PhD defence M.I. (Marith) Francke

Brief summary on the aim of the doctoral thesis:

After transplantation, patients will use lifelong immunosuppressive medication. Tacrolimus is effective in the prevention of rejection. However, its use is complicated by its narrow therapeutic range and large inter-patient variability in its pharmacokinetics. Consequently, a lot of patients are under- or overexposed to tacrolimus in the early phase after transplantation, which increases the risk for rejection or drug-related toxicity. The aim of first part of this thesis was to optimize tacrolimus treatment after transplantation by using computer models and dosing algorithms to predict an individual’s dose requirement (based on genetic information, age, body surface area). By identifying factors associated with tacrolimus pharmacokinetics and using these to predict an individual’s dose requirement, we can minimize under- and overexposure. In the second part of this thesis we investigated new methods to monitor tacrolimus exposure. It was investigated whether the intracellular tacrolimus concentration (where tacrolimus has its immunosuppressive effect) better correlates with clinical outcomes compared to the whole-blood concentration. Finally, we investigated a dried blood spot microsampling method (using a fingerprick)  to measure tacrolimus concentrations. This method is clinically validated, and can therefore be implemented in clinical practice. The aim of this thesis was to minimize tacrolimus under- and overexposure and optimize monitoring tacrolimus concentrations after transplantation to prevent rejection and toxicity.