Pharmacokinetic analysis of nilotinib in Chinese chronic myelogenous leukemia (CML) patients (pts) with imatinib-resistant or-intolerant disease in blast crisis (BC), accelerated phase (AP) or chronic phase (CP)

Abstract

18020 Background: Nilotinib, a potent and highly selective inhibitor of BCR-ABL, has been approved in both the US and EU for the treatment of patients with CML-CP and -AP resistant or intolerant to prior therapy including imatinib. It has previously been suggested that Asian patients may require different dosing regimens for TKIs than that normally recommended in Caucasian patients. We report here a pharmacokinetic (PK) analysis of nilotinib in 21 Chinese imatinib resistant or intolerant CML pts. Methods: The Expanding Nilotinib Access in Clinical Trials (ENACT) is an ongoing global study initiated to provide expanded access to nilotinib and to obtain additional safety information in pts with imatinib-resistant or -intolerant CML-CP, -AP, or blast crisis (-BC). In this study, nilotinib was administered at 400 mg twice daily (BID). Pharmacokinetic parameters of nilotinib, including area under the concentration-time curve (AUC), maximum concentration (Cmax), time to reach Cmax (Tmax), trough concentration (Cmin), and ratio of accumulation (RA), were obtained on days 1 and 15. Results: 21 Chinese CML patients were included in this analysis. 76% were male; mean age was 40 y (range, 19–67 y); mean body weight was 68.3 kg (range, 48–90 kg). Cmax of nilotinib occurred between 1–12.05 h after drug administration. Mean Cmax of the first dose of nilotinib was 638 ng/mL and occurred a median of 3h after first administration. After repeat dose of 400mg BID for 15 days, mean Cmax was 2161 ng/mL and a Cmin of 1743 ng/mL was reached. Mean AUC was 5076.32 ng·hr/mL on day 1 and 17751.30 ng·hr/mL on day 15. Thus, the steady-state serum level of nilotinib was more than 3 times the level measured after the first dose. The steady-state mean Cmax and AUC values observed in this study were comparable to those observed in previous studies with CML patients from other ethnic groups (Cmax=2260 ng/mL and AUC=18000 ng·hr/mL). The adverse event profile in this cohort was similar to that reported for the pivotal phase I/II registration study. Conclusions: The recommended nilotinib dosing of 400 mg BID is appropriate and well tolerated for Chinese patients with CML. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis