High-Throughput Screening for Metabolism-Based Drug–Drug Interactions
Vaughn P. Miller, Charles L. Crespi · 2001
The commercial success of a new drug entity (NDE) depends on its pharmacological activity and several ADME (absorption, distribution, metabolism, and excretion) properties. ADME properties influence the amount and frequency of NDE administration and population variability in pharmacokinetics. One important property is the ability of the NDE to cause metabolism-based pharmacokinetic drug-drug interactions. In such an interaction the NDE inhibits the metabolism of a comedication. As a result, the circulating concentrations of the comedication are increased and, if the comedication has a narrow therapeutic index, an adverse reaction can occur. A NDE which causes drug-drug interactions can be more time-consuming and costly to develop, suffer decreased market acceptance, and in some cases can lead to product withdrawal. As a recent example, shortly after approval Posicor [1] (mibefradil) was withdrawn from the marketplace due to drug-drug interactions at the level of cytochrome P450 (CYP) metabolism. Testing for drug-drug interactions has been the subject of a recent FDA guidance document [2]. These competitive and regulatory pressures have created a need to move this testing into the lead optimization phase of drug development.