title: The Pharmacogenetics of Tacrolimus in Corticosteroid-Sparse Pediatric and Adult Kidney Transplant Recipients.
abstract: BACKGROUND
  Tacrolimus is a calcineurin inhibitor used as an immunosuppressant drug in solid organ transplantation, and is mainly metabolized by cytochrome P450 (CYP) 3A4 and CYP3A5. Studies have shown an association between the CYP3A5 genotype and tacrolimus dose-adjusted trough concentrations. Variants in the genes PPARA, POR and CYP3A4 have recently been shown to influence tacrolimus metabolism. Furthermore, pharmacokinetic interaction between corticosteroid treatment and tacrolimus has been shown. In the present study, we investigated a potential association between CYP3A5*3, PPARA c.209-1003G>A, POR*28 and CYP3A4*22 and dose-adjusted tacrolimus trough concentrations in a primarily corticosteroid-free (>85%) population of Danish pediatric and adult kidney transplant recipients.
  
  
  METHODS
  Seventy-two patients receiving treatment with oral tacrolimus were genotyped using real-time polymerase chain reaction and Primer-Probe Detection. Tacrolimus trough concentrations, corresponding doses and covariates were retrospectively collected from the patients' medical charts.
  
  
  RESULTS
  It was confirmed that CYP3A5*1 wild-type carriers had lower median dose-adjusted tacrolimus trough concentrations compared with noncarriers. Adults had 56 and 77% lower trough concentrations at 6 weeks (p = 0.0003) and 1 year, respectively (p < 0.0017), and, similarly, children had 65 and 39% lower median concentrations, with p values of 0.006 and 0.011, respectively. No association was found for PPARA c.209-1003G>A, POR*28, or CYP3A4*22. An association between the PPARA c.209-1003G>A genotype and an increased number of infections with cytomegalovirus (CMV) within the first year was identified (p < 0.05). Only 29% of trough concentrations measured between 2 and 12 weeks post-transplantation were on target.
  
  
  CONCLUSIONS
  This study shows that the known association of the CYP3A5 genotype with tacrolimus dose-adjusted trough concentrations has the same impact in a corticosteroid-sparse population. The association between PPARA variance and infections with CMV will need further investigation.
authors.affiliation: Department of Nephrology, Odense University Hospital, J B WinslowsVej 19, 5000, Odense C, Denmark.
authors.forename: Mads Juul
authors.initials: MJ
authors.lastname: Madsen
authors.affiliation: Department of Clinical Chemistry and Pharmacology, Odense University Hospital, Odense, Denmark. tbergmann@health.sdu.dk.|Hospital Pharmacy, Hospital of South West Denmark, Esbjerg, Denmark. tbergmann@health.sdu.dk.
authors.forename: Troels K
authors.initials: TK
authors.lastname: Bergmann
authors.affiliation: Department of Clinical Pharmacology and Pharmacy, University of Southern Denmark, Odense, Denmark.
authors.forename: Kim
authors.initials: K
authors.lastname: Brøsen
authors.affiliation: Department of Nephrology, Odense University Hospital, J B WinslowsVej 19, 5000, Odense C, Denmark.
authors.forename: Helle Charlotte
authors.initials: HC
authors.lastname: Thiesson
mesh_terms: D000293:Adolescent; D000305:Adrenal Cortex Hormones / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007223:Infant; D016030:Kidney Transplantation / Q000379:methods; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics / Q000379:methods; D012189:Retrospective Studies; D016559:Tacrolimus / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D000305:Adrenal Cortex Hormones; D007166:Immunosuppressive Agents; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus