title: Tacrolimus population pharmacokinetics according to CYP3A5 genotype and clinical factors in Chinese adult kidney transplant recipients.
abstract: OBJECTIVE
  Tacrolimus is characterized by a narrow therapeutic index and a considerable inter- and intraindividual pharmacokinetic variability. The aim of our study was to develop a population pharmacokinetic model of tacrolimus in adult kidney transplant of Chinese patients, identify factors especially CYP3A5*3 genetic polymorphism that explain variability, and determine dosage regimens.
  
  
  METHODS
  Pharmacogenomic data obtained from 83 Chinese kidney transplant patients treated with tacrolimus were determined using polymerase chain reaction-restriction fragment length polymorphism analysis. Trough blood concentration data were collected from all of the patients during the 12 months of post-transplantation days and were analysed using the nonlinear mixed-effects modelling program. After building the final model, 1000 bootstraps were performed to validate the final model.
  
  
  CONCLUSIONS
  A one-compartment model with first-order absorption and elimination adequately described the pharmacokinetics of tacrolimus. In this study, we observed that POD, HCT and CYP3A5*3 genotype were determinant factors in CL/F and POD related with V/F of tacrolimus significantly. The final model with the clearance covariates was presented as: Cl/F=THETA(1)*EXP(THETA(4)*(83/POD))*(39.1/HCT)**THETA(5)*EXP(THETA(6)*CYP3A5), and the final model with the volume covariates was presented as: Vd/F=THETA(2)*POD**THETA(3). The Ka was fixed to 4.5 h-1.
  
  
  CONCLUSIONS
  The HCT, CYP3A5*3 genetic polymorphism and POD contributed to the interindividual variability of oral tacrolimus in Chinese adult renal transplant patients.
authors.affiliation: Department of Pharmacy, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University, Nanjing, China.|Department of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.
authors.forename: H J
authors.initials: HJ
authors.lastname: Zhang
authors.affiliation: Department of Pharmacy, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University, Nanjing, China.
authors.forename: D Y
authors.initials: DY
authors.lastname: Li
authors.affiliation: Department of Pharmacy, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University, Nanjing, China.
authors.forename: H J
authors.initials: HJ
authors.lastname: Zhu
authors.affiliation: Department of Pharmacy, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University, Nanjing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Fang
authors.affiliation: Department of Urology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University, Nanjing, China.
authors.forename: T S
authors.initials: TS
authors.lastname: Liu
mesh_terms: D000284:Administration, Oral; D000328:Adult; D044466:Asian People / Q000235:genetics; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D017711:Nonlinear Dynamics; D010597:Pharmacogenetics; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D016559:Tacrolimus / Q000008:administration & dosage / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus
keywords: CYP3A5*3; haematocrit; nonlinear mixed-effects modelling; population pharmacokinetics; post-operative days; tacrolimus