Effect of CYP3A5 genotype, steroids, and azoles on tacrolimus in a pediatric renal transplant population.
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.
Pediatric nephrology (Berlin, Germany)
Adolescent; Adrenal Cortex Hormones; Age Factors; Anti-Infective Agents, Local; Child; Child, Preschool; Clotrimazole; Cytochrome P-450 CYP3A; Female; Genotype; Humans; Immunosuppressive Agents; Infant; Kidney Transplantation; Male; Polymorphism, Single Nucleotide; Retrospective Studies; Tacrolimus; Young Adult
Adrenal Cortex Hormones; Local Anti-Infective Agents; Clotrimazole; Cytochrome P-450 CYP3A; Genotype; Immunosuppressive Agents; Kidney Transplantation; Polymorphism, Single Nucleotide; Retrospective Studies; Tacrolimus
Lalan, S., Abdel-Rahman, S., Gaedigk, A., Leeder, J. S., Warady, B. A., Dai, H., Blowey, D. Effect of CYP3A5 genotype, steroids, and azoles on tacrolimus in a pediatric renal transplant population. Pediatric nephrology (Berlin, Germany) 29, 2039-2049 (2014).