Concurrent use of proton pump inhibitors or h2 blockers did not adversely affect nilotinib efficacy in patients with chronic myeloid leukemia

The impact of proton pump inhibitors (PPIs) and histamine H2 receptor antagonists (H2 blockers) on the efficacy of nilotinib was evaluated. Retrospective analyses were performed in patients with newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP; N = 492) and in patients with imatinib-resistant or imatinib-intolerant Ph+ CML-CP (N = 256) treated with nilotinib. In the newly diagnosed population, 87 (17.7 %) and 49 (10.0 %) patients received PPIs and H2 blockers, respectively. Major molecular response at 12 months was achieved by 59 (49.6 %) patients who received at least one PPI or H2 blocker (n = 119) and 153 (41.0 %) patients who did not receive any comedication (n = 373; P = 0.13). PPIs and H2 blockers were used by 77 (30.1 %) and 17 (6.6 %) patients with imatinib-resistant or imatinib-intolerant CML-CP, respectively. Major cytogenetic response by 12 months was achieved by 55 (64.0 %) patients who received at least one PPI or H2 blocker (n = 86) versus 98 (57.6 %) patients who did not receive any comedication (n = 170; P = 0.40); 39 (45.3 %) versus 65 (38.2 %), respectively, achieved complete cytogenetic response by 12 months (P = 0.34). Similar findings were observed in patients who received comedication for > 50 % of the time on nilotinib therapy. Nilotinib steady-state trough concentration was not affected by the presence of PPIs or H2 blockers. Concurrent use of PPIs or H2 blockers did not affect the pharmacokinetics and efficacy of nilotinib in patients with Ph+ CML-CP

Concurrent use of proton pump inhibitors or h2 blockers did not adversely affect nilotinib efficacy in patients with chronic myeloid leukemia

The impact of proton pump inhibitors (PPIs) and histamine H2 receptor antagonists (H2 blockers) on the efficacy of nilotinib was evaluated. Retrospective analyses were performed in patients with newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP; N = 492) and in patients with imatinib-resistant or imatinib-intolerant Ph+ CML-CP (N = 256) treated with nilotinib. In the newly diagnosed population, 87 (17.7 %) and 49 (10.0 %) patients received PPIs and H2 blockers, respectively. Major molecular response at 12 months was achieved by 59 (49.6 %) patients who received at least one PPI or H2 blocker (n = 119) and 153 (41.0 %) patients who did not receive any comedication (n = 373; P = 0.13). PPIs and H2 blockers were used by 77 (30.1 %) and 17 (6.6 %) patients with imatinib-resistant or imatinib-intolerant CML-CP, respectively. Major cytogenetic response by 12 months was achieved by 55 (64.0 %) patients who received at least one PPI or H2 blocker (n = 86) versus 98 (57.6 %) patients who did not receive any comedication (n = 170; P = 0.40); 39 (45.3 %) versus 65 (38.2 %), respectively, achieved complete cytogenetic response by 12 months (P = 0.34). Similar findings were observed in patients who received comedication for > 50 % of the time on nilotinib therapy. Nilotinib steady-state trough concentration was not affected by the presence of PPIs or H2 blockers. Concurrent use of PPIs or H2 blockers did not affect the pharmacokinetics and efficacy of nilotinib in patients with Ph+ CML-CP

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

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.Richard A. Larson & Ophelia Q. P. Yin & Andreas Hochhaus & Giuseppe Saglio & Richard E. Clark & Hirohisa Nakamae & Neil J. Gallagher & Eren Demirhan & Timothy P. Hughes & Hagop M. Kantarjian & Philipp D. le Coutr