title: CYP3A5*3 and POR*28 genetic variants influence the required dose of tacrolimus in heart transplant recipients.
abstract: BACKGROUND
  After heart transplantation (HTx), the interindividual pharmacokinetic variability of immunosuppressive drugs represents a major therapeutic challenge due to the narrow therapeutic window between over-immunosuppression causing toxicity and under-immunosuppression leading to graft rejection. Although genetic polymorphisms have been shown to influence pharmacokinetics of immunosuppressants, data in the context of HTx are scarce. We thus assessed the role of genetic variation in CYP3A4, CYP3A5, POR, NR1I2, and ABCB1 acting jointly in immunosuppressive drug pathways in tacrolimus (TAC) and ciclosporin (CSA) dose requirement in HTx recipients.
  
  
  METHODS
  Associations between 7 functional genetic variants and blood dose-adjusted trough (C0) concentrations of TAC and CSA at 1, 3, 6, and 12 months after HTx were evaluated in cohorts of 52 and 45 patients, respectively.
  
  
  RESULTS
  Compared with CYP3A5 nonexpressors (*3/*3 genotype), CYP3A5 expressors (*1/*3 or *1/*1 genotype) required around 2.2- to 2.6-fold higher daily TAC doses to reach the targeted C0 concentration at all studied time points (P ≤ 0.003). Additionally, the POR*28 variant carriers showed higher dose-adjusted TAC-C0 concentrations at all time points resulting in significant differences at 3 (P = 0.025) and 6 months (P = 0.047) after HTx. No significant associations were observed between the genetic variants and the CSA dose requirement.
  
  
  CONCLUSIONS
  The CYP3A5*3 variant has a major influence on the required TAC dose in HTx recipients, whereas the POR*28 may additionally contribute to the observed variability. These results support the importance of genetic markers in TAC dose optimization after HTx.
authors.affiliation: *Institute of Clinical Chemistry, University Hospital (Inselspital Bern), and University of Bern; †Graduate School for Cellular and Biomedical Sciences, University of Bern; and Departments of ‡Cardiology, and §Cardiovascular Surgery, Swiss Cardiovascular Centre, University Hospital (Inselspital Bern), Bern, Switzerland.
authors.forename: Dorothea
authors.initials: D
authors.lastname: Lesche
authors.forename: Vilborg
authors.initials: V
authors.lastname: Sigurdardottir
authors.forename: Raschid
authors.initials: R
authors.lastname: Setoud
authors.forename: Markus
authors.initials: M
authors.lastname: Oberhänsli
authors.forename: Thierry
authors.initials: T
authors.lastname: Carrel
authors.forename: Georg M
authors.initials: GM
authors.lastname: Fiedler
authors.forename: Carlo R
authors.initials: CR
authors.lastname: Largiadèr
authors.forename: Paul
authors.initials: P
authors.lastname: Mohacsi
authors.forename: Johanna
authors.initials: J
authors.lastname: Sistonen
mesh_terms: D000328:Adult; D015331:Cohort Studies; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D014644:Genetic Variation / Q000235:genetics*; D006084:Graft Rejection / Q000235:genetics* / Q000517:prevention & control; D016027:Heart Transplantation / Q000009:adverse effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009251:NADPH-Ferrihemoprotein Reductase / Q000235:genetics*; D012189:Retrospective Studies; D016559:Tacrolimus / Q000008:administration & dosage*; D066027:Transplant Recipients
chemical_list: D007166:Immunosuppressive Agents; D051544:Cytochrome P-450 CYP3A; D009251:NADPH-Ferrihemoprotein Reductase; D016559:Tacrolimus