Drug Interaction Report

Coadministration with inducers of CYP450 3A4 or dual P-glycoprotein (P-gp) and CYP450 3A4 inducers may decrease the plasma concentrations and effects of unconjugated monomethyl auristatin E (MMAE), the cytotoxic component of enfortumab vedotin. Enfortumab vedotin is an antibody-drug conjugate (ADC) that releases MMAE, via proteolytic cleavage. MMAE has been shown in vitro to be primarily metabolized by CYP450 3A4 as well as being a substrate of P-gp. According to physiologically-based pharmacokinetic (PBPK) modeling, concomitant use of enfortumab vedotin with rifampin, a dual P-gp and strong CYP450 3A4 inducer, is predicted to decrease unconjugated MMAE peak plasma concentration (Cmax) by 28% and systemic exposure (AUC) by 53%, with no change in ADC exposure. Some authorities suggest that the PBPK model may underestimate the full impact of rifampin on the Cmax of MMAE. The clinical significance of the interaction is unclear, since the intact ADC is required to bind to Nectin-4, an adhesion protein found on the surface of cells, which allows for internalization and cleavage by lysosomal proteases to enable intracellular delivery of MMAE. It is not known if, and to what extent, enfortumab vedotin may interact with less potent CYP450 3A4 inducers.

MONITOR: Isolated case reports have suggested that the ingestion of alcohol during griseofulvin therapy may rarely cause disulfiram-like reactions, flushing, tachycardia, or increased effects of alcohol. The mechanism is unknown.

MANAGEMENT: Patients should be advised of the possibility of increased adverse effects or a disulfiram-like reaction.