title: Population pharmacokinetics analysis of cyclophosphamide with genetic effects in patients undergoing hematopoietic stem cell transplantation.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1 Gwanang-ro, Gwanak-gu, Seoul 151-742, Korea.
authors.forename: In-Wha
authors.initials: IW
authors.lastname: Kim
authors.forename: Hwi-yeol
authors.initials: HY
authors.lastname: Yun
authors.forename: Boyoon
authors.initials: B
authors.lastname: Choi
authors.forename: Nayoung
authors.initials: N
authors.lastname: Han
authors.forename: Myeong Gyu
authors.initials: MG
authors.lastname: Kim
authors.forename: Seonyang
authors.initials: S
authors.lastname: Park
authors.forename: Jung Mi
authors.initials: JM
authors.lastname: Oh
mesh_terms: D000293:Adolescent; D000328:Adult; D001219:Aspartate Aminotransferases / Q000097:blood; D003520:Cyclophosphamide / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D005260:Female; D005838:Genotype; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*
chemical_list: D001219:Aspartate Aminotransferases; D003520:Cyclophosphamide; D007166:Immunosuppressive Agents; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C000715087:ABCC2 protein, human; C012358:4-hydroxycyclophosphamide