Drug Interactions between bosentan and ivacaftor / lumacaftor

MONITOR: Coadministration with inducers of CYP450 3A4 may decrease the plasma concentrations of ivacaftor, which is primarily metabolized by the isoenzyme. In study subjects, administration of a single 150 mg dose of ivacaftor with the potent CYP450 3A4 inducer rifampin (600 mg once daily) decreased ivacaftor peak plasma concentration (Cmax) and systemic exposure (AUC) by 80% and 89%, respectively, compared to administration of ivacaftor alone. When lumacaftor/ivacaftor was coadministered with rifampin, lumacaftor pharmacokinetics were minimally affected, but ivacaftor Cmax and AUC decreased by an average of 50% and 57%, respectively. No pharmacokinetic data are available for elexacaftor or tezacaftor, but decreased exposures are expected according to prescribing information.

MANAGEMENT: The potential for diminished pharmacologic effects of ivacaftor-containing medications should be considered during coadministration with CYP450 3A4 inducers. Alternative treatments may be required if an interaction is suspected.

MONITOR: Coadministration with potent CYP450 3A4 and/or 2C9 inducers may decrease the plasma concentrations and therapeutic effects of bosentan. The proposed mechanism is increased clearance of bosentan by induction of CYP450 3A4 and/or 2C9, the isoenzymes responsible for the metabolic clearance of bosentan. In healthy subjects, concomitant use of rifampin initially led to a mean 6-fold increase in bosentan trough levels; however, after 7 days of concomitant use with bosentan 125 mg twice daily, rifampin decreased the plasma concentrations of bosentan by 58%. It was suggested that this decrease could achieve nearly 90% in an individual case.

MANAGEMENT: Until more information is available, the possibility of a diminished therapeutic response to bosentan should be considered when it is coadministered with a potent CYP450 3A4 and/or 2C9 inducer. Clinical and laboratory monitoring should be considered whenever a potent CYP450 3A4 and/or 2C9 inducer is added to or withdrawn from therapy, and the bosentan dosage adjusted as necessary.