Population Pharmacokinetics and Pharmacogenetics Analyses of Dasatinib in Chinese Patients with Chronic Myeloid Leukemia.

Abstract

Dasatinib, a second-generation tyrosine kinase inhibitor of BCR-ABL 1, used for first-line treatment of Philadelphia chromosome-positive chronic myeloid leukemia (CML), exhibits high pharmacokinetic (PK) variability. However, its PK data in Chinese patients with CML remains rarely reported to date. Thus, we developed a population pharmacokinetic (PPK) model of dasatinib in Chinese patients and identified the covariate that could explain the individual variability of PK for optimal individual administration. PPK modeling for dasatinib was performed based on 754 plasma concentrations obtained from 140 CML patients and analysis of various genetic and physicochemical parameters. Modeling was performed with nonlinear mixed-effects (NLME) using Phoenix NLME. The finally developed model was evaluated using internal and external validation. Monte Carlo simulations were used to predict drug exposures at a steady state for various dosages. The PK of dasatinib were well described by a two-compartment with a log-additive residual error model. Patients in the current study had a relatively low estimate of CL/F (126 L/h). A significant association was found between the covariate of age and CL/F of dasatinib, which was incorporated into the final model. None of the genetic factors was confirmed as a significant covariate for dasatinib. The results of external validation with 140 samples from 36 patients were acceptable. Simulation results showed significantly higher exposures in elderly patients. This study's findings suggested that low-dose dasatinib would be better suited for Chinese patients, and the dosage can be appropriately reduced according to the increase of age, especially for the elderly.