In Vitro and Clinical Evaluation of Potential Interactions of Bemnifosbuvir with Drug-Metabolizing Enzymes

Bemnifosbuvir is a novel oral guanosine nucleotide prodrug with potent pan-genotypic inhibitory activity against hepatitis C virus. In vitro studies assessing the inhibition or induction potential of bemnifosbuvir on the CYP450 and UGT1A1 enzymes demonstrated that bemnifosbuvir is a weak inducer and a reversible and time-dependent inhibitor of CYP3A4. These results prompted further evaluation in a Phase 1 clinical study in healthy participants who received midazolam (a sensitive CYP3A4 substrate) without and with simultaneous or staggered doses of bemnifosbuvir. A single simultaneous 550 mg bemnifosbuvir dose increased the total plasma exposure of a single 2 mg midazolam dose by 24% via reversible inhibition. Simultaneous coadministration of bemnifosbuvir 550 mg twice daily increased the total plasma exposure to midazolam by 98% as an outcome of reversible/time-dependent inhibition and induction. Simultaneous coadministration of a single and repeat dose of bemnifosbuvir increased the total plasma exposure to 1-hydroxymidazolam (primary metabolite of midazolam) by 22% and 27%, respectively. Staggered coadministration generally had a lower effect on plasma exposure to both midazolam and 1-hydroxymidazolam. Conversely, midazolam had no significant effect on the pharmacokinetics of bemnifosbuvir. Overall, bemnifosbuvir was a weak clinical inhibitor (geometric mean ratio <2) of CYP3A4.