title: Influence of cytochrome P450 3A5 (CYP3A5) genetic polymorphism on the pharmacokinetics of the prolonged-release, once-daily formulation of tacrolimus in stable renal transplant recipients.
abstract: OBJECTIVE
  Tacrolimus is metabolized by cytochrome P450 (CYP) 3A5. The objective of this study was to investigate the influence of the genetic polymorphism of CYP3A5 on the pharmacokinetics of a new modified-release, once-daily formulation of tacrolimus (Advagraf®) after a switch from the immediate-release formulation (Prograf®).
  
  
  METHODS
  This was a prospective, single-centre, open-label study in stable kidney transplant recipients. Seventeen 'expressor' patients (CYP3A5*1/*3 or *1/*1) were matched to 15 'non-expressor' patients (CYP3A5*3/*3). Exposure variables (concentrations and area under the blood concentration-time curve from 0 to 24 hours [AUC(24)]) were obtained before and 15 days after the switch. Delay since grafting was similar for both groups of patients (expressors: 49 ± 24 months; non-expressors: 45 ± 22 months).
  
  
  RESULTS
  During administration of tacrolimus as Prograf® or Advagraf®, the mean tacrolimus daily dose was significantly higher and the dose-adjusted AUC(24) was significantly lower in the expressor group. Following the switch to Advagraf®, there was a significant decrease in the dose-adjusted AUC(24) for both non-expressor (5910 ± 3019 vs 5334 ± 2668 ng·h/mL per mg/kg/day; p = 0.041) and expressor patients (3701 ± 1409 vs 3273 ± 1372 ng·h/mL per mg/kg/day; p = 0.03). In the non-expressor group, mean blood trough concentration (C(0)) was comparable for both formulations while it decreased significantly in the expressor group after the switch (8.2 ± 2.2 vs 6.3 ± 2.5 ng/mL; p = 0.02). However, a good correlation between AUC(24) and C(0) was observed for both Advagraf® and Prograf® regardless of CYP3A5 genotype.
  
  
  CONCLUSIONS
  Tacrolimus exposure significantly decreases after a switch from Prograf® to Advagraf®, on a milligram-for-milligram basis, in CYP3A5 expressor recipients. Consequently, these patients should be carefully monitored.
authors.affiliation: Equipe d'Accueil 4483, Faculté de Médecine, Pôle Recherche, Lille, France.
authors.forename: François
authors.initials: F
authors.lastname: Glowacki
authors.forename: Arnaud
authors.initials: A
authors.lastname: Lionet
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Hammelin
authors.forename: Myriam
authors.initials: M
authors.lastname: Labalette
authors.forename: François
authors.initials: F
authors.lastname: Provôt
authors.forename: Marc
authors.initials: M
authors.lastname: Hazzan
authors.forename: Franck
authors.initials: F
authors.lastname: Broly
authors.forename: Christian
authors.initials: C
authors.lastname: Noël
authors.forename: Christelle
authors.initials: C
authors.lastname: Cauffiez
mesh_terms: D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D003692:Delayed-Action Preparations; D016903:Drug Monitoring; D005260:Female; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007668:Kidney; D016030:Kidney Transplantation; D008297:Male; D011110:Polymorphism, Genetic; D016559:Tacrolimus / Q000097:blood* / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D003692:Delayed-Action Preparations; D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus