Drug Interactions between amoxicillin / omeprazole / rifabutin and remdesivir

MONITOR: Coadministration of remdesivir with nephrotoxic agents may increase the plasma concentrations of its metabolites, GS-704277 and GS-441524, as well as the excipient, sulfobutylether-beta-cyclodextrin sodium (SBECD). Both GS-441524 and SBECD are primarily eliminated by the kidneys, thus renal impairment secondary to the use of nephrotoxic agents may reduce their clearance and increase the risk of accumulation. Exposures of GS-441524, GS-704277, and SBECD were up to 7.9-, 2.8-, and 21-fold higher, respectively, in adults with renal impairment compared to adults with normal renal function. However, these changes are not generally considered to be clinically significant. Safety data in pediatric patients with renal impairment is limited. Clinical data evaluating the use of remdesivir concurrently with another agent that causes nephrotoxicity are not available.

MANAGEMENT: Caution and additional monitoring may be advisable if remdesivir is used in patients who have recently received or are currently using potentially nephrotoxic agents. Some authorities recommend avoiding the concomitant use of remdesivir with drugs that can reduce renal function; as well as monitoring renal function prior to starting remdesivir and as clinically appropriate during treatment.

Coadministration with remdesivir may increase the plasma concentrations of drugs metabolized via CYP450 3A4, but many sources indicate that clinically significant interactions are unlikely. The proposed mechanism is inhibition of CYP450 3A4 by remdesivir. Two drug interaction studies were conducted using the sensitive CYP450 3A4 substrate, midazolam. In the first study, healthy volunteers (n=19) received a single dose of remdesivir (200 mg) and a single dose of midazolam (2.5 mg), which resulted in midazolam's maximum concentration (Cmax) and systemic exposure (AUC) increasing by 29% and 20%, respectively. In the second study, healthy volunteers (n=14) received remdesivir (200 mg once, followed by 100 mg daily) for a total of 10 doses and a single dose of midazolam (2.5 mg) administered with the last dose of remdesivir. Midazolam's Cmax and AUC increased by 45% and 30%, respectively. Both studies indicated that remdesivir is a weak in vivo inhibitor of CYP450 3A4; however, some authorities consider these findings to be clinically insignificant.