Population Pharmacokinetic Analysis of Tacrolimus Early After Pediatric Liver Transplantation

Background: Tacrolimus (TAC) pharmacokinetics (PKs) show considerable unexplained variability, particularly in the early period after transplantation. Therefore, TAC is a good candidate for therapeutic drug monitoring. The main objective of the present work was to propose a robust PK model for TAC in the early period after transplantation, with the final goal to provide practitioners with a tool for dose individualization in pediatric patients. Methods: TAC concentration data were obtained from 82 pediatric liver allograft recipients during the first 2 weeks after transplantation. Previously published models, and a model recently developed by our group for pediatrics early after pediatric liver transplantation, were fitted to the data and their predictive performance compared with the performances of a model developed using the data from 82 pediatric patients. Results: During the data-driven analysis, the PKs of TAC were best described by a 1-compartment model with time-varying first order elimination. Apparent volume of distribution and blood clearance estimates were 283 L and 10 L/h, respectively. The absorption was also considered to be a first order process, with a first order rate fixed to 4.45 hours. Parameters were estimated with good precision and accuracy. Although hematocrit levels, time after transplantation, liver weight, and body weight influenced the clearance, body weight was the only covariate retained on volume of central and peripheral compartments. Two of the 5 previous models showed acceptable predictive performances using the observed data. Conclusions: Time after transplantation, body weight, and hematocrit levels were shown to influence TAC PK in the early pediatric post-liver transplantation period and should be considered, besides therapeutic drug monitoring, by clinicians for the TAC posology prescription and adaptation.