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Pharmacokinetics, Pharmacodynamics and Safety of Febuxostat, a Non-Purine Selective Inhibitor of Xanthine Oxidase, in a Dose Escalation Study in Healthy Subjects

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Abstract

Background

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

Objective

To investigate the pharmacokinetics, pharmacodynamics and safety of febuxostat over a range of oral doses in healthy subjects.

Methods

In a phase I, dose-escalation study, febuxostat was studied in dose groups (10, 20, 30, 40, 50, 70, 90, 120, 160, 180 and 240mg) of 12 subjects each (10 febuxostat plus 2 placebo). In all groups, subjects were confined for 17 days and were administered febuxostat once daily on day 1, and days 3–14. During the course of the study, blood and urine samples were collected to assess the pharmacokinetics of febuxostat and its metabolites, and its pharmacodynamic effects on uric acid, xanthine and hypoxanthine concentrations after both single and multiple dose administration. Safety measurements were also obtained during the study.

Results

Orally administered febuxostat was rapidly absorbed with a median time to reach maximum plasma concentration following drug administration of 0.5–1.3 hours. The pharmacokinetics of febuxostat were not time dependent (day 14 vs day 1) and remained linear within the 10–120mg dose range, with a mean apparent total clearance of 10–12 L/h and an apparent volume of distribution at steady state of 33–64L. The harmonic mean elimination half-life of febuxostat ranged from 1.3 to 15.8 hours. The increase in the area under the plasma concentration-time curve of febuxostat at doses >120mg appeared to be greater than dose proportional, while the febuxostat maximum plasma drug concentration was dose proportional across all the doses studied. Based on the urinary data, febuxostat appeared to be metabolised via glucuronidation (22–14% of the dose) and oxidation (2–8%) with only 1–6% of the dose being excreted unchanged via the kidneys. Febuxostat resulted in significant decreases in serum and urinary uric acid concentrations and increases in serum and urinary xanthine concentrations. The percentage decrease in serum uric acid concentrations ranged from 27% to 76% (net change: 1.34–3.88 mg/dL) for all doses and was dose linear for the 10–120 mg/day dosage range. The majority of adverse events were mild-to-moderate in intensity.

Conclusion

Febuxostat was well tolerated at once-daily doses of 10–240mg. There appeared to be a linear pharmacokinetic and dose-response (percentage decrease in serum uric acid) relationship for febuxostat dosages within the 10–120mg range. Febuxostat was extensively metabolised and renal function did not seem to play an important role in its elimination from the body.

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Acknowledgements

The authors would like to thank James Kisicki, MD, and Irving Weston, MD, for performing the clinical studies; William Palo, MS, and Galen Witt, MS, for their statistical assistance; Patricia MacDonald, RN, NP, and Christopher Lademacher, MD, for their review of the manuscript; and MDS Pharma Services for performing the bioanalytical sample analyses. The study was funded by TAP Pharmaceutical Products Inc. Part of the results were presented at the 64th and 68th Annual Scientific Conference of American College of Rheumatology and the 11th International and 9th European Symposium on Purines and Pyrimidines in Man.

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Authors and Affiliations

  1. TAP Pharmaceutical Products Inc., Lake Forest, Illinois, USA

    Reza Khosravan, Brian A. Grabowski, Jing-Tao Wu, Nancy Joseph-Ridge & Laurent Vernillet

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  1. Reza Khosravan
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  2. Brian A. Grabowski
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  3. Jing-Tao Wu
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  5. Laurent Vernillet
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Correspondence to Reza Khosravan.

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Khosravan, R., Grabowski, B.A., 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 45, 821–841 (2006). https://doi.org/10.2165/00003088-200645080-00005

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