Precision Guided Tacrolimus Dosing in Pediatric Heart Transplant

Overview

Immunosuppressive therapy is required to prevent organ rejection, however, dosing of immunosuppressive agents is complicated by patient-specific differences impacting the body's absorption and elimination of these agents. The goal of this research proposal is to clinically validate an innovative precision medicine strategy for dosing the immunosuppressant tacrolimus in pediatric heart transplant, which will in turn lead to improvements in long-term transplant survival outcomes. The strategy and techniques used in this project can be extended to improve drug therapy across multiple pediatric diseases requiring chronic therapy.

Of the more than 400 children annually receiving a heart transplant, the likelihood that the child dies within five years (25%) is equivalent to the potential that the child lives \>20 years post-transplant. The success of the transplant, and thus long-term survival of the child, is well known to correlate with achieving adequate immunosuppression to prevent rejection, especially in the period immediately following transplant. Attaining adequate immunosuppression is complicated by several factors, many of which impact the pharmacokinetics (PK) of the immunosuppressive agent. These factors include age of the patient, renal and hepatic function, concomitant medications, patient genetics, and the time post-transplant. Frequent, invasive drug monitoring is used clinically to assess how these factors impact an individual child's PK, and in turn the dose required to achieve and maintain adequate immunosuppression. However, this empirical "guess and check" approach often results in the child spending substantial time receiving immunosuppressive therapy that is either ineffective or unsafe, decreasing the longevity of the transplant organ and thus, long-term patient survival. A more desirable approach would be to guide dosing using a precision medicine approach, wherein patient specific factors are used a priori to predict the dose most likely to achieve adequate immunosuppression. Developing a precision medicine platform for immunosuppression following pediatric heart transplant has the potential to not only improve outcomes in heart transplant recipients, but across all transplant types. This proposal aims to: 1) determine the impact of CYP3A5 genetic variation on tacrolimus concentrations in children, 2) prospectively validate the clinical utility of a PK-guided precision medicine platform in pediatric heart transplant patients receiving tacrolimus-based immunosuppression; and 3) identify and correlate biomarkers of transplant outcomes and tacrolimus safety/effect with the PK of tacrolimus, in order to establish the tacrolimus concentrations required for safe and effective immunosuppression in pediatric heart transplant recipients. The overall objective of this study is to improve the long-term survival of children with heart transplant via optimization of the child's immunosuppressive therapy. Importantly, the interdisciplinary nature of this mentored research proposal will facilitate my progress towards an independent career developing precision medicine tools to improve health outcomes in children.