title: Population pharmacokinetics of cyclosporine in hematopoietic stem cell transplant patients: consideration of genetic polymorphisms.
abstract: BACKGROUND
  Cyclosporine (CsA), which is used for graft-versus-host disease prophylaxis in allogeneic hematopoietic stem cell transplant (allo-HSCT), has a narrow therapeutic range and large interindividual and intraindividual pharmacokinetic variability. Nevertheless, population pharmacokinetic (PopPK) studies of CsA in allo-HSCT are scarce.
  
  
  OBJECTIVE
  The goal of our study was to build a PopPK model of CsA in allo-HSCT in consideration of demographic, clinical, and genetic polymorphisms data.
  
  
  METHODS
  A total of 34 adult allo-HSCT patients who received CsA were enrolled prospectively. Demographic, clinical, and CYP3A5 *1/*3, CYP2C19 *1/*2/*3, ABCB1 3435C>T, 1236C>T, 2677G>T/A, ABCC2 -24C>T, 1249G>A, VDR Bsml, Apal polymorphisms data were collected. A PopPK modeling was conducted with NONMEM program.
  
  
  RESULTS
  A 1-compartment model with a 2-transit absorption compartment model was developed. After the stepwise covariate model building process, weight was incorporated into clearance (CL) as a power function model with the exponent value of 0.419. The final typical estimate of CL was 21.2 L/h; volume of distribution was 430 L; logit-transformed bioavailability was 1.49 (bioavailability: 81%); and transit compartment rate was 2.87/h. None of the genetic polymorphisms in CYP3A5, CYP2C19, ABCB1, ABCC2, and VDR were significant covariates in the pharmacokinetics of CsA.
  
  
  CONCLUSIONS
  In our study, it was observed that weight had a significant effect on CL. Genetic polymorphisms did not affect CsA pharmacokinetics. Prospective studies with a larger number of participants is needed to validate the results of this study.
authors.affiliation: Seoul National University, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul, Korea.
authors.forename: Myeong Gyu
authors.initials: MG
authors.lastname: Kim
authors.affiliation: Seoul National University, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul, Korea.
authors.forename: In-Wha
authors.initials: IW
authors.lastname: Kim
authors.affiliation: Seoul National University, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul, Korea.
authors.forename: Boyoon
authors.initials: B
authors.lastname: Choi
authors.affiliation: Seoul National University, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul, Korea.
authors.forename: Nayoung
authors.initials: N
authors.lastname: Han
authors.affiliation: Chungnam National University, College of Pharmacy, Seoul, Korea.
authors.forename: Hwi-Yeol
authors.initials: HY
authors.lastname: Yun
authors.affiliation: Seoul National University, College of Medicine, Seoul, Korea.
authors.forename: Seonyang
authors.initials: S
authors.lastname: Park
authors.affiliation: Seoul National University, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul, Korea jmoh@snu.ac.kr.
authors.forename: Jung Mi
authors.initials: JM
authors.lastname: Oh
mesh_terms: D000293:Adolescent; D000328:Adult; D001682:Biological Availability; D016572:Cyclosporine / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D006086:Graft vs Host Disease / Q000517:prevention & control; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D000089762:Multidrug Resistance-Associated Protein 2; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D055815:Young Adult
chemical_list: C000715087:ABCC2 protein, human; D007166:Immunosuppressive Agents; D000089762:Multidrug Resistance-Associated Protein 2; D016572:Cyclosporine
keywords: cyclosporine; pharmacogenetics and pharmacogenomics; pharmacokinetics; pharmacometrics; transplantation