Drug Interactions between crizotinib and darunavir

MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of crizotinib, which is primarily metabolized by the isoenzyme. In study subjects, administration of a single 150 mg oral dose of crizotinib during treatment with the potent CYP450 3A4 inhibitor ketoconazole (200 mg twice daily) resulted in an approximately 1.4-fold increase in crizotinib peak plasma concentration (Cmax) and 3.2-fold increase in systemic exposure (AUC) compared to crizotinib administered alone. The effect of CYP450 3A4 inhibitors on steady-state crizotinib exposure has not been evaluated. Because crizotinib is associated with concentration-dependent prolongation of the QT interval, increased levels may potentiate the risk of ventricular arrhythmias such as torsade de pointes and sudden death.

MANAGEMENT: Caution is advised if crizotinib is prescribed in combination with moderate CYP450 3A4 inhibitors. Regular monitoring of ECG and serum electrolytes, including potassium, magnesium and calcium, may be appropriate in some patients. Treatment should be interrupted in patients who develop Grade 3 QTc prolongation until recovery to less than or equal to Grade 1, then resumed at 200 mg twice daily. In case of recurrence of Grade 3 QTc prolongation, therapy should be withheld until recovery to less than or equal to Grade 1, then resumed at 250 mg once daily. Permanently discontinue crizotinib therapy if Grade 3 QTc prolongation recurs or at any time during treatment if Grade 4 QTc prolongation develops. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, palpitations, irregular heartbeat, shortness of breath, or syncope.