Effect of CYP3A5 genotype, steroids, and azoles on tacrolimus in a pediatric renal transplant population

Pediatr Nephrol. 2014 Oct;29(10):2039-49. doi: 10.1007/s00467-014-2827-2. Epub 2014 May 30.

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.

MeSH terms

  • Adolescent
  • Adrenal Cortex Hormones / therapeutic use
  • Age Factors
  • Anti-Infective Agents, Local / therapeutic use
  • Child
  • Child, Preschool
  • Clotrimazole / therapeutic use
  • Cytochrome P-450 CYP3A / genetics*
  • Female
  • Genotype
  • Humans
  • Immunosuppressive Agents / blood*
  • Immunosuppressive Agents / therapeutic use
  • Infant
  • Kidney Transplantation*
  • Male
  • Polymorphism, Single Nucleotide
  • Retrospective Studies
  • Tacrolimus / blood*
  • Tacrolimus / therapeutic use
  • Young Adult

Substances

  • Adrenal Cortex Hormones
  • Anti-Infective Agents, Local
  • Immunosuppressive Agents
  • CYP3A5 protein, human
  • Cytochrome P-450 CYP3A
  • Clotrimazole
  • Tacrolimus