Prediction of metabolizing enzyme-mediated clinical drug interactions using in vitro information

Abstract

Evaluation of drug interactions is an essential step in the new drug development process. Regulatory agencies, including U.S. Food and Drug Administrations and European Medicines Agency, have been published documents containing guidelines to evaluate potential drug interactions. Here, we have streamlined in vitro experiments to assess metabolizing enzyme-mediated drug interactions and provided an overview of the overall process to evaluate potential clinical drug interactions using in vitro data. An experimental approach is presented when an investigational drug (ID) is either a victim or a perpetrator, respectively, and the general procedure to obtain in vitro drug interaction parameters is also described. With the in vitro inhibitory and/or inductive parameters of the ID, basic, static, and/or dynamic models were used to evaluate potential clinical drug interactions. In addition to basic and static models which assume the most conservative conditions, such as the concentration of perpetrators as C_max, dynamic models including physiologically-based pharmacokinetic models take into account changes in in vivo concentrations and metabolizing enzyme levels over time.

Keywords: Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 Enzyme Inhibitors; Drug Interactions; Metabolism.