Population pharmacokinetic (PK) and exposure-response analysis of nilotinib in newly diagnosed Ph+ chronic myeloid leukemia in chronic phase: Results from ENESTnd.

Abstract

6556 Background: Results from ENESTnd at 12 months (mo) demonstrated superior efficacy of nilotinib at both 300 mg BID and 400 mg BID doses over imatinib 400 mg QD. Methods: Full PK profiles of nilotinib were obtained at steady state from a subgroup of 34 pts, and sparse (pre-dose/Cmin and 3 hr post-dose/Cmax) concentration data were obtained over 12 mo from 542/563 treated pts. Results: Nilotinib concentrations were stable over 12 mo in both arms (Cmin: 1,158 ± 568 ng/mL [median 1,097 ng/mL] for 300 mg BID; 1,340 ± 621 ng/mL [median 1,217 ng/mL] for 400 mg BID). The average nilotinib Cmin and Cmax were 15.7% and 14.8% higher in the 400 mg BID arm than the 300 mg BID arm. Estimated relative bioavailability ratio was 0.84 for nilotinib 400 mg BID to 300 mg BID. Gender was a statistically significant covariate for nilotinib bioavailability: male pts had 10% lower bioavailability and systemic exposure than females, although this difference is not clinically meaningful. Age, body weight, ethnicity, and racial group did not significantly affect nilotinib PK. Total bilirubin elevation was higher in pts with higher nilotinib concentrations. For example, pts with nilotinib Cmin in quartiles Q1 (< 829 ng/mL, n = 113), Q2/3 (≥ 829 and ≤ 1,569 ng/mL, n = 229) and Q4 (> 1,569 ng/mL, n = 113), 0.9%, 4.8% and 7.1%, respectively, had grade 3/4 bilirubin elevation. Logistic regression confirmed a significant correlation between nilotinib daily AUC and total bilirubin. There was little evidence for a correlation between nilotinib exposure and elevation in AST or lipase. On average, an increase of 1000 ng/mL in nilotinib serum concentrations was associated with minimal increase in QTcF (4.2 to 6.9 msec). Although no relationship was observed for MMR at 12 mo with average nilotinib Cmin, there was a positive correlation with BCR-ABL transcript level reductions at 12 mo with nilotinib Cmin. Conclusions: There is a less than proportional dose-exposure relationship between nilotinib 300 mg BID and 400 mg BID. Exposure was stable over the 12 mo treatment course at both doses. Demographics were not a clinically important factor affecting nilotinib PK. The study is ongoing and additional PK data will be available. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Bristol-Myers Squibb, Merck, Novartis Novartis Bristol-Myers Squibb, Merck, Novartis Bristol-Myers Squibb, Genzyme, Novartis The Royal Collage of Pathologists