Age and CYP3A5 genotype affect tacrolimus dosing requirements after transplant in pediatric heart recipients

Abstract

BACKGROUND Tacrolimus is one of the commonly used immunosuppressive drugs for pediatric heart transplants. Large variation exists in pharmacokinetics during the direct post-transplant period, resulting in an increased risk of adverse events. Limited data are available on the interaction of age, CYP3A5 and ABCB1 genotype, and disease severity on the variation in disposition and outcome in pediatric heart transplant recipients. METHOD We studied the relationship between age and CYP3A5 and ABCB1 genotype and the Pediatric Risk of Mortality (PRISM) score on tacrolimus dose (mg/kg), steady-state trough concentrations, and concentration/dose ratio, as well as rejection and renal function for 14 days after heart transplant in children. RESULTS Tacrolimus was administered to 39 children (median age, 6.0 years) after transplant. A correlation was found between the age at the time of transplant and the tacrolimus dosing requirements (rs = −0.447, p = 0.004) and the concentration/dose ratio (rs = 0.351, p = 0.029). CYP3A5 expressors required median (interquartile range) higher doses of tacrolimus (0.14 [0.09] vs 0.06 [0.04] mg/kg/12 hours, p = 0.001), and had lower concentration/dose ratios (45.34 [44.54] vs 177.78 [145.38] ng/ml per mg/kg/12 hours, p < 0.0001). This relationship was not seen with the ABCB1 genotype. Age and CYP3A5 genotype predicted the tacrolimus dosing requirements as well as the concentration/dose ratio (R2 = 0.351, p = 0.001 and R2 = 0.521, p < 0.001). No relationship was found between any of the CYP3A5 or ABCB1 genotypes and the estimated glomerular filtration rate. CONCLUSION Younger age and CYP3A5 expressor genotype were independently associated with higher dosing requirements and lower tacrolimus concentration/dose ratios.

A Markov Chain Model to Evaluate the Effect of CYP3A5 and ABCB1 Polymorphisms on Adverse Events Associated with Tacrolimus in Pediatric Renal Transplantation

“…The effect of age in this study population was significant and consistent with that reported in the literature (30)(31)(32). The patient population in our study, however, was mainly older than 5 years of age.…”

“…Numerous age-related differences in drug disposition including CYP3A4/5 metabolism and p-glycoprotein transport have been reported, contributing to large interindividual variability in CYP3A activities (33)(34)(35). In heart, kidney, and liver transplant patients, children younger than 5 years of age were shown to require a larger dose of tacrolimus than older children (30)(31)(32)(36)(37)(38). CYP3A4 activity is very low before birth and rapidly increases to approximately 50% of adult levels between 6 and 12 months of age whereas no developmental patterns were observed for CYP3A5 expression (39)(40)(41).…”

CYP3A5*3 and POR*28 Genetic Variants Influence the Required Dose of Tacrolimus in Heart Transplant Recipients

“…A similar effect of the CYP3A5*3 variant on TAC dose requirement has been shown also in the previous studies on HTx recipients, based on cohorts of 15 and 65 adult patients 21,28 and 37 and 54 pediatric patients. 11,22 This study, however, was the first to investigate the influence of the POR*28 variant on TAC and CSA dose requirement in HTx recipients.…”

“…A microparticle immunoassay on the Abbott IMX was previously used for TAC and a chemiluminescence microparticle immunoassay for CSA on the same platform. Dose-adjusted drug C 0 concentration was used as an outcome variable, as commonly done in other studies, 7,8,11,13,21,22 and defined as drug C 0 concentration per daily…”

Association of CYP3A variants with kidney transplant outcomes

“…Carriers of the CYP3A5*1/*1 variant are expressers of CYP3A5 and have higher dose requirements and lower cyclosporine trough levels in comparison with CYP3A5*3/*3 carriers. 17,18 A potential limitation of our study is that it is a single centre study of a small number of patients. Our study population was all white and, while this limits the possibility of population stratification, the results cannot be extrapolated to other populations.…”