Effects of hepatic impairment on the pharmacokinetics of nilotinib: An open-label, single-dose, parallel-group study

Abstract Background: Nilotinib is a second-generation BCR-ABL tyrosine kinase inhibitor approved for the treatment of patients who have imatinib-resistant Philadelphia chromosome-positive chronic myeloid leukemia in the chronic or accelerated phase or who are unable to tolerate imatinib. Nilotinib is metabolized in the liver via oxidation and hydroxylation pathways, mediated primarily by the cytochrome P450 3A4 isozyme. Interpatient variability in systemic exposure to nilotinib has been reported to range from 32% to 64%. Objective: This study compared the pharmacokinetics of nilotinib in subjects with hepatic impairment and subjects with normal hepatic function. Methods: Hepatic impairment was classified as mild (Child-Pugh grade A), moderate (Child-Pugh grade B), or severe (Child-Pugh grade C). Healthy control subjects were matched with hepatically impaired subjects by age (±10 years) and body weight (±20%). All subjects received a single oral dose of nilotinib 200 mg under fasted conditions, and serial blood samples were collected at specific times up to 120 hours after dosing. Serum nilotinib concentrations were measured using a validated LC-MS/MS assay with a lower limit of quantification of 2.5 ng/mL. The pharmacokinetic parameters analyzed were Cmax , Tmax , AUC0−last , AUC0−∞ , t½ , CL/F, and Vz/F. Tolerability assessments included adverse events (AEs), regular monitoring of clinical laboratory measures (eg, hematology, blood chemistry, urinalysis), physical examinations, vital signs, and ECGs. Each AE was evaluated in terms of its clinical significance, severity, duration, relation to study drug, and action taken. Results: The study enrolled 18 subjects with hepatic impairment (all male; age range, 47–67 years; weight range, 73.9–103.9 kg) and 9 healthy controls (all male; age range, 36–62 years; weight range, 73.3–109.5 kg). Among subjects with hepatic impairment, 6 had mild impairment, 6 moderate impairment, and 6 severe impairment. The nilotinib AUC0−∞ was a mean of 35%, 35%, and 19% higher in subjects with mild, moderate, and severe impairment, respectively, compared with healthy controls. The nilotinib CL/F was lower in all hepatic-impairment groups compared with healthy controls. The mean (SD) t½ was 15.1 (4.97) and 16.0 (9.13) hours in the mild-impairment and control groups, respectively, but was 21.6 (7.77) and 32.4 (10.7) hours in the moderate- and severe-impairment groups, respectively, reflecting the decrease in CL/F and/or increase in V