title: Impact of the CYP3A5 genotype on the distributions of dose-adjusted trough concentrations and incidence of rejection in Japanese renal transplant recipients receiving different tacrolimus formulations.
abstract: BACKGROUND
  We investigated the impact of the CYP3A5 genotype on the distributions of dose-adjusted trough concentrations (C0h/D) and the incidence of rejection in Japanese recipients taking twice-daily (Tac-BID, n = 140) or modified-release once-daily (Tac-QD, n = 80) tacrolimus formulations for 1 year after renal transplantation.
  
  
  METHODS
  Logistic regression analysis was carried out to estimate the distinction rate of CYP3A5 genotypes based on the C0h/D of Tac-BID or Tac-QD. The coefficients of variation (%CVs) were compared in each recipient to estimate the stability of tacrolimus C0h/D between formulations or CYP3A5 genotypes.
  
  
  RESULTS
  Recipients with at least one CYP3A5*1 wild-type allele (EMs) and recipients with homozygous expression of the variant allele CYP3A5*3 (PMs) were significantly identified using the tacrolimus C0h/D cut-off values of 2.77 and 0.85 ng/mL/mg, respectively, and discrimination rates of 75.3 and 85.4%, respectively, for Tac-BID and Tac-QD groups. The %CV of the tacrolimus C0h/D in CYP3A5 EMs taking Tac-QD was significantly lower than that in those taking Tac-BID (20.4 versus 23.3%, P = 0.003). The %CV of the tacrolimus C0h/D was an independent risk factor for rejection (odds ratio = 1.028, P = 0.033).
  
  
  CONCLUSIONS
  The tacrolimus C0h/D values with definite cut-offs for CYP3A5 genotypes were specifically identified in Japanese renal transplant recipients taking Tac-QD. In addition, a larger %CV for the tacrolimus C0h/D correlated with the incidence of rejection. Consequently, the stability of the C0h/D achieved using Tac-QD, which was clearly influenced by the CYP3A5 polymorphism, may prevent the development of rejection.
authors.affiliation: Department of Pharmacy, Akita University Hospital, 1-1-1 Hondo, Akita, 010-8543, Japan.
authors.forename: Takenori
authors.initials: T
authors.lastname: Niioka
authors.affiliation: Department of Pharmacy, Akita University Hospital, 1-1-1 Hondo, Akita, 010-8543, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kagaya
authors.affiliation: Department of Urology, Akita University School of Medicine, 1-1-1 Hondo, Akita, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Saito
authors.affiliation: Department of Urology, Akita University School of Medicine, 1-1-1 Hondo, Akita, Japan.
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Department of Urology, Akita University School of Medicine, 1-1-1 Hondo, Akita, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Numakura
authors.affiliation: Department of Urology, Akita University School of Medicine, 1-1-1 Hondo, Akita, Japan.
authors.forename: Ryohei
authors.initials: R
authors.lastname: Yamamoto
authors.affiliation: Department of Urology, Akita University School of Medicine, 1-1-1 Hondo, Akita, Japan.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Habuchi
authors.affiliation: Center for Kidney Disease and Transplantation, Akita University Hospital, 1-1-1 Hondo, Akita, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Satoh
authors.affiliation: Department of Pharmacy, Akita University Hospital, 1-1-1 Hondo, Akita, 010-8543, Japan. m-miura@hos.akita-u.ac.jp.
authors.forename: Masatomo
authors.initials: M
authors.lastname: Miura
mesh_terms: D044466:Asian People / Q000235:genetics; D065095:Calcineurin Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D016009:Chi-Square Distribution; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D004339:Drug Compounding; D054796:Drug Dosage Calculations; D016903:Drug Monitoring; D005838:Genotype; D006084:Graft Rejection / Q000208:ethnology / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D015994:Incidence; D007564:Japan / Q000453:epidemiology; D016030:Kidney Transplantation / Q000009:adverse effects; D016015:Logistic Models; D015999:Multivariate Analysis; D016017:Odds Ratio; D010597:Pharmacogenetics; D000071184:Pharmacogenomic Variants; D012307:Risk Factors; D016559:Tacrolimus / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus
keywords: CYP3A5 genotype; Dose-adjusted trough concentration; Formulation; Rejection; Renal transplantation; Tacrolimus