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

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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. 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 mechanism of the in vivo DDI. This was a phase I, open-label, single-centre, non-randomised, single-sequence, two-period, two-treatment crossover study. The study population consisted of 12 healthy male and female participants. The two treatment periods included Period 1, wherein a single midazolam dose was administered on Day 1, and Period 2, wherein fexinidazole was administered once daily from Day 1 to Day 5, with a single midazolam dose co-administered on Day 4. Key pharmacokinetic parameters of midazolam and its main metabolites, including the maximum plasma concentration ( C max ), area under the curve (AUC), and elimination half-life ( t 1/2 z ), were evaluated. Additionally, in vitro assessments (protein-binding and CYP enzyme induction studies) were conducted to investigate potential mechanisms contributing to the observed interaction. Contrary to the in vitro predictions, fexinidazole significantly reduced midazolam exposure in vivo, resulting in a reduction of 39% in C max , 57% in AUC, and 33% in t 1/2z , without significant changes in t max . Mechanistic studies ruled out reduced absorption and plasma protein displacement as potential causes. At clinically relevant concentrations, fexinidazole and M1 exhibited weak induction potential on CYP3A4/5 and no significant induction on other enzymes. Further, in vivo investigations on midazolam metabolites confirmed that CYP3A4/5 induction by fexinidazole was the primary mechanism, increasing the first-pass metabolism and clearance of midazolam. The metabolic ratios of 1-hydroxy-midazolam and N -glucuronide-midazolam were increased by 1.63-fold and 1.24-fold, respectively. Steady-state exposures of fexinidazole and its metabolites M1 and M2 were consistent with those previously assessed in other clinical studies. While in vitro studies showed weak induction by fexinidazole and its metabolite M1, the clinical pharmacokinetic data provided stronger evidence, supporting the conclusion that fexinidazole is a moderate inducer of CYP3A4/5 in vivo. Thus, it is suggested to update the product information by including the potential for CYP3A4/5 induction in vitro, removing the risk of CYP3A4 inhibition in vivo, and adding clinical interaction data highlighting the risk of induction on drugs predominantly metabolised by CYP3A4/5. EudraCT No.: 2021–004533–36

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