Drug Interaction Report

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 may increase the plasma concentrations of sunitinib and its pharmacologically active metabolite, both of which are substrates of the isoenzyme. In healthy volunteers, concurrent administration of a single dose of sunitinib with the potent CYP450 3A4 inhibitor, ketoconazole, resulted in a 49% and 51% increase in the combined (i.e., sunitinib plus its primary active metabolite) peak plasma concentration (Cmax) and systemic exposure (AUC) values, respectively, compared to administration of sunitinib alone. Because sunitinib 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: Alternative agents with no or minimal CYP450 3A4-inhibiting activity are recommended in patients treated with sunitinib. Some authorities recommend avoiding concomitant use of sunitinib during and for 2 weeks after treatment with itraconazole. A dose reduction for sunitinib to a minimum of 37.5 mg daily for gastrointestinal stromal tumor (GIST) and metastatic renal cell carcinoma (mRCC) or 25 mg daily for pancreatic neuroendocrine tumors (pNET) should be considered if it must be coadministered with potent CYP450 3A4 inhibitors such as itraconazole, ketoconazole, voriconazole, nefazodone, delavirdine, protease inhibitors, and ketolide and certain macrolide antibiotics.

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 may increase the plasma concentrations of sunitinib and its pharmacologically active metabolite, both of which are substrates of the isoenzyme. In healthy volunteers, concurrent administration of a single dose of sunitinib with the potent CYP450 3A4 inhibitor, ketoconazole, resulted in a 49% and 51% increase in the combined (i.e., sunitinib plus its primary active metabolite) peak plasma concentration (Cmax) and systemic exposure (AUC) values, respectively, compared to administration of sunitinib alone. Because sunitinib 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: Alternative agents with no or minimal CYP450 3A4-inhibiting activity are recommended in patients treated with sunitinib. Some authorities recommend avoiding concomitant use of sunitinib during and for 2 weeks after treatment with itraconazole. A dose reduction for sunitinib to a minimum of 37.5 mg daily for gastrointestinal stromal tumor (GIST) and metastatic renal cell carcinoma (mRCC) or 25 mg daily for pancreatic neuroendocrine tumors (pNET) should be considered if it must be coadministered with potent CYP450 3A4 inhibitors such as itraconazole, ketoconazole, voriconazole, nefazodone, delavirdine, protease inhibitors, and ketolide and certain macrolide antibiotics.

ADJUST DOSING INTERVAL: Administration of atazanavir with food enhances oral bioavailability and reduces pharmacokinetic variability. According to the manufacturer, administration with a light meal increased the peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of a single 400 mg dose of atazanavir by 57% and 70%, respectively, relative to the fasting state. Administration with a high-fat meal resulted in a mean increase of 35% in atazanavir AUC and no change in Cmax compared to fasting. The coefficient of variation of AUC and Cmax decreased by approximately one-half when given with either a light or high-fat meal compared to the fasting state.

MANAGEMENT: To ensure maximal oral absorption, atazanavir should be administered with or immediately after a meal.

GENERALLY AVOID: Consumption of grapefruit or grapefruit juice during sunitinib therapy may increase the plasma concentrations of sunitinib. The proposed mechanism is inhibition of CYP450 3A4-mediated metabolism by certain compounds present in grapefruit.

MANAGEMENT: Although clinical data are lacking, it may be advisable to avoid the consumption of large amounts of grapefruit or grapefruit juice during sunitinib therapy.