Drug Interactions between ivacaftor / lumacaftor and tisotumab vedotin

Coadministration with potent inducers of CYP450 3A4 may decrease the plasma concentrations of unconjugated monomethyl auristatin E (MMAE), the anti-mitotic and cytotoxic component of tisotumab vedotin. Tisotumab vedotin is an antibody-drug conjugate (ADC) that releases MMAE via proteolytic cleavage, and MMAE has been shown in vitro to be primarily metabolized by CYP450 3A4. Although tisotumab vedotin has not been studied with CYP450 3A4 inducers, data for another ADC that contains MMAE (brentuximab vedotin) have been reported. When brentuximab vedotin was administered with the potent CYP450 3A4 inducer rifampin, MMAE peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by 44% and 46%, respectively, with no change in ADC exposure. Using a model-based approach to account for the fact that MMAE exposures are decreased after multiple doses by 20% to 50% compared to the first dose, the adjusted reduction in MMAE AUC by rifampin is predicted to be 31%. Similar effects on unconjugated MMAE and ADC are expected for tisotumab vedotin when coadministered with potent CYP450 3A4 inducers. However, the interaction is not expected to be clinically relevant, since the intact ADC containing the antibody component 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.