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Arzneimittelforschung 2012; 62(10): 463-469
DOI: 10.1055/s-0032-1321847
Original Article
© Georg Thieme Verlag KG Stuttgart · New York

Pharmacokinetics of Febuxostat in Healthy Chinese Volunteers

X.-X. Liu   *
1   Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, P. R. China
,
R.-J. Liu   *
1   Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, P. R. China
,
L. Ding
1   Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, P. R. China
,
Y.-F. Lin
1   Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, P. R. China
,
N.-Y. Huang
1   Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, P. R. China
,
H.-F. Xiao
2   Guangzhou Boji New Drug Clinical Research Center Co., Ltd., Guangzhou, P. R. China
,
Y. Huang
1   Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, P. R. China
,
J. Yang
1   Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, P. R. China
,
S.-L. Wang
1   Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, P. R. China
› Author Affiliations
Further Information

Publication History

received 14 March 2012

accepted 04 July 2012

Publication Date:
06 September 2012 (online)

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Abstract

Background:

Febuxostat is a novel non-purine selective inhibitor of xanthine oxidase developed for the management of hyperuricemia in patients with gout.

Objective:

To investigate the pharmacokinetics and also evaluate the effects of gender and food on the pharmacokinetics of febuxostat in healthy Chinese volunteers.

Methods:

A phase I, 3-period study was performed in healthy Chinese male and female subjects. Subjects either received single 40 mg, multiple 40 mg and single 80 mg doses of febuxostat under fasted conditions, or received single 80 mg doses under fed condition. Plasma concentrations of febuxostat were collected and determined at 14 time points over 48 h.

Results:

After 40 mg and 80 mg single dose administration of febuxostat, the C max were 2.308±0.812 and 4.559±1.246 μg/mL, the T max were 1.6±0.6 and 2.1±1.0 h, the t 1/2 were 6.8±1.7 and 6.7±1.9 h, and the AUC0–∞ were 7.704±1.723 and 16.34±3.87 μg∙h/mL, respectively. In the multiple-dose study at 40 mg dose for 6 consecutive days, the mean (SD) steady-state pharmacokinetic parameters on day 8 were similar to those following a single dose of febuxostat on day 1. In addition, food caused a decrease of 33% for C max and a delay of 0.3 h for T max. Gender had no significant effect on the pharmacokinetics of febuxostat. Febuxostat was well tolerated over the investigated dose range.

Conclusion:

Compared with the previous study, the pharmacokinetics of febuxostat appeared to be different between Chinese and other races.

Key words

febuxostat - pharmacokinetics - chinese volunteers
*

*  Xiaoxue Liu and Ruijuan Liu are co-first authors.


 

  • References

  • 1 Mike S. Management of gout. Trends in Urology & Men’s Health 2011; 2 (03) 24-26
    PubMedGoogle Scholar
  • 2 Hair PI, McCormack PL, Keating GM. Febuxostat. Drugs Aug 2008; 68 (13) 1865-1874
    CrossrefPubMedGoogle Scholar
  • 3 Pande I. An update on gout. Indian J Rheumatol 2006; 1: 60-65
    CrossrefPubMedGoogle Scholar
  • 4 Jansen TL, Richette P, Perez-Ruiz F et al. International position paper on febuxostat. Clin Rheumatol Aug 2010; 29 (08) 835-840
    CrossrefPubMedGoogle Scholar
  • 5 Ernst ME, Fravel MA. Febuxostat: a selective xanthine-oxidase/xanthine-dehydrogenase inhibitor for the management of hyperuricemia in adults with gout. Clin Ther 2009; Nov 31 (11) 2503-2518
    CrossrefPubMedGoogle Scholar
  • 6 Komoriya K, Hoshide S, Takeda K et al. Pharmacokinetics and pharmacodynamics of febuxostat (TMX-67), a non-purine selective inhibitor of xanthine oxidase/xanthine dehydrogenase (NPSIXO) in patients with gout and/or hyperuricemia. Nucleosides Nucleotides Nucleic Acids Oct 2004; 23 (8/9) 1119-1122
    CrossrefPubMedGoogle Scholar
  • 7 Schumacher Jr HR, Becker MA, Lloyd E et al. Febuxostat in the treatment of gout: 5-yr findings of the FOCUS efficacy and safety study. Rheumatology (Oxford) Feb 2009; 48 (02) 188-194
    PubMedGoogle Scholar
  • 8 Naoyuki K, Shin F, Toshikazu H et al. Placebo-controlled, double-blind study of the non-purine-selective xanthine oxidase inhibitor Febuxostat (TMX-67) in patients with hyperuricemia including those with gout in Japan: phase 3 clinical study. J Clin Rheumatol Jun 2011; 17 (Suppl. 02) S19-S26
    CrossrefPubMedGoogle Scholar
  • 9 Kamatani N, Fujimori S, Hada T et al. Multicenter, open-label study of long-term administration of febuxostat (TMX-67) in Japanese patients with hyperuricemia including gout. J Clin Rheumatol Jun 2011; 17 (Suppl. 02) S50-S56
    CrossrefPubMedGoogle Scholar
  • 10 Mayer MD, Khosravan R, Vernillet L et al. Pharmacokinetics and pharmacodynamics of febuxostat, a new non-purine selective inhibitor of xanthine oxidase in subjects with renal impairment. Am J Ther Jan-Feb 2005; 12 (01) 22-34
    CrossrefPubMedGoogle Scholar
  • 11 Khosravan R, Grabowski BA, Wu JT et al. Pharmacokinetics, pharmacodynamics and safety of febuxostat, a non-purine selective inhibitor of xanthine oxidase, in a dose escalation study in healthy subjects. Clin Pharmacokinet 2006; 45 (08) 821-841
    CrossrefPubMedGoogle Scholar
  • 12 Khosravan R, Grabowski BA, Mayer MD et al. The effect of mild and moderate hepatic impairment on pharmacokinetics, pharmacodynamics, and safety of febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase. J Clin Pharmacol Jan 2006; 46 (01) 88-102
    CrossrefPubMedGoogle Scholar
  • 13 Khosravan R, Grabowski BA, Wu JT et al. Effect of food or antacid on pharmacokinetics and pharmacodynamics of febuxostat in healthy subjects. Br J Clin Pharmacol Mar 2008; 65 (03) 355-363
    CrossrefPubMedGoogle Scholar
  • 14 Khosravan R, Kukulka MJ, Wu JT et al. The effect of age and gender on pharmacokinetics, pharmacodynamics, and safety of febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase. J Clin Pharmacol Sep 2008; 48 (09) 1014-1024
    CrossrefPubMedGoogle Scholar
  • 15 Grabowski BA, Khosravan R, Vernillet L et al. Metabolism and excretion of [14C] febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase, in healthy male subjects. J Clin Pharmacol 2011; Feb 51 (02) 189-201
    PubMedGoogle Scholar
  • 16 Poolsup N, Li Wan Po A, Knight TL. Pharmacogenetics and psychopharmacotherapy. J Clin Pharm Ther Jun 2000; 25 (03) 197-220
    CrossrefPubMedGoogle Scholar
  • 17 Burroughs VJ, Maxey RW, Levy RA. Racial and ethnic differences in response to medicines: towards individualized pharmaceutical treatment. J Natl Med Assoc 2002; Oct 94 (10 Suppl) 1-26
    PubMedGoogle Scholar
  • 18 Topic E, Stefanovic M, Samardzija M. Association between the CYP2C9 polymorphism and the drug metabolism phenotype. Clin Chem Lab Med Jan 2004; 42 (01) 72-78
    CrossrefPubMedGoogle Scholar
  • 19 Yasar U, Tybring G, Hidestrand M et al. Role of CYP2C9 polymorphism in losartan oxidation. Drug Metab Dispos Jul 2001; 29 (07) 1051-1056
    PubMedGoogle Scholar
  • 20 Daly AK, Day CP, Aithal GP. CYP2C9 polymorphism and warfarin dose requirements. Br J Clin Pharmacol Apr 2002; 53 (04) 408-409
    CrossrefPubMedGoogle Scholar
  • 21 Miners J. CYP2C9 polymorphism: impact on tolbutamide pharmacokinetics and response. Pharmacogenetics Mar 2002; 12 (02) 91-92
    CrossrefPubMedGoogle Scholar
  • 22 Harris RZ, Benet LZ, Schwartz JB. Gender effects in pharmacokinetics and pharmacodynamics. Drugs Aug 1995; 50 (02) 222-239
    CrossrefPubMedGoogle Scholar
  • 23 Mukoyoshi M, Nishimura S, Hoshide S et al. In vitro drug-drug interaction studies with febuxostat, a novel non-purine selective inhibitor of xanthine oxidase: plasma protein binding, identification of metabolic enzymes and cytochrome P450 inhibition. Xenobiotica May 2008; 38 (05) 496-510
    CrossrefPubMedGoogle Scholar
  • 24 Xie HG, Prasad HC, Kim RB et al. CYP2C9 allelic variants: ethnic distribution and functional significance. Adv Drug Deliv Rev Nov 2002; 54 (10) 1257-1270
    CrossrefPubMedGoogle Scholar
  • 25 Singh BN. Effects of food on clinical pharmacokinetics. Clin Pharmacokinet Sep 1999; 37 (03) 213-255
    CrossrefPubMedGoogle Scholar
  • 26 Fleisher D, Li C, Zhou Y et al. Drug, meal and formulation interactions influencing drug absorption after oral administration. Clin Pharmacokinet 1999; Mar 36 (03) 233-254
    PubMedGoogle Scholar
  • 27 Disanto AR, Golden G. Effect of food on the pharmacokinetics of clozapine orally disintegrating tablet 12.5 mg: a randomized, open-label, crossover study in healthy male subjects. Clin Drug Investig 2009; 29 (08) 539-549
    CrossrefPubMedGoogle Scholar
  • 28 Scallion R, Moore KA. Effects of food intake on the pharmacokinetics of diclofenac potassium soft gelatin capsules: a single-dose, randomized, two-way crossover study. Clin Ther Oct 2009; 31 (10) 2233-2241
    CrossrefPubMedGoogle Scholar
  • 29 Henney HR, Faust B, Blight AR. Effect of food on the single-dose pharmacokinetics and tolerability of dalfampridine extended-release tablets in healthy volunteers. Am J Health Syst Pharm 2011; Nov 68 (22) 2148-2154
    PubMedGoogle Scholar
  • 30 Carrasco-Portugal Mdel C, Flores-Murrieta FJ. Gender differences in the oral pharmacokinetics of fluconazole. Clin Drug Investig 2007; 27 (12) 851-855
    CrossrefPubMedGoogle Scholar
  • 31 Guo T, Sun WJ, Xia DY et al. The pharmacokinetics of fluconazole in healthy Chinese adult volunteers: influence of ethnicity and gender. J Clin Pharm Ther 2010; Apr 35 (02) 231-237
    PubMedGoogle Scholar
  • 32 Jarugula V, Yeh CM, Howard D et al. Influence of body weight and gender on the pharmacokinetics, pharmacodynamics, and antihypertensive efficacy of aliskiren. J Clin Pharmacol Dec 2010; 50 (12) 1358-1366
    CrossrefPubMedGoogle Scholar