Drug Interactions between larotrectinib and macitentan

GENERALLY AVOID: Coadministration with inhibitors of CYP450 3A4 or moderate dual or combined inhibitors of CYP450 3A4 and CYP450 2C9 may increase the plasma concentrations of macitentan. Macitentan is primarily metabolized by CYP450 3A4 and to a minor extent by CYP450 2C8, CYP450 2C9 and CYP450 2C19. In ten healthy subjects, administration of a single 10 mg oral dose of macitentan on day 5 of treatment with the potent CYP450 3A4 inhibitor ketoconazole (400 mg daily for 24 days) resulted in an approximately 2-fold increase in macitentan systemic exposure (AUC) compared to administration alone. Additionally, there was a 26% reduction in the AUC of the active metabolite, which has been reported to be approximately 5-fold less potent than macitentan in vitro, but whose systemic exposure in human is 2.5-fold higher than that of macitentan. The clinical significance of these changes has not been established. Macitentan was well tolerated with or without ketoconazole in the study, and there were no relevant differences in safety parameters between the treatments. In addition, physiologically based pharmacokinetic modeling in poor metabolizers of CYP450 2C9 showed that a 400 mg daily dose of fluconazole, a moderate dual CYP450 3A4 and CYP450 2C9 inhibitor, may increase macitentan exposure by approximately 3.8-fold. However, there was no clinically relevant change in exposure to the active metabolite of macitentan. The clinical significance of these findings is not known.

MANAGEMENT: Caution is advisable if macitentan is used with inhibitors of CYP450 3A4. The product labeling recommends avoiding concomitant use with potent inhibitors (e.g., protease inhibitors, clarithromycin, cobicistat, conivaptan, delavirdine, itraconazole, ketoconazole, nefazodone, posaconazole, voriconazole). The manufacturer of macitentan also recommends avoiding concomitant use with moderate dual inhibitors of CYP450 3A4 and 2C9 (e.g., fluconazole, amiodarone) or in combination with both a moderate CYP450 3A4 inhibitor and a moderate CYP450 2C9 inhibitor.