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Population pharmacokinetic analysis of intravenous busulfan: GSTA1 genotype is not a predictive factor of initial dose in Chinese adult patients undergoing hematopoietic stem cell transplantation

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Abstract

Purpose

This study aimed to develop a population pharmacokinetic (PPK) model to investigate the impact of GSTA1, GSTP1, and GSTM1 genotypes on busulfan pharmacokinetic (PK) variability in Chinese adult patients.

Methods

Forty-three and 19 adult patients who underwent hematopoietic stem cell transplantation (HSCT) were enrolled for modeling group and validation group, respectively. All patients received twice-daily intravenous busulfan as part of conditioning regimen before HSCT. The PPK model was developed by nonlinear mixed-effect modeling. Covariates investigated were age, sex, actual body weight, body surface area, diagnoses, hepatic function markers, GST genotypes and conditioning regimen.

Results

A total of 488 busulfan concentrations from 43 patients were obtained for the PPK model. The PK of intravenous busulfan was described by one-compartment model with first-order elimination with estimated clearance (CL) of 14.2 L/h and volume of distribution of 64.1 L. Inclusion of GSTA1 genotype as a covariate accounted for 1.1% of the inter-individual variability of busulfan CL (from 17.8% in the basic model to 16.7% in the final model). The accuracy and applicability of the final model were externally validated in the independent group. The difference of busulfan PK between Chinese patients and Caucasian patients existed because of the rarity of haplotype *B in Chinese population.

Conclusions

Although the GSTA1 genotype-based PPK model of intravenous busulfan was successfully developed and externally validated, the GSTA1 genotype was not considered to be clinically relevant to busulfan CL. We did not suggest the guidance of GSTA1 genotype on initial busulfan dose in Chinese adult patients.

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Acknowledgments

The authors thank the staff of the Department of Bone Marrow Transplantation, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, for their collaboration and the use of their facilities.

Funding

This work was funded by the National Natural Science Foundation in China (Grant No. 81503137).

Author information

Author notes

  1. Yidan Sun and Jingjing Huang contributed equally to this work.

Authors and Affiliations

  1. Department of Bone Marrow Transplantation, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No.197 Ruijin Er Road, Shanghai, 20025, China

    Yidan Sun & Jiong Hu

  2. Department of Pharmacy, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

    Jingjing Huang, Chenxia Hao, Weixia Zhang, Bing Chen & Wanhua Yang

  3. Shanghai Jiaotong University School of Medicine, Shanghai, China

    Ziwei Li

  4. NeoTrident Co. Ltd., Beijing, China

    Wu Liang

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  1. Yidan Sun
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Contributions

Jiong Hu and Wanhua Yang were in charge of the entire project and reviewed the manuscript. Yidan Sun designed the study and wrote the manuscript. Jingjing Huang performed the study and wrote the manuscript. Chenxia Hao, Ziwei Li, and Wu Liang analyzed the data and interpreted the results. Weixia Zhang and Bing Chen provided the reagents and materials.

Corresponding author

Correspondence to Jiong Hu.

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Conflict of interest

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethical approval

The study protocol was approved by the Ruijin Hospital Research Ethics Committee.

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Supplementary material 1 Figure S1 The histogram and the quantile–quantile (Q–Q) plot of conditional weighted residuals (CWRES) (TIFF 341 kb)

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Sun, Y., Huang, J., Hao, C. et al. Population pharmacokinetic analysis of intravenous busulfan: GSTA1 genotype is not a predictive factor of initial dose in Chinese adult patients undergoing hematopoietic stem cell transplantation. Cancer Chemother Pharmacol 85, 293–308 (2020). https://doi.org/10.1007/s00280-019-04001-2

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