Febuxostat (TMX-67), a novel, non-purine, selective inhibitor of xanthine oxidase, is safe and decreases serum urate in healthy volunteers.
In order to evaluate the safety, pharmacological properties, and urate-lowering efficacy of febuxostat, a non-purine, selective inhibitor of xanthine oxidase, a Phase 1, 2-week, multiple-dose, placebo-controlled, dose-escalation study was conducted in 154 healthy adults of both sexes. Daily febuxostat doses in the range 10 mg to 120 mg resulted in proportional mean serum urate reductions ranging from 25% to 70% and in proportional increases in maximum febuxostat plasma concentrations and area under plasma concentration versus time curves. Accompanying the hypouricemic effect were increases in serum xanthine concentrations, decreases in urinary uric acid excretion, and increases in urinary xanthine and hypoxanthine excretion, confirming inhibition of xanthine oxidase activity by febuxostat. Hepatic conjugation and oxidative metabolism were the major pathways of elimination of febuxostat from the body, and renal elimination did not appear to play a significant role. Although not uncommon, adverse events were mild and self-limited, and no deaths or serious adverse events were observed. Febuxostat is a safe and potent hypouricemic agent in healthy humans.
Becker
M A
MA
University of Chicago, Chicago, Illinois 60637, USA.
Kisicki
J
J
Khosravan
R
R
Wu
J
J
Mulford
D
D
Hunt
B
B
MacDonald
P
P
Joseph-Ridge
N
N
D000328:Adult; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D000069465:Febuxostat; D005260:Female; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D010919:Placebos; D011687:Purines / Q000378:metabolism; D013844:Thiazoles / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013997:Time Factors; D014527:Uric Acid / Q000097:blood*; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D010919:Placebos; D011687:Purines; D013844:Thiazoles; D000069465:Febuxostat; D014527:Uric Acid; D014969:Xanthine Oxidase