Nilotinib population pharmacokinetics and exposure-response analysis in patients with imatinib-resistant or -intolerant chronic myeloid leukemia.

PURPOSE: We evaluated the population pharmacokinetics (PK) and exposure-response relationship of nilotinib in patients with imatinib-resistant or -intolerant chronic myeloid leukemia (CML).

METHODS

Concentration data from 493 patients with CML in chronic phase (CML-CP), accelerated phase, or blast crisis were used to perform a population pharmacokinetic analysis using nonlinear mixed-effect modeling. Steady-state nilotinib trough concentrations (Cmin) in individual patients were estimated from the population PK model for correlation with the efficacy and safety variables. Exposure-efficacy analysis was performed in patients with CML-CP, whereas exposure-safety analysis was performed in all patients who had both nilotinib PK data and efficacy/safety measures available.

RESULTS

Baseline demographics and CML disease phase did not significantly affect nilotinib PK. Patients with a lower Cmin had significantly longer time to complete cytogenetic response (P = 0.010), longer time to major molecular response (P = 0.012), shorter time to progression (TTP; P = 0.009), and a trend toward lower response rates vs. patients with higher Cmin. A joint effect of prognostic risk score and Cmin on TTP was significant (P < 0.001). Nilotinib Cmin was also associated with the occurrence of all-grade elevations in total bilirubin (P < 0.001) and lipase (P = 0.002) levels.

CONCLUSIONS

When tolerability allows, adherence to the nilotinib dose (400 mg twice daily) in order to maintain sufficient Cmin is important in maximizing the efficacy of nilotinib in patients with imatinib-resistant or -intolerant CML.