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.

Although some in vitro data indicate synergism between macrolide antibiotics and penicillins, other in vitro data indicate antagonism. When these drugs are given together, neither has predictable therapeutic efficacy. Data are available for erythromycin, although theoretically this interaction could occur with any macrolide. Except for monitoring of the effectiveness of antibiotic therapy, no special precautions appear to be necessary.

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.

Grapefruit juice may delay the gastrointestinal absorption of clarithromycin but does not appear to affect the overall extent of absorption or inhibit the metabolism of clarithromycin. The mechanism of interaction is unknown but may be related to competition for intestinal CYP450 3A4 and/or absorptive sites. In an open-label, randomized, crossover study consisting of 12 healthy subjects, coadministration with grapefruit juice increased the time to reach peak plasma concentration (Tmax) of both clarithromycin and 14-hydroxyclarithromycin (the active metabolite) by 80% and 104%, respectively, compared to water. Other pharmacokinetic parameters were not significantly altered. This interaction is unlikely to be of clinical significance.