Discussion
neurotoxic, tremor, ®, Envarsus®
SECONDARY
Tacrolimus is an effective immunosuppressive drug that is used immediately and long-term in the majority of LTx recipients. Currently available tacrolimus formulations are characterised by high inter- and intra-variability, high peak levels and low bioavailability, often creating problems in clinical efficacy. Envarsus® is manufactured using MeltDose technology and represents an innovation in the field of immunosuppressive drugs. This galenic formulation increases the amount of active ingredient that reaches the blood, ensuring higher therapeutic efficacy. In a phase 2 study conducted on stable LTx patients [The recently identified C/D ratio as a cost-effective estimate for tacrolimus bioavailability will be calculated at 12 weeks after randomisation as the primary endpoint of EnGraft. Bioavailability studies on Envarsus® in the context of LTx are less prevalent in the scientific literature compared to kidney transplantation, and no prospective phase III or IV studies with Envarsus® have been conducted in de novo LTx recipients. Our aim is to show that Envarsus® confers a superior (higher) C/D ratio in LTx recipients after 12 weeks of therapy. Several studies have identified a relationship between C/D ratio and clinical outcomes in organ transplant recipients. Sánchez Fructuoso et al. demonstrated that a higher C/D ratio is linked to a reduction in neurotoxic side effects, e.g. tremor, after kidney transplantation [EnGraft consists of an optional run-in phase which may last for up to 14 days after transplantation surgery. Within this period, patients may be pre-treated with an immediate-release formulation of tacrolimus (e.g. Prograf®). Tacrolimus target trough levels may be reached faster in this pre-treated subset of patients and unfairly bias the secondary endpoints that are based on drug pharmacokinetics. For this reason, “pre-treatment” was chosen as a stratification factor for the dynamic randomisation algorithm to enable a fair and unbiased evaluation of the secondary pharmacokinetic endpoints. Additionally, patients spending different amounts of time in the run-in phase prior to randomisation consequently affects the time when patients are discharged from the transplantation centres relative to the study visits. This factor may influence compliance with the minimum scheduled trough level measurements resulting in protocol deviations and potentially influencing our chosen secondary endpoints.Results in trough level measurement are only interchangeable if analytic methods are the same. For therapeutic drug monitoring, especially tacrolimus trough level measurement, different types of immunoassays and the tandem mass spectrometry are used depending on local laboratory standards [