Distinction between drug-drug interactions mediated by CYP3A4 and CYP3A5 during pharmacokinetic assessment in drug registration procedures by the EMA: An in-depth analysis

Abstract

The cytochrome P450 3A (CYP3A) subfamily members CYP3A4 and CYP3A5 play an important role in the metabolism of more than 50% of all marketed drugs, often leading to drug-drug interactions (DDIs). The European Medicines Agency (EMA) serves as the regulatory authority for the evaluation and approval of medicinal products during drug development in the European Union. The EMA guidelines outline systematic approaches, including in vitro and in vivo studies, to assess these potential DDIs. CYP3A5 expression, however, can vary among different ethnic groups. In Caucasians, only 20% possesses active CYP3A5 enzyme, leading to interindividual differences in DDI potential for one medicinal product. Low CYP3A5 expression in Caucasian subjects and evidence on differences in CYP3A4 and CYP3A5 substrate and inhibitor specificity raises uncertainty whether the specific role of CYP3A5 in DDIs is adequately studied.