The interactions of age, genetics, and disease severity on tacrolimus dosing requirements after pediatric kidney and liver transplantation

Abstract

PurposeIn children, data on the combined impact of age, genotype, and disease severity on tacrolimus (TAC) disposition are scarce. The aim of this study was to evaluate the effect of these covariates on tacrolimus dose requirements in the immediate post-transplant period in pediatric kidney and liver recipients.MethodsData were retrospectively collected describing tacrolimus disposition, age, CYP3A5 and ABCB1 genotype, and pediatric risk of mortality (PRISM) scores for up to 14 days post-transplant in children receiving liver and renal transplants. Initial TAC dosing was equal in all patients and adjusted using therapeutic drug monitoring. We determined the relationship between covariates and tacrolimus disposition.ResultsForty-eight kidney and 42 liver transplant recipients (median ages 11.5 and 1.5 years, ranges 1.5–17.7 and 0.05–14.8 years, respectively) received TAC post-transplant. In both transplant groups, younger children (<5 years) needed higher TAC doses than older children [kidney: 0.15 (0.07–0.35) vs. 0.09 (0.02–0.20) mg/kg/12h, p = 0.046, liver: 0.12 (0.04–0.32) vs. 0.09 (0.01–0.18) mg/kg/12h, p = 0.038]. In kidney but not liver transplants, CYP3A5 expressors needed significantly higher TAC doses than nonexpressors [0.15 (0.07–0.20) vs. 0.09 (0.02–0.35) mg/kg/12h, P = 0.001]. In these patients, age and CYP3A5 genotype were independently associated with TAC dosing requirement. In liver, but not kidney transplant patients, homozygous ABCB1 T-T-T haplotype carriers needed higher TAC doses than noncarriers [0.26 (0.15–0.32) vs. 0.11 (0.01–0.25) mg/kg/12h, p = 0.013].ConclusionCYP3A5 genotype may explain variation in tacrolimus disposition early after transplant in pediatric kidney recipients, independent of age-related variation. In contrast, in pediatric liver recipients, variation in tacrolimus disposition appears related to age and ABCB1 genotype. These findings illustrate the importance of the interplay among age, genotype, and transplant organ on tacrolimus disposition.

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).…”

Making Every Drop Count for Pediatric Kidney Transplant Patients

“…4 The side effects of tacrolimus are concentration dependent and numerous; they include nephrotoxicity, neurotoxicity, hypertension, infection, glucose intolerance, liver dysfunction, and lymphoproliferative disease. 4,5 …”

“…Most of these regimens include a potent immunosuppressive medication with a narrow therapeutic window and concentration levels that are highly variable, both between patients and within individual patients. 4 The side effects of tacrolimus are concentration dependent and numerous; they include nephrotoxicity, neurotoxicity, hypertension, infection, glucose intolerance, liver dysfunction, and lymphoproliferative disease. 4,5 Given the narrow therapeutic window of tacrolimus, it is crucial to monitor drug levels closely with a 12-hour trough level obtained before the next medication dose.…”

“…4 The side effects of tacrolimus are concentration dependent and numerous; they include nephrotoxicity, neurotoxicity, hypertension, infection, glucose intolerance, liver dysfunction, and lymphoproliferative disease. 4,5 Given the narrow therapeutic window of tacrolimus, it is crucial to monitor drug levels closely with a 12-hour trough level obtained before the next medication dose. In pediatric kidney transplant recipients, the serum concentration dose-response relationship between tacrolimus and nephrotoxicity makes adequate drug level monitoring especially important.…”