Drug Interactions between ivacaftor / lumacaftor and remdesivir

MONITOR: Concomitant use of remdesivir with other agents that are known to induce hepatotoxicity may theoretically increase the risk of liver injury. Data from investigational use and clinical studies suggest that remdesivir may be associated with transaminase elevations. Transient treatment-emergent Grade 1 or Grade 2 elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were observed during multiple-dose Phase 1 studies in healthy volunteers. The mechanism of potential hepatotoxicity is unknown and the contribution of remdesivir is difficult to determine, as transaminase elevations have also been reported as a component of COVID-19, including in patients receiving placebo in clinical trials of remdesivir.

MANAGEMENT: Caution and increased monitoring may be required if remdesivir is given concurrently with other agents associated with liver injury. Hepatic function should be evaluated prior to starting remdesivir and during treatment as clinically appropriate. The manufacturer of remdesivir recommends considering discontinuation of remdesivir if ALT levels increase to greater than 10 times the upper limit of normal. Additionally, the manufacturer recommends discontinuing remdesivir if ALT elevation is accompanied by signs or symptoms of liver inflammation. The labeling of the other agent(s) involved should also be consulted as they may contain dose adjustment or discontinuation recommendations for those agent(s) in the event of hepatotoxicity.

MONITOR: Theoretically, coadministration of remdesivir with potent inducers of CYP450 3A4 may decrease the plasma concentration of remdesivir, which has been shown in vitro to be a substrate of the isoenzyme. However, the potential for this interaction appears low as remdesivir's metabolism is predominantly mediated by hydrolysis via esterases in vivo, which are not significantly affected by CYP450 3A4. When a single dose of remdesivir (100 mg) was administered to healthy volunteers on carbamazepine (300 mg twice daily), remdesivir's peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by 13% and 8%, respectively. One of remdesivir's metabolites (GS-704277) had no change in its Cmax or AUC, while its other metabolite (GS-441524) had a reduction in AUC of 17%.

MANAGEMENT: Caution and clinical monitoring may be advisable if remdesivir is administered concurrently with potent inducers of CYP450 3A4 as they may reduce its concentrations and effects. While clinically significant interactions are not expected, some authorities recommend avoiding concomitant use of remdesivir with potent CYP450 3A4 inducers.