A retrospective analysis of tacrolimus pharmacokinetic in Saudi paediatric patients in early post-liver transplantation period.

Abstract

Background: Tacrolimus is an essential immunosuppressive medication in paediatric patients' post-liver transplantation. Achieving tacrolimus target concentration in early post-transplantation is crucial to minimise the risk of acute rejection; however, this is challenging due to inter- and intra-patient variability in tacrolimus metabolism and clearance. Therefore, our study aims to describe tacrolimus trough concentration variability and pharmacokinetics in paediatric post-liver transplantation during the first two weeks post-transplantation.

Method: This retrospective multicentre observational study included paediatric patients post-liver transplantation. Post-operative data was collected within the initial 14 days using electronic health records, including daily tacrolimus doses, measured trough concentrations, graft data, surgical data, and documented acute rejection. Pharmacokinetic analysis was completed using the Monolix software. We used the empirical Bayesian estimates of clearance and volume of distribution for covariate testing to assess possible correlations. We performed a stepwise regression analysis (alpha = 0.05).

Results: Ninety-one paediatric patients were included in the study, with a mean age of 4.1 years (SD = 4.6). The mean graft-to-recipient weight ratio (GRWR) was 3% (SD = 6). The vast majority of the patients received the liver from living donors (n = 84, 92.3%). The average time needed to reach therapeutic concentration was 4.6 (SD = 2.8) days. The initial clearance (Clini) was very low at baseline (0.012 L/h), then increased dramatically to 9.84 L/h at 14 days post-transplantation. The clearance appeared to be time-dependent, and the time needed to reach 50% of maximum clearance was five days post-transplantation. The covariates that significantly affected clearance included bodyweight and aspartate transaminase, while the only significant covariate for volume of distribution was bodyweight.

Conclusion: Tacrolimus is a drug with high intra- and interindividual variability, making dosing challenging in the paediatric liver transplantation population. Prospective studies with more intensive sampling are needed to address the time-dependent changes in clearance, which will aid in establishing the optimal dosing regimens in this population.