Effect of rifampin on the pharmacokinetics of Axitinib (AG-013736) in Japanese and Caucasian healthy volunteers.
OBJECTIVE
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.
Pithavala
Y K
YK
Pfizer Oncology, Pfizer Global Research and Development, La Jolla Laboratories, 101646 Science Center Drive, San Diego, CA 92121, USA. yazdi.pithavala@pfizer.com
Tortorici
M
M
Toh
M
M
Garrett
M
M
Hee
B
B
Kuruganti
U
U
Ni
G
G
Klamerus
K J
KJ
D000328:Adult; D019540:Area Under Curve; D044466:Asian People; D000077784:Axitinib; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D007093:Imidazoles / Q000097:blood / Q000493:pharmacokinetics*; D007191:Indazoles / Q000097:blood / Q000493:pharmacokinetics*; D007564:Japan; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D012293:Rifampin / Q000494:pharmacology*; D044465:White People; D055815:Young Adult; D000099148:UGT1A1 Enzyme
D000077784:Axitinib; D051544:Cytochrome P-450 CYP3A; D004791:Enzyme Inhibitors; D014453:Glucuronosyltransferase; D007093:Imidazoles; D007191:Indazoles; D012293:Rifampin; D000099148:UGT1A1 Enzyme; C510163:CYP3A4 protein, human