title: Single- and multiple-dose pharmacokinetics, safety and tolerability of zibotentan (ZD4054) in Chinese men with advanced solid tumors.
abstract: OBJECTIVE
  The endothelin axis and the endothelin A (ET(A)) receptor have been implicated in tumor development and bone metastasis. This study aimed to investigate the pharmacokinetic (PK) and safety profiles of the specific ET(A) receptor antagonist, zibotentan, in elderly, male Chinese patients with advanced solid tumors. The PK data generated in these Chinese patients were further compared with those previously reported in Japanese and Caucasian patient populations.
  
  
  METHODS
  In this Phase I, open-label study, patients received a single dose of zibotentan 10 mg on Day 1, followed by a 72-h washout period and 12 consecutive days of once-daily zibotentan 10 mg.
  
  
  RESULTS
  Fifteen patients received at least one dose of zibotentan 10 mg. Exposure was demonstrated in all patients and the PK profiles following single dosing and multiple dosing showed relatively rapid absorption, decline in a monophasic manner, a modest amount of accumulation, and relatively low apparent clearance and volume of distribution. Zibotentan was well tolerated with no new safety concerns. Adverse events reported in >1 patient were pyrexia (n = 4), constipation (n = 3), headache (n = 3) and peripheral edema (n = 2). Comparative analysis found no evidence of significant differences in zibotentan exposure between the Chinese patients in our study, and the previous Japanese and Caucasian studies.
  
  
  CONCLUSIONS
  The PK and safety profiles of zibotentan determined in this Chinese patient population are similar to those previously reported. Our findings suggest no clinically relevant inter-ethnic differences in zibotentan disposition between the patient populations analyzed.
authors.affiliation: Department of Medical Oncology, Fudan University Cancer Hospital, 270 Dong'an Road, Shanghai 200232, China. fudanlijin@163.com
authors.forename: Jin
authors.initials: J
authors.lastname: Li
authors.forename: Yanfei
authors.initials: Y
authors.lastname: Liu
authors.forename: Jun
authors.initials: J
authors.lastname: Qian
authors.forename: Lennie
authors.initials: L
authors.lastname: Wu
authors.forename: John
authors.initials: J
authors.lastname: Kemp
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nii
authors.forename: Helen
authors.initials: H
authors.lastname: Tomkinson
authors.forename: Yunxia
authors.initials: Y
authors.lastname: Zuo
authors.forename: Malcolm
authors.initials: M
authors.lastname: Ranson
authors.forename: Michiyuki
authors.initials: M
authors.lastname: Usami
mesh_terms: D000368:Aged; D019540:Area Under Curve; D044466:Asian People; D002681:China; D003248:Constipation / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005334:Fever / Q000139:chemically induced; D006261:Headache / Q000139:chemically induced; D006801:Humans; D007408:Intestinal Absorption; D007564:Japan; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000208:ethnology / Q000473:pathology; D011759:Pyrrolidines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D044465:White People
chemical_list: D011759:Pyrrolidines; C511404:ZD4054