Evaluation of the pharmacokinetics and safety of bosutinib in patients with chronic hepatic impairment and matched healthy subjects.
OBJECTIVE
Bosutinib, a dual Src/Abl kinase inhibitor in development for treatment of chronic myeloid leukemia, is primarily metabolized by the CYP3A4 hepatic enzyme. This study evaluated the pharmacokinetics and safety of bosutinib in patients with chronic hepatic impairment and matched healthy subjects.


METHODS
Hepatically impaired patients were aged 18-65 years and of Child-Pugh classes A, B, or C; healthy subjects were matched by age, sex, body mass index, and smoking habits. A single oral dose of bosutinib 200 mg was administered on day 1 within 5 min after completion of breakfast.


RESULTS
Compared with healthy subjects (n = 9), maximal plasma concentration (C(max)) and area under the curve increased 2.42-fold and 2.25-fold in Child-Pugh A (n = 6), 1.99-fold and 2.0-fold in Child-Pugh B (n = 6), and 1.52-fold and 1.91-fold in Child-Pugh C patients (n = 6). Time to C(max) decreased from 4 h in healthy subjects to 2.5, 2.0, and 1.5 h in Child-Pugh A, B, and C patients, respectively; the elimination half-life increased from 55 h in healthy subjects to 86, 113, and 111 h in Child-Pugh A, B, and C patients. Bosutinib oral clearance was lower in hepatically impaired patients compared with healthy subjects. Frequently reported adverse events included prolonged QTc interval (37.0%, n = 10), nausea (11.1%, n = 3), and vomiting (7.4%, n = 2).


CONCLUSIONS
A single oral dose of bosutinib 200 mg showed acceptable tolerability in healthy subjects and in patients with mild, moderate, or severe chronic hepatic impairment.
Department of Clinical Pharmacology, Pfizer Inc, Collegeville, PA 19426, USA. richat.abbas-borhan@pfizer.com
Richat
R
Abbas
Stephan
S
Chalon
Cathie
C
Leister
Myriam
M
El Gaaloul
Daryl
D
Sonnichsen
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000814:Aniline Compounds / Q000009:adverse effects / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D016022:Case-Control Studies; D002908:Chronic Disease; D005260:Female; D006207:Half-Life; D006801:Humans; D008107:Liver Diseases / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D009570:Nitriles / Q000009:adverse effects / Q000493:pharmacokinetics*; D011804:Quinolines / Q000009:adverse effects / Q000493:pharmacokinetics*; D013997:Time Factors
D000814:Aniline Compounds; D000970:Antineoplastic Agents; D009570:Nitriles; D011804:Quinolines; C471992:bosutinib