Department of Bone Marrow Transplantation, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No.197 Ruijin Er Road, Shanghai, 20025, China.
Department of Pharmacy, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Cancer Chemother Pharmacol. 2020 Feb;85(2):293-308. doi: 10.1007/s00280-019-04001-2. Epub 2019 Dec 13.
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.
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.
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.
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.
本研究旨在建立群体药代动力学（PPK）模型，以研究 GSTA1、GSTP1 和 GSTM1 基因型对中国成年患者接受造血干细胞移植（HSCT）前接受静脉用白消安的药代动力学（PK）变异性的影响。
本研究纳入 43 名和 19 名接受 HSCT 的成年患者，分别用于模型建立组和验证组。所有患者在 HSCT 前接受两次每日静脉注射白消安作为预处理方案的一部分。通过非线性混合效应模型建立 PPK 模型。考察的协变量包括年龄、性别、实际体重、体表面积、诊断、肝功能标志物、GST 基因型和预处理方案。
从 43 名患者中获得了 488 次静脉用白消安浓度，用于 PPK 模型。静脉用白消安的 PK 采用一室模型和一级消除动力学描述，估计的清除率（CL）为 14.2 L/h，分布容积为 64.1 L。将 GSTA1 基因型作为协变量纳入后，白消安 CL 的个体间变异性占 1.1%（从基础模型的 17.8%降至最终模型的 16.7%）。该最终模型在独立组中进行了外部验证，结果显示其准确性和适用性良好。由于 GSTA1 基因型 *B 在中国人中的罕见性，导致中国患者与高加索患者的白消安 PK 存在差异。
虽然成功建立并外部验证了静脉用白消安的基于 GSTA1 基因型的 PPK 模型，但 GSTA1 基因型被认为与白消安 CL 无临床相关性。我们不建议在中国成年患者中根据 GSTA1 基因型来指导初始白消安剂量。
