The impact of sulfonylureas on tacrolimus apparent clearance revealed by a population pharmacokinetics analysis in chinese adult liver-transplant patients

摘要

Aims: The aims of this study were to determine the population pharmacokinetics of tacrolimus in Chinese adult liver-transplant recipients and to identify factors that may account for this variability. Methods: Tacrolimus dose and blood concentrations, along with clinical data, were collected retrospectively from 262 liver-transplant recipients. Data were analyzed using a nonlinear mixed-effects modeling method. A 1-compartment model with first-order absorption and elimination was selected as the base model. The influence of the following parameters were explored: (1) demographic characteristics, (2) biochemical and hematological laboratory test results, (3) surgery parameters, and (4) commonly used comedications. Results: The typical values (interindividual variability percent coefficient of variation) for apparent clearance (CL/F) and apparent volume of distribution (V/F) were 20.9 L h -1 (23.8%) and 808 l (70.4%), respectively. The residual variability was 33.6%. Finally, the 4 covariates that showed a strong correlation with CL/F in this study were daily dose, hematocrit, total plasma protein, and the coadministration of sulfonylureas. CL/F was reduced significantly with sulfonylureas cotherapy, higher hematocrit levels, and elevated total protein. Moreover, CL/F increased nonlinearly with larger daily doses of tacrolimus. Conclusions: Concurrent therapy with sulfonylureas influenced tacrolimus CL/F in liver transplantation patients. These results and model will help clinicians to optimize tacrolimus regimens in Chinese liver transplantation patients.