title: Impact of CYP3A5 polymorphism on trough concentrations and outcomes of tacrolimus minimization during the early period after kidney transplantation.
abstract: OBJECTIVE
  The purpose of this study is to determine the impacts of CYP3A5 polymorphism on tacrolimus concentration and the proportion of patients within a target therapeutic range during the first week after transplantation together with the 3-month acute rejection rate in kidney transplant patients receiving a minimized tacrolimus regimen.
  
  
  METHODS
  A total of 164 patients participated in the study. All received oral tacrolimus twice daily starting on the day of surgery with the target pre-dose (trough) concentration of 4-8 ng/ml for prevention of allograft rejection. Cytochrome P450 (CYP) 3A5 genotypes were determined. The patients were divided into CYP3A5 expressers (CYP3A5*1 allele carriers) and CYP3A5 nonexpressers (homozygous CYP3A5*3). Whole blood tacrolimus concentrations on days 3 and 7 posttransplantation and the incidence of biopsy-proven acute rejection (BPAR) at 3-month posttransplantation were compared between groups.
  
  
  RESULTS
  On day 3, the median (IQR) dose-and-weight-normalized trough concentration in expressers and nonexpressers were 54.61 (31.98, 78.87) and 91.80 (57.60, 130.20) ng/ml per mg/kg/day, respectively (p < 0.001). Although only 47 and 42% of expressers and nonexpressers were within the target range on day 3, approximately 60% of both groups were within the target range on day 7. Proportions of BPAR among expressers and nonexpressers were 6.0 and 7.4 %, respectively (p = 0.723). The median (IQR) times to the first rejection in CYP3A5 expressers and nonexpressers were 32 (12, 68) and 15 (12, 37) days, respectively (p = 0.410).
  
  
  CONCLUSIONS
  Although CYP3A5 polymorphism significantly influenced the tacrolimus dose required to achieve the target concentration, the impact of CYP3A5 polymorphism on BPAR was not observed in this study.
authors.affiliation: Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, 10330, Thailand.
authors.forename: Khemjira
authors.initials: K
authors.lastname: Yaowakulpatana
authors.affiliation: Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, 10330, Thailand. somratai.v@pharm.chula.ac.th.
authors.forename: Somratai
authors.initials: S
authors.lastname: Vadcharavivad
authors.affiliation: Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Atiporn
authors.initials: A
authors.lastname: Ingsathit
authors.affiliation: Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, 10330, Thailand.
authors.forename: Nutthada
authors.initials: N
authors.lastname: Areepium
authors.affiliation: Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Surasak
authors.initials: S
authors.lastname: Kantachuvesiri
authors.affiliation: Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Bunyong
authors.initials: B
authors.lastname: Phakdeekitcharoen
authors.affiliation: Department of Pathology, Faculty of Medicine and Laboratory for Pharmacogenomics, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Chonlaphat
authors.initials: C
authors.lastname: Sukasem
authors.affiliation: Pharmacy Division, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Supasil
authors.initials: S
authors.lastname: Sra-Ium
authors.affiliation: Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Vasant
authors.initials: V
authors.lastname: Sumethkul
authors.affiliation: Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Chagriya
authors.initials: C
authors.lastname: Kitiyakara
mesh_terms: D000328:Adult; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D006084:Graft Rejection / Q000097:blood / Q000517:prevention & control; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D016559:Tacrolimus / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus
keywords: CNI minimization; CYP3A5; Genetic polymorphism; Kidney transplant; Tacrolimus; Therapeutic drug monitoring