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 Citations (Scopus)

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 - Jan 1 2014
Externally publishedYes

Fingerprint

Cytochrome P-450 CYP3A
Azoles
Tacrolimus
Steroids
Genotype
Pediatrics
Transplants
Kidney
Population
Clotrimazole
Adrenal Cortex Hormones
Immunosuppression
Linear Models
Alleles
Maintenance

Keywords

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

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Nephrology

Cite this

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

Effect of CYP3A5 genotype, steroids, and azoles on tacrolimus in a pediatric renal transplant population. / Lalan, Shwetal; Abdel-Rahman, Susan; Gaedigk, Andrea; Leeder, J. Steven; Warady, Bradley A.; Dai, Hongying; Blowey, Douglas.

In: Pediatric Nephrology, Vol. 29, No. 10, 01.01.2014, p. 2039-2049.

Research output: Contribution to journalArticle

Lalan, S, Abdel-Rahman, S, Gaedigk, A, Leeder, JS, Warady, BA, Dai, H & Blowey, D 2014, 'Effect of CYP3A5 genotype, steroids, and azoles on tacrolimus in a pediatric renal transplant population', Pediatric Nephrology, vol. 29, no. 10, pp. 2039-2049. https://doi.org/10.1007/s00467-014-2827-2
Lalan, Shwetal ; Abdel-Rahman, Susan ; Gaedigk, Andrea ; Leeder, J. Steven ; Warady, Bradley A. ; Dai, Hongying ; Blowey, Douglas. / Effect of CYP3A5 genotype, steroids, and azoles on tacrolimus in a pediatric renal transplant population. In: Pediatric Nephrology. 2014 ; Vol. 29, No. 10. pp. 2039-2049.
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AU - Lalan, Shwetal

AU - Abdel-Rahman, Susan

AU - Gaedigk, Andrea

AU - Leeder, J. Steven

AU - Warady, Bradley A.

AU - Dai, Hongying

AU - Blowey, Douglas

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N2 - 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.

AB - 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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KW - Pharmacogenetics

KW - Renal transplant

KW - Tacrolimus

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