The Impact of CYP3A5 Genotype on Tacrolimus Pharmacokinetics in Children following Heart Transplant

Abstract Tacrolimus is a first-line immunosuppressant used after solid organ transplantation that suffers from extensive intra- and inter-patient variability and a narrow therapeutic window. Tacrolimus clearance is predominantly mediated by CYP3A4 and CYP3A5, with evidence indicating that pharmacogenetic (PG) differences in these enzymes drive significant changes in tacrolimus pharmacokinetics (PK) and therapeutic tacrolimus dosing. The current study investigates the hypothesis that CYP3A4/5 genetic variation alters tacrolimus dose requirement and metabolite concentration in children following pediatric heart transplant. Saliva and whole blood samples were collected from children who previously received a heart transplant as part of a tacrolimus PG/PK study. A total of 64 children were included in the analysis, which found that children carrying a CYP3A5*1 allele required a 2.7-fold higher tacrolimus dose (p<0.0001) than individuals with the CYP3A5*3/*3 genotype. Dose-normalized tacrolimus and metabolite concentrations were significantly lower in children with the CYP3A5*1 allele. Combined, these data support the impact of CYP3A5 genotype on tacrolimus PK and demonstrate the need for larger studies to confirm the clinical importance of this genotype for appropriate tacrolimus dosing in pediatric heart transplant recipients.