Yidan Sun1, Jingjing Huang2, Chenxia Hao2, Ziwei Li3, Wu Liang4, Weixia Zhang2, Bing Chen2, Wanhua Yang2, Jiong Hu5. 1. Department of Bone Marrow Transplantation, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No.197 Ruijin Er Road, Shanghai, 20025, China. 2. Department of Pharmacy, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. 3. Shanghai Jiaotong University School of Medicine, Shanghai, China. 4. NeoTrident Co. Ltd., Beijing, China. 5. Department of Bone Marrow Transplantation, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No.197 Ruijin Er Road, Shanghai, 20025, China. hujiong@medmail.com.cn.
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.
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.
Entities:
Keywords:
Adult; Busulfan; GSTA1; Polymorphism; Population pharmacokinetic
Authors: A M Bolinger; A B Zangwill; J T Slattery; D Glidden; K DeSantes; L Heyn; L J Risler; B Bostrom; M J Cowan Journal: Bone Marrow Transplant Date: 2000-05 Impact factor: 5.483
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