Drug Interactions between axitinib and ivacaftor / lumacaftor

GENERALLY AVOID: Coadministration with potent and moderate inducers of CYP450 3A4 may significantly decrease the plasma concentrations of axitinib, which is primarily metabolized by the isoenzyme. In a study of 40 healthy, nonsmoking, male volunteers, administration of a single 5 mg dose of axitinib on day 8 of treatment with the potent CYP450 3A4 inducer rifampin (600 mg/day for 9 days) resulted in a 71% decrease in mean axitinib peak plasma concentration (Cmax) and 79% decrease in mean systemic exposure. The extent to which other, less potent inducers of CYP450 3A4 may interact with axitinib is unknown.

MANAGEMENT: Concomitant use of axitinib with potent CYP450 3A4 inducers such as apalutamide, carbamazepine, enzalutamide, lumacaftor, mitotane, phenobarbital, phenytoin, rifamycins, and St. John's wort should generally be avoided. Although pharmacokinetic data are lacking, the manufacturer recommends that moderate CYP450 3A4 inducers should also be avoided if possible, including but not limited to bosentan, cenobamate, dabrafenib, dexamethasone, efavirenz, etravirine, lorlatinib, modafinil, nafcillin, pexidartinib, and sotorasib.

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MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of axitinib, which is primarily metabolized by the isoenzyme. In 32 healthy volunteers, administration of a single 5 mg dose of axitinib on day 4 of treatment with the potent CYP450 3A4 inhibitor ketoconazole (400 mg/day for 7 days) resulted in a 1.5-fold increase in mean axitinib peak plasma concentration (Cmax) and 2-fold increase in mean systemic exposure (AUC) compared to administration of axitinib alone. The mean plasma half-life of axitinib also increased from 9.4 hours when given alone to 13.1 hours in the presence of ketoconazole. The combination was well tolerated by study subjects. Most treatment-related adverse events were mild in severity, with headache and nausea reported most frequently. No clinically significant effects on blood pressure were observed for single-dose axitinib plus ketoconazole relative to axitinib alone.

MANAGEMENT: Caution is advised if axitinib is prescribed with CYP450 3A4 inhibitors. Alternative agents with no or minimal CYP450 3A4 inhibition potential are recommended whenever possible. Otherwise, patients should be monitored closely for development of toxicity such as hypertension/hypertensive crisis, arterial and venous thromboembolic complications, hemorrhage, gastrointestinal perforation or fistula, thyroid dysfunction, reversible posterior leukoencephalopathy syndrome, proteinuria, and liver enzyme elevations or hepatic impairment.

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