Pharmacokinetic and tolerability profile of once-daily zibotentan (ZD4054) in Japanese and Caucasian patients with hormone-resistant prostate cancer

M. Ranson, R. H. Wilson, J. M. O'Sullivan, M. Maruoka, A. Yamaguchi, R. A. Cowan, J. P. Logue, H. Tomkinson, N. Tominaga, H. Swaisland, S. Oliver, M. Usami

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Objective: To investigate potential differences in zibotentan pharmacokinetics between Japanese and Caucasian patients with hormone-resistant prostate cancer (HRPC) following single and multiple dosing. Methods: In the Japanese study, 18 patients received a single dose of zibotentan 5, 10 or 15 mg followed by 72 h washout before 26 days' once-daily dosing. In the Caucasian study, 21 patients received a single dose of zibotentan 5, 10 or 15 mg followed by 72 h washout before 12 days' once-daily dosing. Results: Pharmacokinetic parameters were similar between populations. Absorption of zibotentan was rapid with maximum plasma concentrations typically achieved within 3 h of dosing. Mean clearance, 17.9 and 18.7 ml/min in Japanese and Caucasian patients, respectively (range 7.0-36.3 ml/min in Japanese patients and 7.8-29.5 ml/min in Caucasian patients) and volume of distribution, 14.0 and 15.6 l for Japanese and Caucasian patients, respectively (range 7.9-29.1 l in Japanese patients and 9.6-23.8 l in Caucasian patients) were relatively low, and t1/2 was approximately 12 h (range 5.7-18.8 h in Japanese patients and 5.0-22.9 h in Caucasian patients) following single dosing. Little accumulation was observed following daily dosing and multiple-dose pharmacokinetics were predictable. Exposure levels achieved in some Japanese patients receiving zibotentan 15 mg were higher than those observed in Caucasian patients, however, this may be due to differences in body weight, as exposure levels were similar when data were normalized for body weight. Zibotentan was well tolerated in both populations. Conclusions: There are no clinically relevant differences in the disposition and pharmacokinetics of zibotentan between Japanese and Caucasian patients with HRPC. ©2010 Dustri-Verlag Dr. K. Feistle.
    Original languageEnglish
    Pages (from-to)708-717
    Number of pages9
    JournalInternational Journal of Clinical Pharmacology and Therapeutics
    Volume48
    Issue number11
    DOIs
    Publication statusPublished - Nov 2010

    Keywords

    • Caucasian
    • Japanese
    • Pharmacokinetics
    • Prostate cancer
    • Zibotentan

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