Abstract 2770: An open-label comparative study of the pharmacokinetics and tolerability of zibotentan (ZD4054) in subjects with mild, moderate, or severe hepatic impairment, or normal hepatic function
Authors: Kemp John , Tomkinson Helen , Taboada Maria , Cieslarová Blanka , Oliver Stuart , Morris Thomas 
Published: February 2011

Zibotentan (ZD4054) is a small-molecule, specific endothelin A (ETA) receptor antagonist being investigated for the treatment of hormone-resistant prostate cancer. Zibotentan is eliminated by both renal (58%) and metabolic clearance. The current study investigated whether hepatic impairment has a clinically relevant effect on exposure to zibotentan.

This open-label, two-centre study investigated the PK and tolerability of zibotentan in subjects with hepatic impairment, compared with subjects with normal hepatic function. Subjects were divided into four categories using the Child-Pugh (CP) classification: mild hepatic impairment (CP A), moderate hepatic impairment (CP B), severe hepatic impairment (CP C) and normal hepatic function. Each subject received a single oral dose of zibotentan 10 mg. AUC and Cmax are expressed as the ratio (R) of geometric means and 90% confidence intervals (CI) for each hepatic impairment group compared with the normal function group. The possibility that hepatic impairment had a clinically relevant effect on exposure of zibotentan was considered if the upper 90% CI for the ratio exceeded two. Thirty-seven subjects were enrolled and 32 subjects (eight per group) received zibotentan and completed the study. Compared with the normal function group, zibotentan Cmax was 7% (R 0.93; 90% CI 0.75-1.15), 11% (R 0.89; 90% CI 0.72-1.1) and 5% (R 0.95; 90% CI 0.77-1.17) lower in subjects with CP A, CP B and CP C hepatic impairment, respectively. Zibotentan AUC was 40% (R 1.40; 90% CI 0.91-2.17), 45% (R 1.45; 90% CI 0.94-2.24) and 190% (R 2.90; 90% CI 1.88-4.49) higher in subjects with CP A, CP B and CP C hepatic impairment, respectively, compared with those with normal function. Mean t½ was 9.28 h, 13.0 h, 14.6 h and 24.8 h for the normal function, CP A, CP B and CP C hepatic impairment groups, respectively. Compared with the normal function group, CL/F was approximately 25%, 29% and 64% lower, respectively, in the CP A, CP B and CP C hepatic impairment groups. Zibotentan was well tolerated by all subjects, with headache (CTC Grade 1-2) being the most common adverse event in each group. Despite increased exposure to zibotentan with increased hepatic impairment, there were no differences in the type or severity of adverse events.

In conclusion, following a single oral dose of zibotentan 10 mg, there was no significant difference in Cmax with degree of hepatic impairment, indicating that hepatic impairment did not affect the absorption of zibotentan. AUC was higher and t½ longer in subjects with hepatic impairment than in those with normal function due to the slower clearance of zibotentan, with the extent of the difference being related to the degree of impairment. Trial sponsored by AstraZeneca (NCT00672581; AZ code D4320C00025).

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2770.