Model Informed Precision Dosing of Tacrolimus in Children Following Heart Transplant

Tacrolimus is a first-line immunosuppressant used after solid organ transplantation that suffers from extensive intra- and inter-patient variability and a narrow therapeutic window. Its critical role in a fragile population, coupled with the difficulties identifying and maintaining an appropriate dose within a given patient, make it an ideal candidate for population pharmacokinetic (popPK)-guided individualized dosing approaches (i.e., model informed precision dosing, MIPD). We previously published a tacrolimus popPK model in pediatric heart transplant recipients that showed promise in its ability to predict future concentrations within an individual. Using that model, we developed a Bayesian forecasting decision support tool (DST) clinical use to more rapidly attain appropriate tacrolimus dosing in this population. After rigorous in silico testing of the DST's mathematical fidelity to the popPK model, we implemented the DST within a clinical trial (NCT04380311). Fifteen children between 6 months and 17 years of age had their tacrolimus doses guided by the DST to determine the time to stable therapeutic tacrolimus dosing (defined by three consecutive concentrations within the targeted therapeutic range). DST-guided dosing achieved stable tacrolimus dosing ∼3 days faster (6.9 days, P = .03) as compared to a historical cohort (9.8 days). This was despite the poor performance of the DST in two children treated with continuous renal replacement therapy. These results demonstrate the clinical utility and benefit of the described DST, which is the first targeted to the pediatric heart transplant population. Rapid attainment of stable therapeutic tacrolimus dosing has benefits for the patient, clinician, and the healthcare system.