Optimising tacrolimus treatment in solid organ transplant recipients: Bioanalysis, clinical variability, and monitoring

Solid organ transplantation is an effective, life-saving intervention to restore organ function. Key concern is the prevention of allograft rejection, in which tacrolimus is used as cornerstone treatment for maintaining immunosuppression. Treatment with tacrolimus is complex due to a delicate balance between effectiveness and adverse events, and a high variability in pharmacokinetics. For these reasons, therapeutic drug monitoring is recommended for tacrolimus, characterised by dose personalisation on basis of measured drug concentrations. Even after introduction of therapeutic drug monitoring challenges exist, given that after transplantation, adverse events and rejection still occur.
Therefore, the objective of this thesis was to take a next step in optimising tacrolimus therapy for solid organ transplant recipients.
Regarding bioanalysis, part 1 describes multiple bioanalytical approaches for tacrolimus therapeutic drug monitoring, including measurements using less invasive sample types, a new system configuration for routine measurements and the measurement of tacrolimus in plasma.
Regarding clinical variability, part 2 focuses on factors that could explain differences in measured tacrolimus concentrations between patients and within patients over time. It describes a well-known drug-drug interaction which was different between two tacrolimus formulations used, and influence of sex and menopausal status.
Regarding monitoring of drug exposure, part 3 highlights the need for smart drug monitoring using objective electronic or bioanalytical measures, focusing on development of smart devices and further use of bioanalytical methods as a tool for adherence monitoring to allow for personalised medicine in clinical trials.