Characterization of Drug–Drug Interactions for Remdesivir, an Intravenous Antiviral for SARS‐CoV‐2, in Healthy Participants

Remdesivir is an intravenous antiviral approved worldwide for the treatment of COVID-19 in adults and children. Remdesivir, as a prodrug inhibitor of RNA polymerase, undergoes intracellular activation to form the active metabolite along with 2 inactive circulating metabolites, GS-704277 and GS-441524. Based on drug-drug interaction (DDI) risks identified in vitro, three Phase 1 crossover DDI studies were conducted to evaluate remdesivir as a potential (i) object, (ii) inhibitor, or (iii) inducer of enzymes and transporters. As an object of organic anion transporting polypeptide (OATP) 1B1/1B3 and P-glycoprotein inhibition (cyclosporine A), remdesivir and GS-704277 exposures increased 2-fold and 3-fold, respectively, while GS-441524 was unchanged. Increased exposures were not clinically relevant as remdesivir and GS-704277 exposures remained transient (approximately 1-h half-life) and were unlikely to affect the formation of the active metabolite. As an object of strong cytochrome P450 (CYP) 3A induction (carbamazepine), exposure changes of remdesivir and its metabolites were not clinically significant. As an inhibitor, single-dose remdesivir did not impact pitavastatin (OATP1B1/1B3 substrate) exposures but increased midazolam (CYP3A substrate) C_max (29%) to a greater extent than AUC_inf (20%). Given that remdesivir exposures are transient, CYP3A inhibitory effects were similarly transient and were not clinically relevant. As an inducer with midazolam (CYP3A substrate), multiple-dose remdesivir did not decrease exposures but rather transiently increased midazolam exposures to a similar degree as observed in the inhibition study. Remdesivir may be coadministered with other medications without restrictions.