Evaluation of the Impact of Tacrolimus-based Immunosuppression on Heidelberg Liver Transplant Cohort (HDTACRO): Study Protocol for an Investigator Initiated, Non-interventional Prospective Study

Tacrolimus is considered a narrow therapeutic index drug requiring individual dose titration, to achieve a satisfactory balance between maximizing efficacy and minimizing dose-related toxicity. The pharmacokinetic profile of Tacrolimus is characterized by a high degree of inter- and intraindividual variability. Although it is rapidly absorbed, the bioavailability of Tacrolimus in the twice-daily capsule formulation is low and variable, ranging from 17 to 23%. This could be due to poor water solubility, extensive first pass metabolism, p-glycoprotein-mediated efflux and the ingestion of food. Tacrolimus twice-daily capsules are also associated with a characteristic high peak following dosing, which may be associated with increased toxicity. Furthermore, transplanted recipients have to remain to a very demanding medication regimen for a long time. The burden of pills required is associated with decreased adherence, and lack of adherence can lead to rejection and possibly graft loss. The development of once-daily Tacrolimus forms without any change of the form of dissolving has already been shown to increase patients' adherence, while little difference has been demonstrated in the Tacrolimus pharmacokinetic profile. The pharmacokinetic profile of Tacrolimus is characterized by flatter kinetics (i.e., less fluctuation and swing) compared to twice-daily Tacrolimus providing for a balanced concentration-time consistency over 24 hours which can also lead to reduced incidence and/or intensity of drug toxicity-related adverse events. Since the development of LCP-Tacrolimus once-daily tablets, with the use of MeltDose® technology, clinical data have shown lower peak and reduced peak-to-tough fluctuations.