Optimizing immunosuppression with mTOR inhibitors in renal transplant recipients

Abstract

The aim of this thesis was to optimize immunosuppressive therapy, especially everolimus therapy in renal transplantation recipients by identifying pharmacological and pharmacogenetic risk factors influencing pharmacokinetics, and dynamics such as side effects and patient outcome. Therapeutic Drug Monitoring (TDM) of oral immunosuppressive agents is essential to prevent toxicity and or rejection; therefore it is very important to use a reliable and accurate bioanalytical assay. Differences between the most used analytical assays of measuring everolimus in whole blood and its effect on dosing advice were investigated. TDM is performed based on either trough or AUC monitoring and pharmacogenetics might be a valuable addition to TDM. Therefore the population pharmacokinetics of everolimus in a calcineurin free regimen was investigated and predictive factors such as pharmacogenetics were evaluated. In addition a limited sampling model was developed. MTOR inhibitors are known for a variety of side effects and high dropout rates. In this thesis a comprehensive analysis was performed aimed at identifying risk factors for discontinuation and a number of serious side effects. This thesis also describes an analysis aimed at identifying risk factor associated with delayed graft function, acute rejection and subclinical rejection in patients on a cyclosporine based immunosuppressive regimen.