title: The effects of liver impairment on the pharmacokinetics of brivanib, a dual inhibitor of fibroblast growth factor receptor and vascular endothelial growth factor receptor tyrosine kinases.
abstract: OBJECTIVE
  Hepatic impairment may impede tyrosine kinase inhibitor metabolism. This phase I study compared the pharmacokinetics of brivanib in patients with hepatocellular carcinoma (HCC) and varying levels of hepatic impairment with those with non-HCC malignancies and normal liver function.
  
  
  METHODS
  Patients were assigned to the following groups: Groups A, B, and C (HCC plus mild, moderate, or severe hepatic impairment, respectively) and Group D (non-HCC malignancy and normal hepatic function). Brivanib alaninate (brivanib prodrug) doses were 400 mg in Groups A, B, and D and 200 mg in Group C. Brivanib exposure was determined on day 1 (single dose) and day 28 (multiple doses).
  
  
  RESULTS
  Twenty-four patients participated in the study. After a single brivanib alaninate dose, brivanib exposure was comparable between Groups A, B, and D. Area under the concentration-time curve was 50 % higher in Group C versus Group D. There were not enough data to draw conclusions on multiple doses. Safety profile in Groups A, B, and D was consistent with previous brivanib monotherapy experience. Tolerability could not be assessed in Group C because of dose interruptions and discontinuations, generally due to the disease natural history.
  
  
  CONCLUSIONS
  Brivanib exposure was similar in patients with HCC and mild or moderate hepatic impairment (Child-Pugh [CP] A or B status) and those with non-HCC malignancies and normal hepatic function, suggesting dose adjustment is unnecessary with CP A or B status. Experience with HCC and severe hepatic impairment (CP C status) is insufficient to recommend brivanib use in this population.
authors.affiliation: USC Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA. elkhouei@usc.edu
authors.forename: Anthony
authors.initials: A
authors.lastname: El-Khoueiry
authors.forename: James A
authors.initials: JA
authors.lastname: Posey
authors.forename: Juan Ramón
authors.initials: JR
authors.lastname: Castillo Ferrando
authors.forename: Smitha S
authors.initials: SS
authors.lastname: Krishnamurthi
authors.forename: Shariq
authors.initials: S
authors.lastname: Syed
authors.forename: Georgia
authors.initials: G
authors.lastname: Kollia
authors.forename: Ian
authors.initials: I
authors.lastname: Walters
authors.forename: Bruce S
authors.initials: BS
authors.lastname: Fischer
authors.forename: Eric
authors.initials: E
authors.lastname: Masson
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000409:Alanine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D048550:Hepatic Insufficiency / Q000097:blood / Q000150:complications* / Q000209:etiology / Q000503:physiopathology; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D008113:Liver Neoplasms / Q000097:blood / Q000150:complications / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D010352:Patient Dropouts; D011355:Prodrugs / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D012720:Severity of Illness Index; D014227:Triazines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D011355:Prodrugs; D047428:Protein Kinase Inhibitors; D017468:Receptors, Fibroblast Growth Factor; D014227:Triazines; C509922:brivanib; D040262:Receptors, Vascular Endothelial Growth Factor; D000409:Alanine