Identification of Factors Affecting Tacrolimus Trough Levels in Latin American Pediatric Liver Transplant Patients

Abstract

Tacrolimus is the cornerstone in pediatric liver transplant immunosuppression. Despite close monitoring, fluctuations in tacrolimus blood levels affect safety and efficacy of immunosuppressive treatments. Identifying the factors related to the variability in tacrolimus exposure may be helpful in tailoring the dose. The aim of the present study was to characterize the clinical, pharmacological, and genetic variables associated with systemic tacrolimus exposure in pediatric liver transplant patients. De novo transplant patients with a survival of more than 1 month were considered for inclusion and were genotyped for cytochrome P450 3A5 (CYP3A5). Peritransplant clinical factors and laboratory covariates were recorded retrospectively between 1 month and 2 years after transplant, including alanine aminotransferase (ALT), aspartate aminotransferase, hematocrit, and tacrolimus predose steady‐state blood concentrations collected 12 hours after tacrolimus dosing. A linear mixed effect (LME) model was used to assess the association of these factors and the log‐transformed tacrolimus dose‐normalized trough concentration (logC0/D) levels. Bootstrapping was used to internally validate the final model. External validation was performed in an independent group of patients who matched the original population. The developed LME model described that logC0/D increases with increases in time after transplant (β = 0.019, 95% confidence interval [CI], 0.010‐0.028) and ALT values (β = 0.00030, 95% CI, 0.00002‐0.00056), whereas logC0/D is significantly lower in graft CYP3A5 expressers compared with nonexpressers (β = −0.349, 95% CI, −0.631 to −0.062). In conclusion, donor CYP3A5 genotype, time after transplant, and ALT values are associated with tacrolimus disposition between 1 month and 2 years after transplant. A better understanding of tacrolimus exposure is essential to minimize the occurrence of an out‐of‐range therapeutic window that may lead to adverse drug reactions or acute rejection.

Plasma metabolomic profiling reveals factors associated with dose-adjusted trough concentration of tacrolimus in liver transplant recipients

“…Tacrolimus is largely bound to erythrocytes ( Woillard et al, 2018 ), and the increased tacrolimus C0/D with postoperative days in our study may be related to the increase of hematocrit over time after liver transplantation. Additionally, increased bioavailability and the variation of drug-drug interaction could also attribute to that ( Riva et al, 2019 ). In fact, the frequency of comedication with Wuzhi capsule was increased when the graft function was stable in our study.…”

“…Thus, the biomarkers for tacrolimus disposition identified in healthy controls should be applied in clinical practice with caution, and a study performed in liver transplant recipients may provide more insight views for metabolomics-guided dosing. Additionally, dose-adjusted tacrolimus trough concentration (C0/D) was commonly used as a surrogate marker for dose response or an index of clearance in most of the studies conducted in patient ( Riva et al, 2019 ). Thus, the present study attempted to identify potential plasma endogenous metabolites associated with tacrolimus C0/D in liver transplant recipients by using a global metabolomic approach.…”

Pharmacokinetics of Tacrolimus in Egyptian Liver Transplant Recipients: Role of the Classic Co-variables

“…corticosteroid doses 38,39 , the C/D ratio, in the present study, was assessed 6 months post liver transplantation to determine the tacrolimus metabolism rate at which corticosteroid was discontinued. The study classified the patients into 3 groups according to their tacrolimus metabolism rate as defined previously 16,19 .…”