title: Effect of CYP3A5 genotype, steroids, and azoles on tacrolimus in a pediatric renal transplant population.
abstract: BACKGROUND
  Numerous studies have described the impact of cytochrome P450 3A5 (CYP3A5) genotype on Tacrolimus (TAC) exposure. The purpose of this study was to conduct a comprehensive analysis of genetic and non-genetic factors affecting the TAC dose-exposure relationship over the first year post pediatric renal transplant.
  
  
  METHODS
  Data were collected retrospectively for the first year post-transplant in pediatric renal transplant patients receiving TAC maintenance immunosuppression. The effect of CYP3A5 genotype (CYP3A5*3 and *6 alleles), age, azoles, and corticosteroids on TAC trough concentration normalized for dose (TAC Co/D ng/ml/mg/kg/day) was assessed using a linear mixed model.
  
  
  RESULTS
  Over time, TAC Co/D was lower in recipients with CYP3A5*1/*3 genotype compared to those with CYP3A5*3/*3 genotype (44.5 ± 14.4 vs. 107.6 ± 6.4, p = 0.03), increased in patients >12 years of age compared to < 12 years (93.9 ± 8.7 vs. 53.1 ± 12.9, p = 0.007), and decreased by concomitant corticosteroids (69.5 ± 12.7 vs. 89.9 ± 20.0, p = 0.04). The observed increased TAC Co/D in the presence of azoles (271 ± 41 vs. 111 ± 91, p = 0.016) could be attributed to clotrimazole.
  
  
  CONCLUSIONS
  Multiple factors, including CYP3A5 genotype, and age, influence TAC Co/D in pediatric kidney transplant recipients. Clotrimazole administered as troches also contribute to TAC Co/D variability.
authors.affiliation: Division of Nephrology, Children's Mercy Hospital, University of Missouri-Kansas City, 2401 Gilham Road, Kansas City, MO, 64108, USA, shwetal_lalan@hotmail.com.
authors.forename: Shwetal
authors.initials: S
authors.lastname: Lalan
authors.forename: Susan
authors.initials: S
authors.lastname: Abdel-Rahman
authors.forename: Andrea
authors.initials: A
authors.lastname: Gaedigk
authors.forename: J Steven
authors.initials: JS
authors.lastname: Leeder
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Warady
authors.forename: Hongying
authors.initials: H
authors.lastname: Dai
authors.forename: Douglas
authors.initials: D
authors.lastname: Blowey
mesh_terms: D000293:Adolescent; D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D000367:Age Factors; D000891:Anti-Infective Agents, Local / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D003022:Clotrimazole / Q000627:therapeutic use; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood* / Q000627:therapeutic use; D007223:Infant; D016030:Kidney Transplantation; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D016559:Tacrolimus / Q000097:blood* / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D000305:Adrenal Cortex Hormones; D000891:Anti-Infective Agents, Local; D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D003022:Clotrimazole; D016559:Tacrolimus