Population pharmacokinetics analysis of cyclophosphamide with genetic effects in patients undergoing hematopoietic stem cell transplantation

Purpose: To build a population pharmacokinetic (PK) model of cyclophosphamide (CY) and its metabolite, 4-hydroxycyclophosphamide (HCY), in patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT) and to identify covariates, including genetic polymorphisms, which affect CY and HCY PK parameters. Method: The study cohort comprised 21 patients undergoing HSCT who received CY intravenously between 2009 and 2011. Clinical characteristics and CY and HCY concentration data were collected for all patients, and ABCB1, ABCC2, GSTA1, GSTM1, GSTP1, GSTT1, CYP2B6, CYP2C19, and CYP3A5 genotyping was performed. A hypothetical enzyme compartment was conducted using the NONMEM program. Results: A population PK analysis showed that the ABCC2 1249 genotype and aspartate aminotransferase levels significantly affected non-induced clearance (CL _UI) and induced clearance (CL _I) of CY, respectively. The final estimate of the mean CL _UI and CL _I of CY was 15.5 and 0.683 L/h, respectively, and the mean volume of distribution (V ₁) of CY was 88.0 L. The inter-individual variability for CL _UI, CL _I, and V ₁ of CY was 52.8, 200, and 18.0 %, respectively. Additionally, the CL _UI of CY was significantly decreased to approximately 51 % in patients with the 1249 GA heterozygous genotype compared to those with the 1249 GG wild-type genotype (p < 0.05). There were only three heterozygous GA variants of ABCC2 1249 in the study patients. Conclusions: The population PK model developed in this study implies an influence of genetic factors on the clearance of CY. Clearance was moderately reduced in patients with the ABCC2 1249GA heterozygous genotype.