Abstract

Background: To characterise the population pharmacokinetics of tacrolimus in paediatric BMT recipients and to develop a dosing tool to assist with initial dosage selection.
Material/Methods: Data were collected retrospectively from the medical records of 22 children. Tacrolimus treatment started 36 hours pre-transplant as a continuous intravenous infusion of 0.03 mg/kg/day. Patients were converted to oral therapy two to three weeks post-transplant. Population pharmacokinetic analysis was performed using NONMEM. A macro was constructed in MS Excel, utilising Bayesian forecasting techniques and the population model, to recommend an initial dose in new individuals in order to achieve a target concentration of 12 ng/ml at the time of transplantation.
Results: 743 blood concentration-time points were analysed. Data were collected for a median of 95 days post transplant. All 514 samples collected during oral therapy represented trough values, and samples during infusion were collected 3 times/week. A one-compartment model with first order absorption and elimination was selected. In the final model, typical parameter values were clearance (CL) = 0.135L/h/kg0.75, distribution volume (V) =7.09L/kg and bioavailability (F) = 14.4%. Inter-individual variability in CL, V and F was 56%, 97% and 58%, respectively. Covariate analysis suggested CL positively correlated with creatinine clearance and F decreased with time post-transplant. Use of the model in the Macro, based on a 'typical patient' indicated a 50% higher dose than that currently used initially (0.03 mg/kg/day) is needed to achieve the target trough concentration.
Conclusions: The developed dosage adaptation tool may assist with tacrolimus dosing in paediatric BMT recipients, utilizing TDM concentrations.

Keywords: Creatinine, Tacrolimus, NONMEM