In vitro prediction of clinical drug interactions with CYP3A substrates: we are not there yet

Abstract

In 1973, Malcolm Rowland and associates described an approach to predicting clinical pharmacokinetic drug-drug interactions (DDIs) using an inhibition constant determined in vitro (Ki) together with anticipated inhibitor exposure in vivo ([I]). Despite numerous modifications and refinements of the core model over the following 40 years, we still have not achieved a predictive paradigm having accuracy sufficient to justify bypassing all, or even most, clinical DDI studies in the course of drug development.