Drug Interactions between ivacaftor / lumacaftor and zafirlukast

MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of ivacaftor, which is primarily metabolized by the isoenzyme. The interaction occurs to a greater extent when ivacaftor is administered as monotherapy than when administered in combination with lumacaftor, a potent CYP450 3A4 inducer. In study subjects, ivacaftor systemic exposure (AUC) increased by 8.5-fold when it was administered concomitantly with the potent CYP450 3A4 inhibitor ketoconazole and by 3-fold with the moderate CYP450 3A4 inhibitor fluconazole. By contrast, when lumacaftor/ivacaftor was coadministered with the potent CYP450 3A4 inhibitor itraconazole, ivacaftor peak plasma concentration (Cmax) and AUC increased by an average of 3.7- and 4.3-fold, respectively, and when coadministered with the moderate CYP450 3A4 inhibitor ciprofloxacin, ivacaftor Cmax and AUC increased by just 29% each.

MANAGEMENT: Caution is advised if ivacaftor is used with CYP450 3A4 inhibitors. A dosage adjustment for ivacaftor may be required if undue adverse effects occur.

MONITOR: Coadministration with lumacaftor may decrease the plasma concentrations and therapeutic efficacy of drugs that are substrates of CYP450 3A4, 2B6, 2C19, 2C8, and/or 2C9. Lumacaftor is a potent inducer of CYP450 3A4 in vivo. Coadministration of lumacaftor with ivacaftor, a sensitive CYP450 3A4 substrate, decreased ivacaftor systemic exposure (AUC) by approximately 80%. In vitro, lumacaftor is an inducer of several other CYP450 isoenzymes including CYP450 2B6, 2C19, 2C8 and 2C9, although inhibition of the latter two isoenzymes has also been observed in vitro. Drugs that are substrates of CYP450 2C8 and 2C9 (e.g., sulfonylureas and other hypoglycemic agents, warfarin) may demonstrate decreased or increased exposures.

MANAGEMENT: Caution is advised when lumacaftor/ivacaftor is prescribed with drugs that undergo metabolism by CYP450 3A4, 2B6, 2C19, 2C8 and/or 2C9, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever lumacaftor/ivacaftor is added to or withdrawn from therapy.