairs, Dr Reddy’s Laboratories, Hyderabad 500016, India
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12
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Paixão P, Silva N, Guerreiro RB, Blake K, Bonelli M, Morais JAG, García-Arieta A, Gouveia LF. Evaluation of a Proposed Approach for the Determination of the Bioequivalence Acceptance Range for Narrow Therapeutic Index Drugs in the European Union. Pharmaceutics 2022; 14:pharmaceutics14112349. [PMID: 36365166 PMCID: PMC9697618 DOI: 10.3390/pharmaceutics14112349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 10/24/2022] [Accepted: 10/26/2022] [Indexed: 11/06/2022] Open
Abstract
Bioequivalence (BE) of products containing narrow therapeutic index (NTI) drugs in the European Union is currently established by demonstrating that the 90% confidence interval for the ratio of the population geometric means of the test compared to the reference product’s AUC, and in certain cases Cmax, is included within the tighter acceptance range of 90.00−111.11%. An alternative criterion, consisting of narrowed limits based on the within-subject variability of the reference product, was recently proposed. Its performance for a three-period partial replicate design was tested by simulation in terms of power to show BE, type I error (T1E) and sample size requirements. A new condition, a constraint on the test-to-reference geometric mean ratio (cGMR) to be contained within the range of 90.00−111.11%, was also tested. The probability of showing BE when the products differ more than 10% was increased, but only if the reference product’s within-subject variability was moderate-to-high. The inclusion of the additional cGMR limited this. An increase in the T1E (<7%) was observed. The inclusion of the additional cGMR did not change the highest inflation of the T1E. Finally, a significant sample size reduction was observed and the inclusion of the cGMR usually did not increase the required sample size.
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Affiliation(s)
- Paulo Paixão
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-004 Lisboa, Portugal
- EMA’s Pharmacokinetics Working Party, 1083 HS Amsterdam, The Netherlands
- Correspondence:
| | - Nuno Silva
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-004 Lisboa, Portugal
| | - Rita Bento Guerreiro
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-004 Lisboa, Portugal
| | - Kevin Blake
- European Medicines Agency (EMA), 1083 HS Amsterdam, The Netherlands
| | - Milton Bonelli
- European Medicines Agency (EMA), 1083 HS Amsterdam, The Netherlands
| | - José Augusto Guimarães Morais
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-004 Lisboa, Portugal
| | - Alfredo García-Arieta
- EMA’s Pharmacokinetics Working Party, 1083 HS Amsterdam, The Netherlands
- The Spanish Agency of Medicines and Medical Devices, 28022 Madrid, Spain
| | - Luís Filipe Gouveia
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-004 Lisboa, Portugal
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13
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Gupta VK, Patel G, Gasink L, Bajraktari F, Lei Y, Jain A, Srivastava P, Talley AK. Bioequivalence of Two Oral Formulations of Tebipenem Pivoxil Hydrobromide in Healthy Subjects. Clin Transl Sci 2022; 15:1654-1663. [PMID: 35411579 PMCID: PMC9283737 DOI: 10.1111/cts.13280] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 02/07/2022] [Accepted: 03/23/2022] [Indexed: 11/29/2022] Open
Abstract
Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is a novel oral carbapenem prodrug of tebipenem (TBP), the active moiety, currently in development for treating serious bacterial infections. This study assessed the bioequivalence (BE) of the clinical trial and registration tablet formulations of TBP-PI-HBr and evaluated the effect of food on the pharmacokinetics (PK) of tebipenem. This was a single center, open-label, randomized, single-dose, 3-sequence, 4-period crossover, BE and food-effect study. Subjects received single 600 mg oral doses of TBP-PI-HBr as the reference clinical trial tablet (Treatment A) and test registration tablet (Treatment B) formulations in alternating sequence while fasting, and then the test formulation under fed conditions. Whole blood samples were collected predose and at specified intervals up to 24 hours postdose to evaluate TBP PK parameters. Safety and tolerability were monitored. Thirty-six healthy, adult subjects were enrolled and completed the study. The criteria for bioequivalence were met for the TBP-PI-HBr test (registration tablet) and reference (clinical trial tablet) formulations as the 90% confidence intervals (CIs) for the geometric mean ratios for TBP AUC0-t , AUC0-inf , and Cmax fell within the established 80% to 125% BE limits. Dosing with food had no meaningful effect on TBP PK parameters. Five (14%) subjects reported adverse events of mild severity. No deaths, serious AEs or discontinuations due to AEs were reported, and no clinically relevant ECGs, vital signs or safety laboratory findings were observed. Results demonstrate the bioequivalence of oral TBP-PI-HBr registration and clinical trial tablet formulations and indicate that TBP-PI-HBr can be administered without regard to meals.
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Affiliation(s)
| | | | | | | | - Yang Lei
- Spero Therapeutics, Inc., Cambridge, MA
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14
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Na JY, Yang E, Kim JH, Kwon IS, Jin EH, Yu KS, Kim J, Lee S, Hong JH. Comparative Pharmacokinetics Between a Fixed-Dose Combination of Pitavastatin/Valsartan 4/160 mg and the Corresponding Individual Components Through a Partial Replicated Crossover Design in Healthy Male Subjects. Clin Pharmacol Drug Dev 2022; 11:615-622. [PMID: 34997835 DOI: 10.1002/cpdd.1054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Accepted: 11/10/2021] [Indexed: 11/05/2022]
Abstract
Hypertension and hyperlipidemia are often comorbid, requiring combination therapies of antihypertensive drugs and antihyperlipidemia drugs. Taking 1 fixed-dose combination (FDC) may increase patient compliance rather than taking each of the drugs separately. This study aimed to evaluate the pharmacokinetic bioequivalence between an FDC of pitavastatin/valsartan 4/160 mg and the corresponding individual components. Considering that valsartan is a highly variable drug for maximum plasma concentration (Cmax ), an open-label, randomized, partial replicated crossover study was conducted in 54 healthy subjects. The subjects received a single oral dose of the FDC of pitavastatin/valsartan 4/160 mg in 1 period or the corresponding individual components in the other 2 periods. The geometric mean ratios and their 90%CIs of the FDC to the corresponding individual components for Cmax and area under the concentration-time curve from time 0 to the last measurable time point were 1.05 (90%CI, 0.96-1.15) and 0.10 (90%CI, 0.95-1.04) for pitavastatin and 1.15 (90%CI, 1.06-1.25) and 1.06 (0.99-1.14) for valsartan, respectively. The geometric mean ratios (90%CIs) for area under the concentration-time curve from time 0 to the last measurable time point and Cmax of both drugs were included in the bioequivalence criteria. In conclusion, the FDC of pitavastatin/valsartan 4/160 mg showed pharmacokinetic equivalence with the corresponding individual components.
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Affiliation(s)
- Joo Young Na
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea
| | - Eunsol Yang
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea
| | - Jae-Hoon Kim
- Department of Pharmacology, Chungnam National University College of Medicine, Daejeon, Republic of Korea.,Department of Clinical Pharmacology and Therapeutics, Chungnam National University Hospital, Daejeon, Republic of Korea
| | - In Sun Kwon
- Department of Pharmacology, Chungnam National University College of Medicine, Daejeon, Republic of Korea.,Department of Clinical Pharmacology and Therapeutics, Chungnam National University Hospital, Daejeon, Republic of Korea
| | - Eun-Heui Jin
- Department of Pharmacology, Chungnam National University College of Medicine, Daejeon, Republic of Korea
| | - Kyung-Sang Yu
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea
| | - Jinsook Kim
- JW Pharmaceutical Corporation, Seoul, Republic of Korea
| | - SeungHwan Lee
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea
| | - Jang Hee Hong
- Department of Pharmacology, Chungnam National University College of Medicine, Daejeon, Republic of Korea.,Department of Clinical Pharmacology and Therapeutics, Chungnam National University Hospital, Daejeon, Republic of Korea
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15
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Ren X, Yu H, Qi X, Chen Q, Yang J, Fang Y, Lei Y, Zhang D, Zuo Q, Liu D. A Bioequivalence Study of Avanafil in Healthy Chinese Male Subjects Under Fasting and Fed Conditions: Results of a Randomized, Open-Label, Single-Dose, 2-Sequence, 2-Period Crossover Study. Clin Pharmacol Drug Dev 2021; 10:1495-1502. [PMID: 34288578 PMCID: PMC9291160 DOI: 10.1002/cpdd.998] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Accepted: 06/15/2021] [Indexed: 11/07/2022]
Abstract
This bioequivalence study was conducted to determine the pharmacokinetics and safety profiles of an originator and a generic avanafil formulation in Chinese male subjects under fed and fasting conditions. Each eligible subject was initially randomly given avanafil (200 mg) in a test‐reference or reference‐test order, before being switched to another study drug sequence after 7 drug‐free days. The bioequivalence of test and reference avanafil were determined if the 90%CIs of the geometric mean ratio (GMR) for the area under plasma concentration‐time curve (AUC) from time 0 to infinity (AUC0‐∞), AUC from time 0 to the last detectable concentration (AUC0‐t), and the maximum plasma concentration (Cmax) fell within the range 80%‐125%. Under fasting/fed conditions, the 90%CIs of GMR for AUC0‐∞, AUC0‐t, and Cmax were 98.9% to 109.5%/96.0% to 101.2%, 99.6% to 110.3%/96.6% to 102.4%, and 99.3% to 116.8%/94.3% to 106.7%, respectively, which were all within the 80%‐125% range. Adverse events (AEs) occurred in 20.8% of subjects under fasting conditions and 20.7% of subjects under fed conditions, with a severity of grade 1. No significant difference was found in the rate of occurrence of AEs and drug‐related AEs in the test and reference‐avanafil groups (all P > .05). We concluded that the test and reference avanafil were bioequivalent in healthy Chinese male subjects under fasting and fed conditions.
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Affiliation(s)
- Xiuhua Ren
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hengyi Yu
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xingxing Qi
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qian Chen
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jingwen Yang
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yinian Fang
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yongfang Lei
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Donglin Zhang
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qin Zuo
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dong Liu
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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16
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Paramanindita AS, Harahap Y, Prasaja B, Wijayanti TR, Lusthom W, Sofiah RE, Sandra M, Trisari Y. A bioequivalence study of two telmisartan 80 mg tablets in healthy Indonesian subjects: an open label, three-way, three-period, partial replicate crossover study. Drug Dev Ind Pharm 2020; 46:1747-1752. [PMID: 32892655 DOI: 10.1080/03639045.2020.1820042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Telmisartan is highly variable drug indicated for treatment of hypertension. This study aimed to compare the bioavailability of two 80 mg telmisartan tablets in healthy Indonesian subjects. A randomized, open-label, single-dose, three-sequence, three-way, reference-formulation-replicated crossover study was conducted under fasting period with two-week washout period. In this study, 31 Indonesian subjects were enrolled and 28 subjects were completed the study. Serial blood samples were collected up to 72 h following drug administration. Plasma concentrations of telmisartan were determined using high-performance liquid chromatography method with fluorescence detector. The pharmacokinetic parameters of AUC0- t , AUC0-∞, and C max were assessed for bioequivalence. Bioequivalence acceptance was based on predefined criteria of 90% confidence interval (CI) of 80.00-125.00% for AUC parameters and reference-scaled-average bioequivalence of 71.73-139.42% for C max. The 90% CI for AUC0- t , AUC0-∞, and C max was 96.11-107.25%, 93.06-104.36%, and 94.23-127.01%, respectively. These results indicated that the two formulations of telmisartan were bioequivalent.
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Affiliation(s)
| | | | - Budi Prasaja
- P.T. Clinisindo Laboratories, Jakarta, Indonesia
| | | | | | | | | | - Yunia Trisari
- P.T. Novell Pharmaceutical Laboratories, Jakarta, Indonesia
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17
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Ghosh SK, Dong L. A Functional Metric Approach to Assess Biosimilarity With Application to Rheumatoid Arthritis Trials. Stat Biopharm Res 2020. [DOI: 10.1080/19466315.2020.1733071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Affiliation(s)
- Sujit K. Ghosh
- Department of Statistics, North Carolina State University, Raleigh, NC
| | - Lin Dong
- Department of Statistics, North Carolina State University, Raleigh, NC
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18
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Liao JJZ, Li Y. Approximate confidence limit for the reference scaled bioequivalence with a parallel design. J Biopharm Stat 2019; 30:231-243. [PMID: 31455199 DOI: 10.1080/10543406.2019.1657438] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
The reference scaled bioequivalence has been proposed with many successful applications for the highly variable products. The statistical properties for the reference scaled bioequivalence have been studied for the commonly used crossover design. However, a crossover design may not be feasible in a real application such as the biosimilar study, instead a parallel design is a more timely and cost-effective choice. In this paper, the approximate upper confidence interval limit for the linearized criteria in the reference scaled bioequivalence from a parallel design is derived. The performance of the approximation is evaluated through the simulation. The simulation results show that this approximation performs well and gives reasonable power and well-controlled type I error.
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Affiliation(s)
- Jason J Z Liao
- Biostatistics and Research Decision Sciences, Merck & Co., Inc, North Wales, PA, USA
| | - Yifang Li
- Early Development Biostatistics, Novartis Pharmaceuticals Corporation, Cambridge, MA, USA
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19
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Ocaña J, Muñoz J. Controlling type I error in the reference-scaled bioequivalence evaluation of highly variable drugs. Pharm Stat 2019; 18:583-599. [PMID: 31190418 DOI: 10.1002/pst.1950] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 04/10/2019] [Accepted: 04/11/2019] [Indexed: 11/08/2022]
Abstract
Reference-scaled average bioequivalence (RSABE) approaches for highly variable drugs are based on linearly scaling the bioequivalence limits according to the reference formulation within-subject variability. RSABE methods have type I error control problems around the value where the limits change from constant to scaled. In all these methods, the probability of type I error has only one absolute maximum at this switching variability value. This allows adjusting the significance level to obtain statistically correct procedures (that is, those in which the probability of type I error remains below the nominal significance level), at the expense of some potential power loss. In this paper, we explore adjustments to the EMA and FDA regulatory RSABE approaches, and to a possible improvement of the original EMA method, designated as HoweEMA. The resulting adjusted methods are completely correct with respect to type I error probability. The power loss is generally small and tends to become irrelevant for moderately large (affordable in real studies) sample sizes.
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Affiliation(s)
- Jordi Ocaña
- Department of Genetics, Microbiology and Statistics, Universitat de Barcelona, Barcelona, Spain
| | - Joel Muñoz
- Faculty of Physical and Mathematical Sciences, Department of Statistics, University of Concepcion, Concepcion, Chile
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20
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Endrenyi L, Tothfalusi L. Bioequivalence for highly variable drugs: regulatory agreements, disagreements, and harmonization. J Pharmacokinet Pharmacodyn 2019; 46:117-126. [PMID: 30798390 DOI: 10.1007/s10928-019-09623-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Accepted: 02/12/2019] [Indexed: 01/08/2023]
Abstract
Regulatory authorities introduced procedures in the last decade for evaluating the bioequivalence (BE) for highly variable drugs. These approaches are similar in principle but differ in details. For example, the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) recommend differing regulatory constants. The constant suggested by FDA results in discontinuity of the BE limits around the switching variation at 30% observed within-subject variation of the reference product. The regulatory constant of EMA does not have these problems. The Type I error reaches 6-7% around the switching variation with the EMA constant but 16-17% with the FDA constant. Various procedures were recently suggested, especially for the EMA approach, to eliminate the inflation of the Type I error. Notably, the so-called Exact algorithms try to amalgamate the positive features of both EMA and FDA procedures without their negative sides. The computational procedure for the EMA approach is simple and has a straightforward interpretation. The procedure for the FDA approach is based on an approximation, has a bias at small degrees of freedom, and requires a suitable computer program. All regulatory agencies impose a second requirement constraining the point estimate of the ratio of geometric means. In addition, EMA and Health Canada impose an upper limit for applying the recommended procedures. These expectations have psychological motivation and political rationale but no scientific foundations. Their inclusion results in incorrect and misleading interpretation of the principal criterion which involves confidence intervals. Different regulatory authorities expect to apply their approaches either to both AUC and Cmax or only to AUC or only to Cmax. Rational resolution of the disharmonization is needed.
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Affiliation(s)
- Laszlo Endrenyi
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, M5S 1A8, Canada.
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21
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Ding Y, Liu B, Lou J, Sun J, Wu M, Zhu X, Chen G, Zhang H, Li X, Chen H, Liu C, Shen Z, Li C. Bioequivalence of Sarpogrelate in Healthy Chinese Subjects Under Fasting and Fed Conditions: A 4-Way Replicate Crossover Investigation by a Reference-Scaled Average Bioequivalence Approach. Clin Pharmacol Drug Dev 2018; 8:713-720. [PMID: 30325583 DOI: 10.1002/cpdd.624] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Accepted: 09/17/2018] [Indexed: 11/11/2022]
Affiliation(s)
- Y.H. Ding
- Phase 1 Clinical Unit, China-Frontage USA, First Hospital; Jilin University; Changchun Jilin China
| | - B. Liu
- Department of Hand Surgery, First Hospital; Jilin University; Changchun Jilin China
| | - J.F. Lou
- Department of Geriatrics, First Hospital; Jilin University; Changchun Jilin China
| | - J.X. Sun
- Phase 1 Clinical Unit, China-Frontage USA, First Hospital; Jilin University; Changchun Jilin China
| | - M. Wu
- Phase 1 Clinical Unit, China-Frontage USA, First Hospital; Jilin University; Changchun Jilin China
| | - X.X. Zhu
- Phase 1 Clinical Unit, China-Frontage USA, First Hospital; Jilin University; Changchun Jilin China
| | - G.L. Chen
- Phase 1 Clinical Unit, China-Frontage USA, First Hospital; Jilin University; Changchun Jilin China
| | - H. Zhang
- Phase 1 Clinical Unit, China-Frontage USA, First Hospital; Jilin University; Changchun Jilin China
| | - X.J. Li
- Phase 1 Clinical Unit, China-Frontage USA, First Hospital; Jilin University; Changchun Jilin China
| | - H. Chen
- Phase 1 Clinical Unit, China-Frontage USA, First Hospital; Jilin University; Changchun Jilin China
| | - C.J. Liu
- Phase 1 Clinical Unit, China-Frontage USA, First Hospital; Jilin University; Changchun Jilin China
| | - Z.W. Shen
- First Hospital; and Institute of Immunology; Jilin University; Changchun Jilin China
| | - C.Y. Li
- Phase 1 Clinical Unit, China-Frontage USA, First Hospital; Jilin University; Changchun Jilin China
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22
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Drug Interchangeability of Generic and Brand Products of Fixed Dose Combination Tablets of Sofosbuvir and Ledipasvir (400/90 mg): Employment of Reference Scaled Average Bioequivalence Study on Healthy Egyptian Volunteers. Clin Drug Investig 2018; 38:439-448. [PMID: 29417463 DOI: 10.1007/s40261-018-0622-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND AND OBJECTIVES The purpose of this study was to apply the reference-scaled average bioequivalence (RSABE) approach to evaluate the bioequivalence and to investigate the pharmacokinetic properties of two formulations of fixed dose combination (FDC) tablet of sofosbuvir (SOF) and ledipasvir (LED) (400/90 mg) in 36 healthy Egyptian volunteers. METHODS The study was performed in single-dose, randomized-sequence, open-label, reference-replicated, 3-period crossover design (RTR, TRR, RRT), with a washout period of 2 weeks. A rapid and simple LC-MS/MS method was developed and validated for the simultaneous estimation of SOF and LED using eplerenone as an internal standard (IS). RESULTS The results showed that the 90% confidence intervals (CIs) for natural log-transformed ratios of Cmax, AUClast and AUC∞ of SOF (89.95-115.31, 98.77-109.75 and 98.79-109.75) were within the RSABE acceptance limits. The 90% CIs for natural log-transformed ratios of Cmax and AUClast of LED (87.33-115.15 and 83.82-112.26) were within the FDA bioequivalence limits (80.00-125.00). In addition, the in vitro dissolution study was done and both formulations released > 85% of drug within 15 min in the proposed dissolution medium. CONCLUSIONS In conclusion, bioequivalence between the two fixed-dose combination products was demonstrated for both active ingredients.
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23
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Dragojević-Simić V, Kovačević A, Jaćević V, Rančić N, Djordjević S, Kilibarda V, Mikov M, Bokonjić D. Bioequivalence study of two formulations of itraconazole 100 mg capsules in healthy volunteers under fed conditions: a randomized, three-period, reference-replicated, crossover study. Expert Opin Drug Metab Toxicol 2018; 14:979-988. [PMID: 30028640 DOI: 10.1080/17425255.2018.1503649] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Abstract
BACKGROUND The aim of the study was to evaluate the bioequivalence of two itraconazole 100 mg capsule formulations. RESEARCH DESIGN AND METHODS The single-center, open-label, randomized, three-period, three-sequence, reference-replicated, cross-over study included 38 healthy subjects under fed conditions. In each study period (separated by a 14-day washout), a single oral dose of the test (T) or reference (R) product was administered. Blood samples were collected at pre-dose and up to 72.0 h after administration. The calculated pharmacokinetic parameters, based on the plasma concentrations of itraconazole and hydroxy itraconazole, were AUC0-72h, AUC0-∝, Cmax, Tmax, T1/2 and Kel. RESULTS The 90% CI for the test/reference geometric means ratio for the parent compound, itraconazole, was in the range from 85.29% to 116.07% for AUC0-72h. Since the coefficient of variation (CV) for the reference product was 44.95% for Cmax, the 90% CI for this parameter for itraconazole was 93.49-133.78%, which was within the proposed limits of the EMA for bioequivalence of 72.15-138.59%. During the study, 4 subjects encountered a total of 14 mild adverse events. CONCLUSIONS The use of the reference-scaling approach with 3-period design (TRR, RTR, and RRT) was an efficient way to demonstrate that two commercially available oral itraconazole formulations met the predetermined bioequivalence criteria.
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Affiliation(s)
- Viktorija Dragojević-Simić
- a Centre for Clinical Pharmacology , Military Medical Academy , Belgrade , Serbia.,b Medical Faculty of the Military Medical Academy , University of Defense in Belgrade , Belgrade , Serbia
| | - Aleksandra Kovačević
- a Centre for Clinical Pharmacology , Military Medical Academy , Belgrade , Serbia.,b Medical Faculty of the Military Medical Academy , University of Defense in Belgrade , Belgrade , Serbia
| | - Vesna Jaćević
- b Medical Faculty of the Military Medical Academy , University of Defense in Belgrade , Belgrade , Serbia.,c National Poison Control Centre , Military Medical Academy , Belgrade , Serbia.,d Department of Chemistry, Faculty of Science , University of Hradec Kralove , Hradec Kralove , Czech Republic
| | - Nemanja Rančić
- a Centre for Clinical Pharmacology , Military Medical Academy , Belgrade , Serbia.,b Medical Faculty of the Military Medical Academy , University of Defense in Belgrade , Belgrade , Serbia
| | - Snežana Djordjević
- b Medical Faculty of the Military Medical Academy , University of Defense in Belgrade , Belgrade , Serbia.,c National Poison Control Centre , Military Medical Academy , Belgrade , Serbia
| | - Vesna Kilibarda
- b Medical Faculty of the Military Medical Academy , University of Defense in Belgrade , Belgrade , Serbia.,c National Poison Control Centre , Military Medical Academy , Belgrade , Serbia
| | - Momir Mikov
- e Institute for Pharmacology, Clinical Pharmacology and Toxicology , University of Novi Sad, Faculty of Medicine , Novi Sad , Serbia
| | - Dubravko Bokonjić
- b Medical Faculty of the Military Medical Academy , University of Defense in Belgrade , Belgrade , Serbia
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24
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Oh M, Ghim JL, Park SE, Kim EY, Shin JG. Pharmacokinetic comparison of a fixed-dose combination versus concomitant administration of fimasartan, amlodipine, and rosuvastatin using partial replicated design in healthy adult subjects. DRUG DESIGN DEVELOPMENT AND THERAPY 2018; 12:1157-1164. [PMID: 29780236 PMCID: PMC5951219 DOI: 10.2147/dddt.s164215] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Objective The aim of this study was to compare the pharmacokinetics (PK) and safety profiles of a fixed-dose combination (FDC) formulation of fimasartan, amlodipine, and rosuvastatin with the co-administration of the two products by using a replicated crossover study design in healthy male subjects. Results This was an open-label, randomized, three-sequence, three-period replicated crossover study in healthy male subjects. The replicated crossover design was done because of high coefficient of variation of PK parameter for fimasartan, that is, >30%. With a 14 days washout period, an FDC tablet containing 60 mg fimasartan, 10 mg amlodipine, and 20 mg rosuvastatin was administered only once, and separate formulations of fimasartan/amlodipine 60 mg/10 mg FDC tablet and 20 mg rosuvastatin tablet administered twice. Blood samples were collected up to 72 hours following drug administration. The plasma concentrations of fimasartan, amlodipine, and rosuvastatin were measured by liquid chromatography tandem mass spectrometry. Safety was assessed by evaluating vital signs, clinical laboratory parameters, physical examinations, and medical interviews. Results The geometric mean ratios and 90% confidence intervals (CIs) for the maximum plasma concentration (Cmax) and area under the curve from time zero to the last measurable sampling time (AUCt) were 1.0776 (0.9201-1.2622) and 0.9978 (0.9538-1.0439) for fimasartan, 1.0038 (0.9782-1.0301) and 1.0055 (0.9828-1.0288) for amlodipine, and 1.0006 (0.9290-1.0776) and 0.9986 (0.9532-1.0461) for rosuvastatin, respectively. A total of 22 adverse events (AEs) were reported by 60 subjects; there were no significant differences in the incidence of AEs between the two groups. Conclusion The 90% CI of the Cmax of fimasartan was within the widened acceptance limit, ln(0.6984)-ln(1.4319). The 90% CIs of the other PK parameters for drugs were between ln(0.8) and ln(1.25). These results suggest that the FDC formulation is pharmacokinetically bioequivalent and has a similar safety profile, to the co-administration of its three constituent drugs.
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Affiliation(s)
- Minkyung Oh
- Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, Republic of Korea
| | - Jong-Lyul Ghim
- Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, Republic of Korea.,Department of Clinical Pharmacology, Inje University Busan Paik Hospital, Busan, Republic of Korea
| | - Sung-Eun Park
- Department of Clinical Pharmacology, Inje University Busan Paik Hospital, Busan, Republic of Korea
| | - Eun-Young Kim
- Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, Republic of Korea.,Department of Clinical Pharmacology, Inje University Busan Paik Hospital, Busan, Republic of Korea
| | - Jae-Gook Shin
- Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, Republic of Korea.,Department of Clinical Pharmacology, Inje University Busan Paik Hospital, Busan, Republic of Korea
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Knahl SIE, Lang B, Fleischer F, Kieser M. A comparison of group sequential and fixed sample size designs for bioequivalence trials with highly variable drugs. Eur J Clin Pharmacol 2018; 74:549-559. [PMID: 29362819 DOI: 10.1007/s00228-018-2415-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Accepted: 01/09/2018] [Indexed: 10/18/2022]
Abstract
PURPOSE A drug is defined as highly variable if its intra-individual coefficient of variation (CV) is greater than or equal to 30%. In such a case, bioequivalence may be assessed by means of methods that take the (high) variability into account. The Scaled Average Bioequivalence (SABE) approach is such a procedure and represents the recommendations of FDA. The aim of this investigation is to compare the performance characteristics of classical group sequential designs (GSD) and fixed design settings for three-period crossover bioequivalence studies with highly variable drugs, where the SABE procedure is utilized. METHODS Monte Carlo simulations were performed to assess type I error rate, power, and average sample size for GSDs with Pocock's and O'Brien-Fleming's stopping rules and various timings of the interim analysis and for fixed design settings. RESULTS Based on our investigated scenarios, the GSDs show comparable properties with regard to power and type I error rate as compared to the corresponding fixed designs. However, due to an advantage in average sample size, the most appealing design is Pocock's approach with interim analysis after 50% information fraction. CONCLUSIONS Due to their favorable performance characteristics, two-stage GSDs are an appealing alternative to fixed sample designs when assessing bioequivalence in highly variable drugs.
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Affiliation(s)
- Sophie I E Knahl
- Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Straße 65, 88397, Biberach, Germany
| | - Benjamin Lang
- Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Straße 65, 88397, Biberach, Germany
| | - Frank Fleischer
- Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Straße 65, 88397, Biberach, Germany
| | - Meinhard Kieser
- Institute of Medical Biometry and Informatics, University of Heidelberg, Im Neuenheimer Feld 130.3, 69120, Heidelberg, Germany.
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26
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Tothfalusi L, Endrenyi L. Algorithms for evaluating reference scaled average bioequivalence: power, bias, and consumer risk. Stat Med 2017; 36:4378-4390. [PMID: 28850696 DOI: 10.1002/sim.7440] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2017] [Revised: 07/21/2017] [Accepted: 07/26/2017] [Indexed: 11/09/2022]
Abstract
The determination of the bioequivalence between highly variable drug products involves the evaluation of reference scaled average bioequivalence. The European and US regulatory authorities suggest different algorithms for the implementation of this approach. Both algorithms are based on approximations reflected in lower than the achievable power or higher than the nominal consumer risk of 5%. To overcome these deficiencies, a new class of algorithms, the so-called Exact methods, was earlier introduced. However, their applicability was limited. We propose 2 modifications which make their computation simpler and also applicable with any study design. Four algorithms were evaluated in simulated 3-period and 4-period bioequivalence studies: Hyslop's approach recommended by the US FDA, the method of average bioequivalence with expanding limits requested by the European EMA, and 2 versions of the new Exact methods. At small sample sizes, the Exact methods had substantially higher statistical power than Hyslop's algorithm and had lower consumer risk than the method of average bioequivalence with expanding limits. Similarly to the Hyslop's algorithm, higher than 5% consumer risk was observed only with either unbalanced study design or with additional regulatory requirements. The improved Exact algorithms compare favorably with the alternative procedures. They are based on the bias correction method of Hedges. The recognition that the scaled difference statistics is measured with bias has important practical implications when results of pilot bioequivalence studies are evaluated and, at the same time, calls for the revision of the statistical theory of RSABE and its related methods.
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Affiliation(s)
- Laszlo Tothfalusi
- Department of Pharmacodynamics, Semmelweis University, Budapest, Hungary
| | - Laszlo Endrenyi
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
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27
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Kang Q, Vahl CI. Testing for bioequivalence of highly variable drugs from TR-RT crossover designs with heterogeneous residual variances. Pharm Stat 2017. [PMID: 28620937 DOI: 10.1002/pst.1816] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Traditional bioavailability studies assess average bioequivalence (ABE) between the test (T) and reference (R) products under the crossover design with TR and RT sequences. With highly variable (HV) drugs whose intrasubject coefficient of variation in pharmacokinetic measures is 30% or greater, assertion of ABE becomes difficult due to the large sample sizes needed to achieve adequate power. In 2011, the FDA adopted a more relaxed, yet complex, ABE criterion and supplied a procedure to assess this criterion exclusively under TRR-RTR-RRT and TRTR-RTRT designs. However, designs with more than 2 periods are not always feasible. This present work investigates how to evaluate HV drugs under TR-RT designs. A mixed model with heterogeneous residual variances is used to fit data from TR-RT designs. Under the assumption of zero subject-by-formulation interaction, this basic model is comparable to the FDA-recommended model for TRR-RTR-RRT and TRTR-RTRT designs, suggesting the conceptual plausibility of our approach. To overcome the distributional dependency among summary statistics of model parameters, we develop statistical tests via the generalized pivotal quantity (GPQ). A real-world data example is given to illustrate the utility of the resulting procedures. Our simulation study identifies a GPQ-based testing procedure that evaluates HV drugs under practical TR-RT designs with desirable type I error rate and reasonable power. In comparison to the FDA's approach, this GPQ-based procedure gives similar performance when the product's intersubject standard deviation is low (≤0.4) and is most useful when practical considerations restrict the crossover design to 2 periods.
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Affiliation(s)
- Qing Kang
- The Statistical Intelligence Group LLC, Manhattan, KS, USA
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Raney SG, Franz TJ, Lehman PA, Lionberger R, Chen ML. Pharmacokinetics-Based Approaches for Bioequivalence Evaluation of Topical Dermatological Drug Products. Clin Pharmacokinet 2016; 54:1095-106. [PMID: 26063051 DOI: 10.1007/s40262-015-0292-0] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
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.
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Affiliation(s)
- Sam G Raney
- Office of Research and Standards, Center for Drug Evaluation and Research, United States Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA.
| | - Thomas J Franz
- , 10716 SE Forest View Lane, Happy Valley, OR, 97086, USA
| | | | - Robert Lionberger
- Office of Research and Standards, Center for Drug Evaluation and Research, United States Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA
| | - Mei-Ling Chen
- Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD, USA
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29
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Yang B, Wu C, Ji B, Wu M, He Z, Shang L, Sun J. Virtual population pharmacokinetic using physiologically based pharmacokinetic model for evaluating bioequivalence of oral lacidipine formulations in dogs. Asian J Pharm Sci 2016; 12:98-104. [PMID: 32104318 PMCID: PMC7032150 DOI: 10.1016/j.ajps.2016.03.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2016] [Revised: 03/11/2016] [Accepted: 03/14/2016] [Indexed: 11/29/2022] Open
Abstract
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.
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Affiliation(s)
- Bin Yang
- Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, China
| | - Chunnuan Wu
- Department of Pharmacy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Bin Ji
- Department of Pharmaceutical analysis, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, China
| | - Mingrui Wu
- Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, China
| | - Zhonggui He
- Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, China
| | - Lei Shang
- School of Pharmacy, China Medical University, Shenyang, China
| | - Jin Sun
- Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, China.,Municipal Key Laboratory of Biopharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, China
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Muñoz J, Alcaide D, Ocaña J. Consumer's risk in the EMA and FDA regulatory approaches for bioequivalence in highly variable drugs. Stat Med 2015; 35:1933-43. [PMID: 26707698 DOI: 10.1002/sim.6834] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2015] [Revised: 09/17/2015] [Accepted: 11/17/2015] [Indexed: 11/05/2022]
Abstract
The 2010 US Food and Drug Administration and European Medicines Agency regulatory approaches to establish bioequivalence in highly variable drugs are both based on linearly scaling the bioequivalence limits, both take a 'scaled average bioequivalence' approach. The present paper corroborates previous work suggesting that none of them adequately controls type I error or consumer's risk, so they result in invalid test procedures in the neighbourhood of a within-subject coefficient of variation osf 30% for the reference (R) formulation. The problem is particularly serious in the US Food and Drug Administration regulation, but it is also appreciable in the European Medicines Agency one. For the partially replicated TRR/RTR/RRT and the replicated TRTR/RTRT crossover designs, we quantify these type I error problems by means of a simulation study, discuss their possible causes and propose straightforward improvements on both regulatory procedures that improve their type I error control while maintaining an adequate power. Copyright © 2015 John Wiley & Sons, Ltd.
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Affiliation(s)
- Joel Muñoz
- Department of Statistics, Universitat de Barcelona, Av. Diagonal 643, Barcelona, 08028, Spain
| | | | - Jordi Ocaña
- Department of Statistics, Universitat de Barcelona, Av. Diagonal 643, Barcelona, 08028, Spain
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31
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Grosser S, Park M, Raney SG, Rantou E. Determining Equivalence for Generic Locally Acting Drug Products. Stat Biopharm Res 2015. [DOI: 10.1080/19466315.2015.1093541] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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Jiang W, Makhlouf F, Schuirmann DJ, Zhang X, Zheng N, Conner D, Yu LX, Lionberger R. A Bioequivalence Approach for Generic Narrow Therapeutic Index Drugs: Evaluation of the Reference-Scaled Approach and Variability Comparison Criterion. AAPS JOURNAL 2015; 17:891-901. [PMID: 25840883 DOI: 10.1208/s12248-015-9753-5] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Accepted: 03/16/2015] [Indexed: 11/30/2022]
Abstract
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.
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Affiliation(s)
- Wenlei Jiang
- Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA
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33
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Du L, Choi L. Likelihood approach for evaluating bioequivalence of highly variable drugs. Pharm Stat 2015; 14:82-94. [PMID: 25408492 PMCID: PMC4482106 DOI: 10.1002/pst.1661] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2014] [Revised: 09/22/2014] [Accepted: 10/23/2014] [Indexed: 01/31/2023]
Abstract
Bioequivalence (BE) is required for approving a generic drug. The two one-sided tests procedure (TOST, or the 90% confidence interval approach) has been used as the mainstream methodology to test average BE (ABE) on pharmacokinetic parameters such as the area under the blood concentration-time curve and the peak concentration. However, for highly variable drugs (%CV > 30%), it is difficult to demonstrate ABE in a standard cross-over study with the typical number of subjects using the TOST because of lack of power. Recently, the US Food and Drug Administration and the European Medicines Agency recommended similar but not identical reference-scaled average BE (RSABE) approaches to address this issue. Although the power is improved, the new approaches may not guarantee a high level of confidence for the true difference between two drugs at the ABE boundaries. It is also difficult for these approaches to address the issues of population BE (PBE) and individual BE (IBE). We advocate the use of a likelihood approach for representing and interpreting BE data as evidence. Using example data from a full replicate 2 × 4 cross-over study, we demonstrate how to present evidence using the profile likelihoods for the mean difference and standard deviation ratios of the two drugs for the pharmacokinetic parameters. With this approach, we present evidence for PBE and IBE as well as ABE within a unified framework. Our simulations show that the operating characteristics of the proposed likelihood approach are comparable with the RSABE approaches when the same criteria are applied.
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Affiliation(s)
- Liping Du
- Vanderbilt Center for Quantitative Sciences, Vanderbilt University, 2525 West End, Suite 11000, Nashville TN 37203
| | - Leena Choi
- Department of Biostatistics, School of Medicine, Vanderbilt University, 2525 West End, Suite 11000, Nashville TN 37203
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Evaluation of the highly variable agomelatine pharmacokinetics in Chinese healthy subjects to support bioequivalence study. PLoS One 2014; 9:e109300. [PMID: 25330096 PMCID: PMC4203722 DOI: 10.1371/journal.pone.0109300] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2014] [Accepted: 08/25/2014] [Indexed: 11/19/2022] Open
Abstract
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.
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Wonnemann M, Frömke C, Koch A. Inflation of the type I error: investigations on regulatory recommendations for bioequivalence of highly variable drugs. Pharm Res 2014; 32:135-43. [PMID: 25033764 DOI: 10.1007/s11095-014-1450-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2014] [Accepted: 07/02/2014] [Indexed: 11/30/2022]
Abstract
PURPOSE We investigated different evaluation strategies for bioequivalence trials with highly variable drugs on their resulting empirical type I error and empirical power. The classical 'unscaled' crossover design with average bioequivalence evaluation, the Add-on concept of the Japanese guideline, and the current 'scaling' approach of EMA were compared. METHODS Simulation studies were performed based on the assumption of a single dose drug administration while changing the underlying intra-individual variability. RESULTS Inclusion of Add-on subjects following the Japanese concept led to slight increases of the empirical α-error (≈7.5%). For the approach of EMA we noted an unexpected tremendous increase of the rejection rate at a geometric mean ratio of 1.25. Moreover, we detected error rates slightly above the pre-set limit of 5% even at the proposed 'scaled' bioequivalence limits. CONCLUSIONS With the classical 'unscaled' approach and the Japanese guideline concept the goal of reduced subject numbers in bioequivalence trials of HVDs cannot be achieved. On the other hand, widening the acceptance range comes at the price that quite a number of products will be accepted bioequivalent that had not been accepted in the past. A two-stage design with control of the global α therefore seems the better alternative.
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Affiliation(s)
- Meinolf Wonnemann
- Institut für Biometrie, Medizinische Hochschule Hannover, OE 8410, 30625, Hannover, Germany,
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Abstract
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.
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Affiliation(s)
- Shein-Chung Chow
- Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, North Carolina, USA
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Generic products of antiepileptic drugs: a perspective on bioequivalence, bioavailability, and formulation switches using Monte Carlo simulations. CNS Drugs 2014; 28:69-77. [PMID: 24092569 DOI: 10.1007/s40263-013-0112-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
INTRODUCTION Generic products of antiepileptic drugs (AEDs) are currently a controversial topic as neurologists and patients are reluctant to switch from brand products to generics and to switch between generics. OBJECTIVE The aim of this study was to provide enlightenment on issues of bioequivalence (BE) and interchangeability of AED products. METHODS Monte Carlo simulations of the classic 2 × 2 BE studies were performed to study the effect of sample size, within-subject variability, and the true difference in pharmacokinetic values of the products under comparison on BE acceptance of generic AED products. Simulations were extended to study the comparative performance of two generic AED products against the same innovative product. The simulated results are compared with literature data on AEDs. RESULTS The question with regard to bioavailability (BA) is whether two formulations are different, while for BE the question is whether two formulations are sufficiently similar in terms of extent and rate of absorption. Therefore, the criteria for BA and BE and the statistical analysis involved in their analysis are different. Two generic formulations that meet regulatory approval requirements for generics by being bioequivalent to the same innovative AED may not be bioequivalent to one another and therefore should not be regarded as equal or as therapeutically equivalent products. A switch from a standard or an immediate-release formulation to a modified-release product, which comprises extended-release or delayed-release formulations, should not be regarded as a switch between generics, but rather as a switch between different formulation types. DISCUSSION Switches between bioequivalent generic AED products could potentially lead to larger changes in plasma levels and exposure than the brand-to-generic switch. The simulation work verified the clinical findings that not all generic AED products bioequivalent to the same innovative product are bioequivalent to one another. CONCLUSIONS Two generic formulations that meet regulatory approval requirements for generics, by being bioequivalent to the innovative AED, may not be bioequivalent to one another. Additional BE criteria are needed for a formulation switch, particularly in epilepsy, where a breakthrough seizure may change a patient's status from seizure-free to refractory.
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40
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Karalis V, Bialer M, Macheras P. Quantitative assessment of the switchability of generic products. Eur J Pharm Sci 2013; 50:476-83. [DOI: 10.1016/j.ejps.2013.08.023] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2013] [Accepted: 08/13/2013] [Indexed: 11/24/2022]
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Edwards ES, Gunn R, Simons ER, Carr K, Chinchilli VM, Painter G, Goldwater R. Bioavailability of epinephrine from Auvi-Q compared with EpiPen. Ann Allergy Asthma Immunol 2013; 111:132-7. [PMID: 23886232 DOI: 10.1016/j.anai.2013.06.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2013] [Revised: 05/23/2013] [Accepted: 06/02/2013] [Indexed: 10/26/2022]
Abstract
BACKGROUND Epinephrine autoinjectors are underused for the treatment of anaphylaxis in community settings. Auvi-Q, a novel epinephrine autoinjector, was designed to be intuitive to use and reduce the potential for use-related errors. OBJECTIVE To compare the bioavailability of 0.3 mg of epinephrine (adrenaline) injected with Auvi-Q and EpiPen in healthy adults. METHODS In this randomized, single-blind, 2-treatment, 3-period, 3-sequence crossover study, healthy adults (18-45 years old) received a single injection of 0.3 mg of epinephrine with Auvi-Q in one period and with EpiPen in the other 2 periods. Blood samples were obtained before and 14 times during 6 hours after the dose. Outcomes included peak plasma concentration (Cmax), total epinephrine exposure (area under the concentration-time curve [AUC] from baseline to the last measurable concentration [AUC0-t] and extrapolated to infinity [AUCinf]), and adverse events. RESULTS Seventy-one volunteers (53 male, 74.6%), with a mean age of 33.2 years and a mean body mass index of 25.4, were randomized. Epinephrine peak concentration and total exposure were similar between Auvi-Q (Cmax = 0.486 ng/mL; AUC0-t = 0.536 ng·h/mL; AUCinf = 0.724 ng·h/mL) and EpiPen (Cmax = 0.520 ng/mL; AUC0-t = 0.466 ng·h/mL; AUCinf = 0.583 ng·h/mL). Cmax and AUC analyses demonstrated bioequivalence between Auvi-Q and EpiPen. Most treatment-emergent adverse events were mild (98%), and all resolved spontaneously. Rates of injection-site pain and bleeding were 13% and 5%, respectively, for Auvi-Q vs 24% and 10%, respectively, for EpiPen. CONCLUSION After a single injection of 0.3 mg of epinephrine, Auvi-Q and EpiPen had similar peak and total epinephrine exposure, were bioequivalent, and had similar safety profiles.
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Innovative approaches for demonstration of bioequivalence: the US FDA perspective. Ther Deliv 2013; 4:725-40. [PMID: 23738669 DOI: 10.4155/tde.13.41] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
In this article, the authors will briefly introduce the general concepts and background of bioavailability and bioequivalence (BE), discuss the conventional method for BE demonstration, and present case examples where novel approaches have been adopted by the US FDA for BE demonstration. Here, 'novel approaches' include unconventional BE studies, as well as statistical criteria for comparison. More specifically, biowaivers, methods to demonstrate BE for highly variable drugs and drug products, and narrow therapeutic index drugs, partial AUCs as additional metrics for some modified-release drug products, methods to demonstrate BE for locally acting gastrointestinal, dermatological, nasal and inhalation products, and non-biological complex drug products, and future perspectives in the field of BE assessment will be discussed. Methods adopted by other agencies, such as European Medicines Agency and Health Canada will be compared with the FDA approaches when appropriate.
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Pathak SM, Aggarwal D, Venkateswarlu V. Establishment of in vitro-in vivo equivalence of highly variable drugs - a generic product development perspective. Pharm Dev Technol 2013; 19:401-10. [PMID: 23607272 DOI: 10.3109/10837450.2013.788513] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
In vivo equivalence of highly variable drugs (HVD) has always been a subject of great concern, in terms of both safety and efficacy, for regulatory agencies. Successful demonstration of their bioequivalence thus presents the most crucial component of a generic application, significantly contributing toward the cost and time of development. For poorly soluble drugs, such as telmisartan, dissolution represents the rate-limiting step in the gastric region and in many cases may not be complete, thereby contributing to low and highly variable bioavailability. Consequently, simulation of gastrointestinal conditions is essential to adequately predict the in vivo behavior of drug formulations. In this study, we evaluated usefulness of physiologically relevant dissolution method over commonly used acidic media to forecast comparable in vivo performance of telmisartan formulation to that of reference samples. In the present study, telmisartan was classified as a HVD and a partial replicate design with repeating the reference product and scaling the bioequivalence for the reference variability has been presented. The design has effectively decreased sample size, without increasing patient risk. Results from this project suggest that scaled average bioequivalence (SABE) provides a good approach for evaluating the bioequivalence of HVD, meeting the need for international guidelines for bioequivalence.
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Affiliation(s)
- Shriram M Pathak
- Dr. Reddy's Laboratories, Centre of Excellence - Bio Studies , IPDO, Innovation Plaza, Bachupally, Hyderabad-500072, Andhra Pradesh , India
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Macheras P, Karalis V, Valsami G. Keeping a critical eye on the science and the regulation of oral drug absorption: a review. J Pharm Sci 2013; 102:3018-36. [PMID: 23568812 DOI: 10.1002/jps.23534] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2012] [Revised: 03/01/2013] [Accepted: 03/15/2013] [Indexed: 11/08/2022]
Abstract
This review starts with an introduction on the theoretical aspects of biopharmaceutics and developments in this field from mid-1950s to late 1970s. It critically addresses issues related to fundamental processes in oral drug absorption such as the complex interplay between drugs and the gastrointestinal system. Special emphasis is placed on drug dissolution and permeability phenomena as well as on the mathematical modeling of oral drug absorption. The review ends with regulatory aspects of oral drug absorption focusing on bioequivalence studies and the US Food and Drug Administration and European Medicines Agency guidelines dealing with Biopharmaceutics Classification System and Biopharmaceutic Drug Disposition Classification System.
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Affiliation(s)
- Panos Macheras
- Laboratory of Biopharmaceutics-Pharmacokinetics, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens 15771, Greece.
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Davit BM, Chen ML, Conner DP, Haidar SH, Kim S, Lee CH, Lionberger RA, Makhlouf FT, Nwakama PE, Patel DT, Schuirmann DJ, Yu LX. Implementation of a reference-scaled average bioequivalence approach for highly variable generic drug products by the US Food and Drug Administration. AAPS J 2012; 14:915-24. [PMID: 22972221 PMCID: PMC3475857 DOI: 10.1208/s12248-012-9406-x] [Citation(s) in RCA: 83] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2012] [Accepted: 08/27/2012] [Indexed: 12/13/2022] Open
Abstract
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.
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Affiliation(s)
- Barbara M Davit
- Office of Generic Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, 7520 Standish Place, Metro Park North One, Rockville, Maryland 20855, USA.
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Zhang N, Yang J, Chow SC, Endrenyi L, Chi E. Impact of variability on the choice of biosimilarity limits in assessing follow-on biologics. Stat Med 2012; 32:424-33. [DOI: 10.1002/sim.5567] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2012] [Accepted: 07/26/2012] [Indexed: 11/09/2022]
Affiliation(s)
| | - Jun Yang
- Amgen, Inc.; Thousand Oaks CA U.S.A
| | | | - Laszlo Endrenyi
- University of Toronto Department of Pharmacology and Toxicology; Toronto Ontario Canada
| | - Eric Chi
- Amgen, Inc.; Thousand Oaks CA U.S.A
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El-Tahtawy A, Harrison F, Zirkelbach JF, Jackson AJ. Bioequivalence of long half-life drugs--informative sampling determination--using truncated area in parallel-designed studies for slow sustained-release formulations. J Pharm Sci 2012; 101:4337-46. [PMID: 22927120 DOI: 10.1002/jps.23296] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2012] [Revised: 06/25/2012] [Accepted: 07/31/2012] [Indexed: 11/12/2022]
Abstract
A simulation study was done to determine if 72 h is the most informative sampling duration for bioequivalence (BE) determination in parallel-designed BE studies with drugs that have half-lives of at least 30 h. The impact of absorption and elimination half-lives on informative sampling was evaluated. Two-treatment parallel-designed BE studies using a one-compartment oral absorption model with half-lives of 30 and 350 h was simulated. Area under the curve (AUC) values were truncated at 12-360 h. Experimental BE data [median time to reach the maximum concentration (T(max) ) = 20 h and low clearance = 0.192 L/h) indicated a decrease and then an increase in the intrasubject variability [root mean square error (RMSE)] for truncated AUC as a function of time. Simulations supported these findings with the highest probability of passing the BE confidence interval criteria being between 60 and 96 h, depending on half-life and percent coefficient of variation. The 30-h simulation exhibited a minimum in RMSE at 24-h truncation that continued to increase up to 360 h, whereas the 350-h simulation exhibited a minimum at 60 h, which increased after 96 h. Power curves at the 350-h half-life showed higher probabilities of rejection of BE for true test/reference ratios greater than 0.9. For parallel-designed BE studies, sampling beyond 120 h will not affect the BE decision and therefore is unnecessary.
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Affiliation(s)
- Ahmed El-Tahtawy
- Pfizer Laboratories, Division of Global Clinical Pharmacology, Pharmacometrics, New York, New York, USA
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Liao JJ, Darken PF. Comparability of critical quality attributes for establishing biosimilarity. Stat Med 2012; 32:462-9. [DOI: 10.1002/sim.5564] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2012] [Accepted: 07/26/2012] [Indexed: 11/12/2022]
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Karalis V, Macheras P. Current regulatory approaches of bioequivalence testing. Expert Opin Drug Metab Toxicol 2012; 8:929-42. [PMID: 22681436 DOI: 10.1517/17425255.2012.690394] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
INTRODUCTION Nowadays, reducing medication costs is vital for health care agencies. Prescription of generic drug products can help lower these expenses. A generally accepted assumption is that therapeutic equivalence, between a generic and a brand-name medication, can be claimed if bioequivalence is demonstrated. AREAS COVERED This article reviews the current regulatory procedures on bioequivalence testing. Special focus is placed on the guidelines recommended by the European Medicines Agency and the US Food and Drug administration. The authors also describe the evolution of these issues and the alternatives proposed in the literature. EXPERT OPINION Defining bioequivalence, as the condition of no significant differences in the extent and rate of absorption between the generic and the brand-name medication, sounds simple. However, the scientific and regulatory basis of bioequivalence appears rather complicated in practice. Even though the regulatory authorities have elucidated many issues, several aspects of bioequivalence assessment are still unresolved. Examples, of these open questions, in bioequivalence, include the assessment of complex drugs, such as biologics and iron-carbohydrates, the assessment of immunosuppressive agents as well as the role that pharmacogenomics plays in bioequivalence.
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Affiliation(s)
- Vangelis Karalis
- National and Kapodistrian University of Athens, School of Pharmacy, Laboratory of Biopharmaceutics-Pharmacokinetics, Athens, Greece.
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Mitra A, Wu Y. Challenges and opportunities in achieving bioequivalence for fixed-dose combination products. AAPS JOURNAL 2012; 14:646-55. [PMID: 22684403 DOI: 10.1208/s12248-012-9378-x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/09/2012] [Accepted: 05/24/2012] [Indexed: 11/30/2022]
Abstract
Fixed-dose combination (FDC) products are becoming a popular treatment option because of increased patient compliance and convenience, improved clinical effectiveness, and reduced cost to the patient, among several other reasons. A commonly applied approach for approval of a FDC product is demonstrating bioequivalence between the FDC and co-administration of individual mono-products, provided that there is adequate safety and efficacy data for co-administration of the individual agents. However, achieving bioequivalence between the FDC and individual mono-products can be very challenging, and sometimes not possible since combining multiple active ingredients, especially insoluble molecules, in a single drug product could complicate its biopharmaceutical and pharmacokinetic behavior. In this review, some of the major challenges often encountered while assessing bioequivalence during FDC development will be presented along with discussion of future opportunities to facilitate FDC development and approval.
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Affiliation(s)
- Amitava Mitra
- Biopharmaceutics, Product Value Enhancement, Pharmaceutical Sciences and Clinical Supply, Merck Sharp & Dohme Corp., West Point, Pennsylvania 19486, USA.
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