title: Pharmacokinetics and tolerability of zibotentan (ZD4054) in subjects with hepatic or renal impairment: two open-label comparative studies.
abstract: BACKGROUND
  Zibotentan (ZD4054) is a specific endothelin A (ETA) receptor antagonist being investigated for the treatment of prostate cancer. As zibotentan is eliminated by renal and metabolic routes, clearance may be reduced in patients with hepatic or renal impairment, leading to greater drug exposure.
  
  
  METHODS
  Open-label studies investigated the PK and tolerability of zibotentan in subjects with hepatic or renal impairment, compared with those with normal organ function. In the hepatic and renal studies, respectively, subjects were divided into categories using Child-Pugh classification or 24-hour urine creatinine clearance (mild, moderate, or severe impairment and normal function). Each subject received a single oral dose of zibotentan 10 mg and PK sampling was undertaken. Within the hepatic study, AUC and Cmax were expressed as the ratio of geometric means and 90% CI for each impairment group compared with the normal function group. The possibility that hepatic impairment had a clinically relevant effect on exposure was considered if the upper 90% CI for the ratio exceeded 2. In the renal study, AUC, Cmax and t1/2 were analyzed using linear regression fitting effects for creatinine clearance and age.
  
  
  RESULTS
  In the hepatic and renal studies respectively, 32 subjects (eight per group) and 48 subjects received treatment (n = 18 normal, n = 12 mild, n = 9 moderate, n = 9 severe). Zibotentan Cmax was not significantly affected by hepatic or renal impairment. Compared with the normal function group, zibotentan AUC was 40% (1.40; 90% CI 0.91-2.17), 45% (1.45; 90% CI 0.94-2.24) and 190% (2.90; 90% CI 1.88-4.49) higher in subjects with mild, moderate and severe hepatic impairment, respectively, and 66% (1.66; 90% CI 1.38-1.99), 89% (1.89; 90% CI 1.50-2.39) and 117% (2.17; 90% CI 1.64-2.86) higher in subjects with mild, moderate and severe renal impairment, respectively. In both studies mean t1/2 increased and zibotentan clearance decreased with the degree of impairment. Headache was the most common AE in all groups.
  
  
  CONCLUSIONS
  Zibotentan absorption was unchanged, however, exposure was higher in subjects with hepatic or renal impairment due to slower clearance. This increased exposure did not result in differences in the range or severity of AEs observed.
  
  
  BACKGROUND
  ClinicalTrials.gov: NCT00672581 and AstraZeneca study number D4320C00016 (renal trial; conducted in Germany).
authors.affiliation: AstraZeneca, Alderley Park, Macclesfield, UK. helen.tomkinson@astrazeneca.com
authors.forename: Helen
authors.initials: H
authors.lastname: Tomkinson
authors.forename: John
authors.initials: J
authors.lastname: Kemp
authors.forename: Stuart
authors.initials: S
authors.lastname: Oliver
authors.forename: Helen
authors.initials: H
authors.lastname: Swaisland
authors.forename: Maria
authors.initials: M
authors.lastname: Taboada
authors.forename: Thomas
authors.initials: T
authors.lastname: Morris
mesh_terms: D000284:Administration, Oral; D019540:Area Under Curve; D003404:Creatinine / Q000652:urine; D005260:Female; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008107:Liver Diseases / Q000097:blood / Q000378:metabolism* / Q000652:urine; D008297:Male; D008875:Middle Aged; D011759:Pyrrolidines / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D051437:Renal Insufficiency / Q000097:blood / Q000378:metabolism* / Q000652:urine
chemical_list: D011759:Pyrrolidines; C511404:ZD4054; D003404:Creatinine