Population pharmacokinetic and exposure-response analysis of nilotinib in patients with newly diagnosed Ph+ chronic myeloid leukemia in chronic phase

Abstract

Purpose: We investigated the population pharmacokinetics and exposure-response relationship of nilotinib in patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase.

Methods: Nilotinib was given at 300 mg or 400 mg twice daily. Serum concentration data (sparse and full pharmacokinetic profiles) were obtained from 542 patients over 12 months. A population pharmacokinetic analysis was performed using nonlinear mixed-effect modeling. Exposure-response relationships were explored graphically or using logistic regression models.

Results: Nilotinib concentrations were stable over 12 months. Patients in the 400 mg twice-daily arm had an 11.5% higher exposure than did those in the 300 mg twice-daily arm, and the relative bioavailability of nilotinib 400 mg twice daily was 0.84 times that of 300 mg twice daily. Patient demographics did not significantly affect nilotinib pharmacokinetics. The occurrence of all-grade total bilirubin elevation was significantly higher in patients with higher nilotinib exposure, and a positive correlation was also observed between nilotinib exposure and QTcF change on electrocardiograms from baseline. There was no significant relationship between nilotinib exposure and major molecular response at 12 months.

Conclusions: There is a less than proportional dose-exposure relationship between nilotinib 300 mg and 400 mg twice-daily doses. Blood level testing is unlikely to play an important role in the general management of patients with newly diagnosed CML treated with nilotinib.

Trial registration: ClinicalTrials.gov NCT00471497.

Conflict of interest statement

Conflicts of interest: Dr Larson received research support, honoraria, and consulting fees from Novartis; Dr Yin is an employee and stock holder of Novartis; Dr Hochhaus has received research support, honoraria, and consulting fees from Novartis and Bristol-Myers Squibb; Dr Saglio has received honoraria and consulting fees from Novartis and Bristol-Myers Squibb; Dr Clark has received research support, honoraria, and consulting fees from Novartis; Dr Nakamae has received honoraria from Novartis and Bristol-Myers Squibb; Dr Gallagher is a Novartis employee and stock holder; Dr. Eren Demirhan is a Novartis employee; Dr Hughes has received research support, honoraria, and consulting fees from Novartis and Bristol-Myers Squibb; Dr Kantarjian has received research support and consulting fees from Novartis; and Dr le Coutre has received research support and honoraria from Novartis and consulting fees from Novartis and Bristol-Myers Squibb.

Figures

Fig. 1. Mean serum concentration-time profiles of nilotinib obtained at steady state in the full PK cohort

Fig. 2. Nilotinib Cmin (a) and Cmax (b) over time in the 300 mg twice-daily and 400 mg twice-daily arms

Fig. 3

Goodness-of-fit plots for the population PK model: observed concentrations versus population (a) and individual (b) predictions. Values <1 (including observed values reported below LLOQ) are plotted at 1.0. The line of identity is plotted as a reference

Fig. 4. All grade and grade 3/4 reductions in hemoglobin, absolute neutrophils, and platelets (a) and in blood chemistry elevations (b) according to nilotinib Cmin

Fig. 5. QTcF change from baseline according to nilotinib Cmax at days 8 (a) and 84 (b) and according to nilotinib Cmin at days 8 (c) and 84 (d)