Unexpected Clinical Drug-Drug Interaction of Fexinidazole on Midazolam Pharmacokinetics: Insights into Underlying Mechanisms from Clinical Phase I Study Results and Supporting In Vivo/Vitro Evidence.

ABSTRACT:

Background

Fexinidazole, a nitroimidazole antiparasitic, has been approved to treat human African trypanosomiasis (HAT) worldwide. In vitro studies have shown that fexinidazole inhibits and weakly induces CYP3A4/5. In silico predictions indicated that fexinidazole, which has a significant intestinal and liver first-pass metabolism, could increase the exposure of a sensitive probe substrate of CYP3A4 by two-fold. Therefore, this study investigated the potential clinical drug-drug interactions (DDIs) of fexinidazole with CYP3A4 substrates.

Objective

To assess the effect of fexinidazole on the pharmacokinetics of midazolam, a well-recognised sensitive CYP3A4 substrate (and its metabolites 1-hydroxy-midazolam and N-glucuronide-midazolam) in humans and to elucidate the underlying

SUBMITTER: Gassiot M 

PROVIDER: S-EPMC12872618 | biostudies-literature | 2026 Feb

REPOSITORIES: biostudies-literature