Effect of rifampin on the pharmacokinetics of Axitinib (AG-013736) in Japanese and Caucasian healthy volunteers

PURPOSE: Axitinib, a potent and selective inhibitor of vascular endothelial growth factor receptors 1, 2, 3, is metabolized by cytochrome P450 3A4 and glucuronidation. This study evaluated the effect of rifampin, a potent inducer of drug-metabolizing enzymes, on axitinib plasma pharmacokinetics. Equal numbers of Japanese and Caucasian subjects were enrolled to assess the potential differences in axitinib pharmacokinetics between the two ethnicities. METHODS: Forty healthy volunteers were randomized to receive 5 mg axitinib alone and with 600 mg rifampin. RESULTS: Rifampin expectedly decreased AUCinf and Cmax of axitinib (geometric mean reduced by 79 and 71%, respectively). However, differences in axitinib pharmacokinetics were not observed between Japanese and Caucasian subjects (geometric mean ratios for axitinib treatment alone for AUCinf and Cmax were 103 and 96%). CONCLUSIONS: The results support a common axitinib starting dose in both populations. Potent inducers of drug-metabolizing enzymes reduce axitinib exposure and dose adjustments may be needed for optimal efficacy.