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In silico prediction of bioequivalence of Isosorbide Mononitrate tablets with different dissolution profiles using PBPK modeling and simulation. Zhang Fan,Zhou Yinping,Wu Ni,Jia Ranran,Liu Aijing,Liu Bo,Zhou Zhou,Hu Haitang,Han Zhihui,Ye Xiang,Ding Ying,He Qing,Wang Hongyun European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences AIM:The waiver of bioequivalence (BE) studies is well accepted for Biopharmaceutics Classification System (BCS) class I drugs in form of immediate-release solid oral products. This study aimed to assess whether the rapid dissolution profiles (≥85% in 30 min) was crucial to guarantee bioequivalence of isosorbide mononitrate (ISMN) and then established a clinically relevant dissolution specification (CRDS) for screening BE or non-BE batches. METHOD:A physiologically based pharmacokinetic (PBPK) model was constructed by integrating clinical and non-clinical data by BO simulator. The model was verified by an actual clinical study (NMPA registration number: CTR20191360) with 28 healthy Chinese subjects. Then a virtual BE study was simulated to evaluate the bioequivalence of 7 virtual batches of ISMN tablets with different dissolution profiles, and the CRDS was established by integrating the results. RESULT:The simulated PK behavior of ISMN was comparable to the observed. Even though the batches with slower dissolution were not equivalent to a rapid dissolution profile (≥85% in 30 min), it was demonstrated these batches would exhibit the similar in vivo performance. Meanwhile, the in vitro dissolution specification time point and the percentage of drug release (75% in 45 min) proved to have clinical relevance. CONCLUSION:The virtual BE simulation by integrating in vitro dissolution profiles into the PBPK model provided a powerful tool for screening formulations, contributing to gaining time and reducing costs in BE evaluations. 10.1016/j.ejps.2020.105618
In Silico Modeling and Simulation to Guide Bioequivalence Testing for Oral Drugs in a Virtual Population. Clinical pharmacokinetics Model-informed drug discovery and development (MID3) shows great advantages in facilitating drug development. A physiologically based pharmacokinetic model is one of the powerful computational approaches of MID3, and the emerging field of virtual bioequivalence is well recognized to be the future of the physiologically based pharmacokinetic model. Based on the translational link between in vitro, in silico, and in vivo, virtual bioequivalence study can evaluate the similarity and potential difference of pharmacokinetic and clinical performance between test and reference formulations. With the aid of virtual bioequivalence study, the pivotal information of clinical trials can be provided to streamline the development for both new and generic drugs. However, a regulatory framework of virtual bioequivalence study has not reached its full maturity. Therefore, this article aims to present an overview of the current status of bioequivalence study, identify the framework of virtual bioequivalence studies for oral drugs, and also discuss the future opportunities of virtual bioequivalence in supporting the waiver and optimization of in vivo clinical trials. 10.1007/s40262-021-01045-7
Physiologically-based pharmacokinetics in drug development and regulatory science. Rowland Malcolm,Peck Carl,Tucker Geoffrey Annual review of pharmacology and toxicology The application of physiologically-based pharmacokinetic (PBPK) modeling is coming of age in drug development and regulation, reflecting significant advances over the past 10 years in the predictability of key pharmacokinetic (PK) parameters from human in vitro data and in the availability of dedicated software platforms and associated databases. Specific advances and contemporary challenges with respect to predicting the processes of drug clearance, distribution, and absorption are reviewed, together with the ability to anticipate the quantitative extent of PK-based drug-drug interactions and the impact of age, genetics, disease, and formulation. The value of this capability in selecting and designing appropriate clinical studies, its implications for resource-sparing techniques, and a more holistic view of the application of PK across the preclinical/clinical divide are considered. Finally, some attention is given to the positioning of PBPK within the drug development and approval paradigm and its future application in truly personalized medicine. 10.1146/annurev-pharmtox-010510-100540