Identification of factors affecting tacrolimus trough levels in Latin‐American pediatric liver transplant patients

RIVA, NATALIA; WOILLARD, JEAN?BAPTISTE; DISTEFANO, MAXIMILIANO; MORAGAS, MATIAS; DIP, MARCELO; HALAC, ESTEBAN; CÁCERES GUIDO, PAULO; LICCIARDONE, NIEVES; MANGANO, ANDREA; BOSALEH, ANDREA; DE DAVILA, MARÍA TERESA; SCHAIQUEVICH, PAULA; IMVENTARZA, OSCAR

LIVER TRANSPLANTATION

JOHN WILEY & SONS INC

Lugar: New York; Año: 2019

1527-6465

Tacrolimus is the milestone 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 tacrolimus systemic exposure in pediatric liver transplant patients. De-novo transplant patients with a survival of more than one month were considered for inclusion and genotyped for CYP3A5. Peri-transplant clinical factors and laboratory covariates, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), hematocrit, and tacrolimus pre-dose steady-state blood concentrations collected 12 h after tacrolimus dose (C0), were recorded retrospectively between one month and two years post-transplant. A linear mixed effect (LME) model was used to assess the association of these factors and the log-transformed tacrolimus dose-normalized C0 (logC0/D). Bootstrapping was used to internally validate the final model. External validation was performed in an independent group of patients that matched the original population. The developed LME model described that logC0/D increases as time post-transplant and ALT values increase (β=0.019, 95% CI, 0.010-0.028 and β=0.00030, 95% CI, 0.00002-0.00056, respectively), whereas it is significantly lower in graft CYP3A5-expressers compared to non-expressers [β= -0.349, 95% CI, -0.631-(-0.062)]. CONCLUSIONS: Donor CYP3A5 genotype, time post-transplant and, alanine aminotransferase values are associated with tacrolimus disposition between one month and two years post-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