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Usage of In Vitro Metabolism Data for Drug‐Drug Interaction in Physiologically Based Pharmacokinetic Analysis Submissions to the US Food and Drug Administration
Author(s) -
Lee Jieon,
Yang Yuching,
Zhang Xinyuan,
Fan Jianghong,
Grimstein Manuela,
Zhu Hao,
Wang Yaning
Publication year - 2021
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.1819
Subject(s) - physiologically based pharmacokinetic modelling , pharmacokinetics , pharmacology , drug , drug drug interaction , in vivo , drug metabolism , in vitro , chemistry , food and drug administration , drug interaction , medicine , biology , biochemistry , microbiology and biotechnology
The key parameters necessary to predict drug‐drug interactions (DDIs) are intrinsic clearance (CL int ) and fractional contribution of the metabolizing enzyme toward total metabolism (f m ). Herein, we summarize the accumulated knowledge from 53 approved new drug applications submitted to the Office of Clinical Pharmacology, US Food and Drug Administration, from 2016 to 2018 that contained physiologically based pharmacokinetic (PBPK) models to understand how in vitro data are used in PBPK models to assess drug metabolism and predict DDIs. For evaluation of CL int and f m , 29 and 20 new drug applications were included for evaluation, respectively. For CL int , 86.2% of the PBPK models used modified values based on in vivo data with modifications ranging from –82.5% to 2752.5%. For f m , 45.0% of the models used modified values with modifications ranging from –28% to 178.6%. When values for CL int were used from in vitro testing without modification, the model resulted in up to a 14.3‐fold overprediction of the area under the concentration‐time curve of the substrate. When values for f m from in vitro testing were used directly, the model resulted in up to a 2.9‐fold underprediction of its DDI magnitude with an inducer, and up to a 1.7‐fold overprediction of its DDI magnitude with an inhibitor. Our analyses suggested that the in vitro system usually provides a reasonable estimation of f m when the drug metabolism by a given CYP pathway is more than 70% of the total clearance. In vitro experiments provide important information about basic PK properties of new drugs and can serve as a starting point for building a PBPK model. However, key PBPK parameters such as CL int and f m still need to be optimized based on in vivo data.