TY - JOUR
T1 - Population pharmacokinetics analysis of cyclophosphamide with genetic effects in patients undergoing hematopoietic stem cell transplantation
AU - Kim, In Wha
AU - Yun, Hwi Yeol
AU - Choi, Boyoon
AU - Han, Nayoung
AU - Kim, Myeong Gyu
AU - Park, Seonyang
AU - Oh, Jung Mi
N1 - Funding Information:
Acknowledgments This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (No. 2012-0000185).
PY - 2013/8
Y1 - 2013/8
N2 - 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.
AB - 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.
KW - 4-hydroxycyclophosphamide
KW - Cyclophosphamide
KW - Hematopoietic stem cell transplantation
KW - Pharmacogenetics
KW - Population pharmacokinetics
UR - http://www.scopus.com/inward/record.url?scp=84880511682&partnerID=8YFLogxK
U2 - 10.1007/s00228-013-1507-7
DO - 10.1007/s00228-013-1507-7
M3 - Article
C2 - 23588565
AN - SCOPUS:84880511682
SN - 0031-6970
VL - 69
SP - 1543
EP - 1551
JO - European Journal of Clinical Pharmacology
JF - European Journal of Clinical Pharmacology
IS - 8
ER -