Effects of CYP3A inhibitors ketoconazole, voriconazole, and itraconazole on the pharmacokinetics of sunitinib and its main metabolite in rats.

ABSTRACT Sunitinib is a small molecule inhibitor of multiple receptor tyrosine kinases such as platelet derived growth factor receptor, vascular endothelial growth factor receptor, kit receptor and other receptors. The US Food and Administration (FDA) have approved sunitinib for the treatment of advanced renal cell carcinoma and gastrointestinal stromal tumors. It had been reported that sunitinib was mainly metabolized by CYP3A4 but was barely explained from pharmacokinetic interaction. In this study, we investigate whether CYP3A4 inhibitors (ketoconazole, voriconazole, and itraconazole) could influence the pharmacokinetics of sunitinib and its equipotent metabolite N-desethyl sunitinib from a drug-drug interaction study in Sprague Dawley (SD) rats. The results showed that ketoconazole and voriconazole significantly increased the exposure of sunitinib and decreased the exposure of N-desethyl sunitinib, and inhibited the metabolism of sunitinib in rats. However, itraconazole showed weak effect on the pharmacokinetics and the metabolism.Co-administration of sunitinib with ketoconazole and voriconazole could be avoided if possible or be underwent therapeutic drug monitoring of the levels of sunitinib and N-desethyl sunitinib. Therefore, the drug-drug interaction should be attention when sunitinib is administration in conjunction with CYP3A4 inhibitor, which might lead to toxicity.