Considerations from the Innovation and Quality Induction Working Group in Response to Drug-Drug Interaction Guidance from Regulatory Agencies: Guidelines on Model Fitting and Recommendations on Time Course for In Vitro Cytochrome P450 Induction Studies Including Impact on Drug Interaction Risk Assessment
Open Access
- 2 November 2020
- journal article
- research article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in Drug Metabolism and Disposition
- Vol. 49 (1), 94-110
- https://doi.org/10.1124/dmd.120.000055
Abstract
Translational and ADME Sciences Leadership Group (TALG) Induction Working Group (IWG) presents an analysis on the time-course for cytochrome P450 induction in primary human hepatocytes. Induction of CYP1A2, CYP2B6, and CYP3A4 was evaluated by seven IWG laboratories following incubation with prototypical inducers (omeprazole, phenobarbital, rifampicin, and efavirenz) for 6 to 72 hours. The effect of incubation duration and model-fitting approaches on induction parameters (Emax and EC50) and drug-drug interaction (DDI) risk assessment was determined. Despite variability in induction response across hepatocyte donors, the following recommendations are proposed: i) 48 hours should be the primary time point for in vitro assessment of induction, based on mRNA level or activity, with no further benefit from 72 hours, ii) when using mRNA, 24 hour incubations provide reliable assessment of induction and DDI risk, iii) if validated using prototypical inducers (>10-fold induction), 12-hour incubations may provide an estimate of induction potential including characterization as negative if < 2-fold induction of mRNA and no concentration-dependence, iv) atypical dose-response ('bell-shaped') curves can be addressed by removing points outside an established confidence interval and %CV, v) when maximum fold induction is well-defined, the choice of non-linear regression model has limited impact on estimated induction parameters, vi) when the maximum-fold induction is not well-defined, conservative DDI risk assessment can be obtained using sigmoidal-3-parameter fit or constraining logistic 3/4 parameter fits to the maximum observed fold induction, vii) preliminary data suggest initial slope of the fold induction curve can be used to estimate Emax/EC50 and for induction risk assessment. Significance Statement Regulatory agencies have provided inconsistent guidance on the optimum length of time to evaluate CYP induction in human hepatocytes, with the EMA recommending 72 h and the FDA suggesting 48 to 72 h. The IWG analyzed a large dataset generated by 7 member companies and determined that induction response and drug-drug risk assessment determined after 48 h incubations was representative of 72 h incubations. Additional recommendations are provided on model-fitting techniques for induction parameter estimation and addressing atypical concentration-response curves.Keywords
This publication has 35 references indexed in Scilit:
- Considerations from the IQ Induction Working Group in Response to Drug-Drug Interaction Guidance from Regulatory Agencies: Focus on Downregulation, CYP2C Induction, and CYP2B6 Positive ControlDrug Metabolism and Disposition, 2017
- The relative performance of AIC, AICC and BIC in the presence of unobserved heterogeneityMethods in Ecology and Evolution, 2016
- Characterization of primary human hepatocyte spheroids as a model system for drug-induced liver injury, liver function and diseaseScientific Reports, 2016
- Evaluation of models for predicting drug–drug interactions due to inductionExpert Opinion on Drug Metabolism & Toxicology, 2010
- In Vitro and in Vivo Induction of Cytochrome P450: A Survey of the Current Practices and Recommendations: A Pharmaceutical Research and Manufacturers of America PerspectiveDrug Metabolism and Disposition, 2009
- Development ofIn VitroMethods to Predict Induction of CYP1A2 and CYP3A4 in HumansASSAY and Drug Development Technologies, 2007
- Molecular Mechanisms Underlying the Dedifferentiation Process of Isolated Hepatocytes and Their CulturesCurrent Drug Metabolism, 2006
- REGULATION OF CYP2B6 IN PRIMARY HUMAN HEPATOCYTES BY PROTOTYPICAL INDUCERSDrug Metabolism and Disposition, 2004
- Regulation of cell morphology and cytochrome P450 expression in human hepatocytes by extracellular matrix and cell-cell interactionsCell and tissue research, 2001
- Is It Possible To Estimate the Parameters of the Sigmoid Emax Model with Truncated Data Typical of Clinical Studies?Journal of Pharmaceutical Sciences, 1996