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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.

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Abbreviations

CYP3A5 :

Cytochrome P450 3A5

TAC:

Tacrolimus

TAC Co/D:

TAC exposure normalized for dose

TDM:

Therapeutic drug monitoring

MMF:

Mycophenolate mofetil

CAN:

Chronic allograft nephropathy

BMP:

Basic metabolic panel

CBC:

Complete blood count

eGFR:

Estimated glomerular filtration rate

μl:

Microliter

LMM:

Linear mixed model

LC-MS/MS:

Liquid chromatography-tandem mass spectrometry

SD:

Standard deviation

ABCB1:

ATP-Binding Cassette, Sub-Family B1 drug transporter gene: also known as MDR1)

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Correspondence to Shwetal Lalan.

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Lalan, S., Abdel-Rahman, S., Gaedigk, A. et al. Effect of CYP3A5 genotype, steroids, and azoles on tacrolimus in a pediatric renal transplant population. Pediatr Nephrol 29, 2039–2049 (2014). https://doi.org/10.1007/s00467-014-2827-2

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  • DOI: https://doi.org/10.1007/s00467-014-2827-2

Keywords

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