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

Shwetal Lalan, Susan Abdel-Rahman, Andrea Gaedigk, J. Steven Leeder, Bradley A. Warady, Hongying Dai, Douglas Blowey

Research output: Contribution to journalArticle

11 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2039-2049
Number of pages11
JournalPediatric Nephrology
Volume29
Issue number10
DOIs
StatePublished - 2014

Keywords

  • CYP3A5
  • Children
  • Clotrimazole
  • Fluconazole
  • Pharmacogenetics
  • Renal transplant
  • Tacrolimus

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Nephrology

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    Lalan, S., Abdel-Rahman, S., Gaedigk, A., Leeder, J. S., Warady, B. A., Dai, H., & Blowey, D. (2014). Effect of CYP3A5 genotype, steroids, and azoles on tacrolimus in a pediatric renal transplant population. Pediatric Nephrology, 29(10), 2039-2049. https://doi.org/10.1007/s00467-014-2827-2