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Updated: Jul 19, 2025
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An Intestine/Liver Microphysiological System for Drug Pharmacokinetic and Toxicological Assessment
Published on: December 3, 2020
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Predicting bioequivalence and developing dissolution bioequivalence safe space in vitro for warfarin using a
Zi-Zhao Cheng1, Xiao Hu1, Ya-Li Li1
1Department of Pharmacology, Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing Engineering Research Center for Nerve System Drugs,Beijing Municipal Geriatric Medical Research Center, Beijing 100053, China.
Summary
Physiologically-based pharmacokinetic (PBPK) models can predict bioequivalence (BE) for narrow therapeutic index (NTI) drugs like warfarin. This study successfully developed a PBPK model for warfarin sodium, aiding generic drug development and clinical trials.
Area of Science:
- Pharmacokinetics and Drug Development
- Computational Modeling in Pharmacology
- Bioequivalence Studies
Background:
- Bioequivalence (BE) studies are crucial for drug approval, but narrow therapeutic index (NTI) drugs present challenges due to high costs and low clinical trial success rates.
- Physiologically-based pharmacokinetic (PBPK) modeling offers a potential solution for evaluating the BE of drug preparations, especially for high-risk NTI drugs.
Purpose of the Study:
- To develop and validate a physiologically-based pharmacokinetic (PBPK) model for assessing the bioequivalence (BE) of warfarin sodium 2.5 mg tablets in Chinese individuals.
- To establish in vitro dissolution limits for warfarin sodium under fasted conditions that correlate with in vivo bioequivalence.
- To demonstrate the utility of PBPK modeling in reducing the risk of BE failure for NTI drugs.
Main Methods:
- Utilized GastroPlus™ software incorporating the Advanced Compartmental Absorption and Transit (ACAT™) model.
- Inputted physical and chemical properties of warfarin sodium.
- Developed the PBPK model using pharmacokinetic data from reference preparations in Chinese individuals under fasted conditions.
- Validated the model with data from reference and test preparations from various domestic manufacturers.
Main Results:
- Established dissolution limits: ≥30% release at 30 min at pH 4.5 and ≥80% release at 30 min at pH 6.8 for fasted conditions.
- Demonstrated that achieving bioequivalence under fasted conditions can significantly reduce the risk of BE failure in fed conditions for warfarin sodium.
- Successfully developed and validated PBPK models for 2.5 mg warfarin sodium tablets in the Chinese population.
Conclusions:
- Physiologically-based pharmacokinetic (PBPK) models are effectively developed for warfarin sodium 2.5 mg tablets in Chinese individuals.
- Developing PBPK models using in vitro dissolution data in specialized software is a promising and valuable approach for bioequivalence evaluation of narrow therapeutic index (NTI) drugs.
- This methodology can significantly aid in the development of new drugs and the clinical trial research for generic drug bioequivalence.
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