External assessment and refinement of a population pharmacokinetic model to guide tacrolimus dosing in pediatric heart transplant

Abstract

AbstractStudy ObjectiveThe immunosuppressant tacrolimus is a first‐line agent to prevent graft rejection following pediatric heart transplant; however, it suffers from extensive inter‐patient variability and a narrow therapeutic window. Personalized tacrolimus dosing may improve transplant outcomes by more efficiently achieving and maintaining therapeutic tacrolimus concentrations. We sought to externally validate a previously published population pharmacokinetic (PK) model that was constructed with data from a single site.Data SourceData were collected from Seattle, Texas, and Boston Children's Hospitals, and assessed using standard population PK modeling techniques in NONMEMv7.2.Main ResultsWhile the model was not successfully validated for use with external data, further covariate searching identified weight (p < 0.0001 on both volume and elimination rate) as a model‐significant covariate. This refined model acceptably predicted future tacrolimus concentrations when guided by as few as three concentrations (median prediction error = 7%; median absolute prediction error = 27%).ConclusionThese findings support the potential clinical utility of a population PK model to provide personalized tacrolimus dosing guidance.