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

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Abstract

Aims

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.

Methods

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.

Results

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.

Conclusions

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.

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Data availability

The datasets analysed during the current study are available from the corresponding author upon reasonable request.

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Funding

This work was supported by the Beijing Municipal Natural Science Foundation (grant number 7192218).

Author information

Authors and Affiliations

  1. Department of Pharmacy, Peking University People’s Hospital, No. 11 Xizhimen South StreetXicheng District, Beijing, 100044, China

    Shiyu He, Jinxia Zhao, Jialu Bian, Yinyu Zhao, Yuanyuan Li, Nan Guo, Lei Hu, Boyu Liu, Qianhang Shao & Lin Huang

  2. Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University, Beijing, China

    Shiyu He, Jinxia Zhao, Jialu Bian & Yinyu Zhao

  3. Department of Pharmacy, Beijing Children’s Hospital of Capital Medical University, Beijing, China

    Huan He

  4. Peking University People’s Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, No. 11 Xizhimen South StreetXicheng District, Beijing, 100044, China

    Qian Jiang

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  1. Shiyu He
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  2. Jinxia Zhao
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  10. Huan He
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  11. Lin Huang
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Corresponding authors

Correspondence to Lin Huang or Qian Jiang.

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Ethics approval

This study was conducted following the Declaration of Helsinki, and the protocol was approved by the Ethics Committee of the People’s Hospital of Peking University (2022PHB095-001).

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Informed consent was obtained from all individual participants included in the study.

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All authors declare no conflicts of interest.

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He, S., Zhao, J., Bian, J. et al. Population Pharmacokinetics and Pharmacogenetics Analyses of Dasatinib in Chinese Patients with Chronic Myeloid Leukemia. Pharm Res 40, 2413–2422 (2023). https://doi.org/10.1007/s11095-023-03603-z

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  • DOI: https://doi.org/10.1007/s11095-023-03603-z

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