Drug Interactions between atazanavir and axitinib

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 may significantly 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: Concomitant use of axitinib with potent CYP450 3A4 inhibitors should generally be avoided. Some authorities recommend avoiding concomitant use of axitinib during and for 2 weeks after treatment with itraconazole. Alternative agents with no or minimal CYP450 3A4 inhibition potential are recommended whenever possible. Should concomitant treatment with a potent inhibitor be required, the manufacturer recommends that axitinib dosage be reduced by approximately one-half, as this is predicted to adjust the axitinib systemic exposure (AUC) to the range observed without inhibitors; however, clinical data are lacking. Subsequent dosage adjustments can be made according to individual therapeutic response and tolerability. Following discontinuation of the potent CYP450 3A4 inhibitor, the axitinib dosage should be returned (after 3 to 5 half-lives of the inhibitor) to that used prior to initiation of the inhibitor.