Pharmacokinetics of Nilotinib in Subjects with Normal or Impaired Hepatic Function.

Nilotinib, a selective and potent inhibitor of Bcr-Abl tyrosine kinase, has demonstrated activity at 400 mg twice daily dosing against imatinib-resistant forms of Bcr-Abl in patients with CML or Ph+ALL in an open label phase I/II study. In this patient population, elevated liver transaminases levels over baseline, which may be related to a combination of past medical history and the hepatotoxic effects of previous medications, are frequently observed but are generally mild and self-limiting. Nilotinib is metabolized in the liver by CYP3A4, and the metabolites are excreted exclusively via the bile into feces. This study was designed to assess pharmacokinetics of nilotinib across a broad spectrum of hepatic impairment in comparison to a control group with normal hepatic function in order to provide guidance for the safe use of the drug in patients with hepatic impairment. Hepatic impairment was categorized using the three Child-Pugh categories (mild, moderate, and severe). The demographics of the impaired and control group were similar with respect to ethnicity, age (years) impaired (47–64) control (48–62), BMI (kg/m2) impaired (23.6–34.7) control (22.8–32.0), and weight (kg) impaired (73.9–103.9) control (73.3–109.5). Serum samples for determination of nilotinib serum concentration by liquid chromatography tandem mass spectrometry were collected up to 120 hours following a single oral 200 mg dose of nilotinib after an overnight fast. Pharmacokinetic parameters were derived from the individual serum concentration-time data by non-compartmental methods. Pre-dose (nilotinib-free) serum samples were obtained to determine ex vivo nilotinib serum protein binding. The results from 14 subjects (6 subjects in each of the mildly and moderately impaired groups and 8 in the control group) in this ongoing study are reported here. Nilotinib exposure at 200 mg dose was similar in patients from a previous clinical study and subjects in the control group of this study. Nilotinib AUC was increased on average by 18% in the mild impairment group, and 23% in the moderate impairment group as compared to the control group. A total of 6 grade 1 and 2 adverse events were reported comprising of back pain, worsening abdominal pain, headache, nausea, heart burn, and indigestion. One adverse event (grade 2 worsening back pain) was reported in the control group. No laboratory or cardiac monitoring findings were considered as adverse events during the treatment period. The currently available results suggest that the pharmacokinetic profile of nilotinib is comparable between subjects with normal hepatic function and subjects with mild or moderate hepatic impairment.