PhD defence L.M. (Louise) Andrews

Multiple factors influence the pharmacokinetics of tacrolimus, including hematocrit, CYP3A5, age and bodyweight. Basing the starting dose on a dosing algorithm which includes genetic, demographic and clinical factors, seems more rational than basing the dose solely on bodyweight. A dosing algorithm was developed for children and validated in an external validation cohort. This study concluded that the relative starting dose of tacrolimus should be higher in children with a lower bodyweight, CYP3A5 expressers and recipients of a kidney from a deceased donor. Subsequently a prospective study was performed in which the starting dose of tacrolimus after kidney transplantation was based on the dosing algorithm. Unfortunately the dosing algorithm could not adequately predict the tacrolimus exposure in CYP3A5 expressers who received a kidney from a deceased donor. The dosing algorithm was improved. In adults we concluded that if the starting dose is based solely on bodyweight, more than half of the overweight patients (BMI>25) had tacrolimus concentration above the target range. In this study guidelines were developed for dosing tacrolimus in overweight and obese patients. In a new study a dosing algorithm for the starting dose of tacrolimus in adults after kidney transplantation was developed and validated. The tacrolimus starting dose should be higher in CYP3A5 expressers, younger patients and patients with a large body surface area. The starting dose should be lower in patients carrying CYP3A4*22. Currently a prospective clinical trial is ongoing in which 60 renal transplant recipients receive a tacrolimus starting dose based on the dosing algorithm.

The public defence will take place at the Prof. Andries Queridoroom, 3rd floor Education Center, Erasmus MC. The ceremony will begin exactly at 13.30 hrs. In light of the solemn nature of the ceremony, we recommend that you do not take children under the age of 6 to the first part of the ceremony.