title: CYP3A5 polymorphism effect on cyclosporine pharmacokinetics in living donor renal transplant recipients: analysis by population pharmacokinetics.
abstract: BACKGROUND
  Cyclosporine is often used to prevent allograft rejection in renal transplant recipients. However, cyclosporine has a narrow therapeutic window and large variability in its pharmacokinetics. Individual characteristics and genetic polymorphisms can cause the variation. Hence, it is important to determine the cause(s) of the variation in cyclosporine pharmacokinetics. To our knowledge, this is the first reported population pharmacokinetic study of cyclosporine in living donor renal transplant recipients that considered the genetic polymorphism as a covariate.
  
  
  OBJECTIVE
  To build a population pharmacokinetic model of cyclosporine in living donor renal transplant recipients and identify covariates including CYP3A5*3, ABCB1 genetic polymorphisms that affect cyclosporine pharmacokinetic parameters.
  
  
  METHODS
  Clinical characteristics and cyclosporine concentration data for 69 patients who received cyclosporine-based immunosuppressive therapy after living donor renal transplantation were collected retrospectively for up to 400 postoperative days. CYP3A5*1/*3 and ABCB1C1236T, G2677T/A, C3435T geno-typing was performed. A population pharmacokinetic analysis was conducted using a NONMEM program. After building the final model, 1000 bootstrappings were performed to validate the final model.
  
  
  RESULTS
  In total, 2034 blood samples were collected. A 1-compartment open model with first-order absorption and elimination was chosen to describe the pharmacokinetics of cyclosporine. A population pharmacokinetic analysis showed that postoperative days, sex, and CYP3A5 genotype significantly affected the pharmacokinetics of cyclosporine. The final estimate of mean clearance was 56 L/h, and the mean volume of distribution was 4650 L. The interindividual variability for these parameters was 22.98% and 51.48%, respectively.
  
  
  CONCLUSIONS
  Using the present model to calculate the dose of cyclosporine with CYP3A5 genotyping can be possible for the patients whose cyclosporine concentration is not within the therapeutic range even with therapeutic drug monitoring.
authors.affiliation: College of Pharmacy, Seoul National University, Seoul,  Korea.
authors.forename: Joohan
authors.initials: J
authors.lastname: Song
authors.forename: Myeong Gyu
authors.initials: MG
authors.lastname: Kim
authors.forename: Boyoon
authors.initials: B
authors.lastname: Choi
authors.forename: Na Young
authors.initials: NY
authors.lastname: Han
authors.forename: Hwi-Yeol
authors.initials: HY
authors.lastname: Yun
authors.forename: Jeong-Hyun
authors.initials: JH
authors.lastname: Yoon
authors.forename: Jung Mi
authors.initials: JM
authors.lastname: Oh
mesh_terms: D000328:Adult; D016572:Cyclosporine / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D005838:Genotype; D006084:Graft Rejection / Q000517:prevention & control; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016030:Kidney Transplantation; D019520:Living Donors; D008297:Male; D008954:Models, Biological; D011110:Polymorphism, Genetic
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A