Maintenance immunosuppression in kidney transplantation is evolving, with recent studies showing a benefit of Calcineurin Inhibitor (CNI) together with an mTOR inhibitor (mTORi). Pharmacokinetic parameters of such immunosuppressive regimen are not well understood yet. We report on our experience with early combined immunosuppression with tacrolimus and everolimus, the MADELEINE (coMbined tAcrolimus anD EveroLimus Early ImmuNosupprEssion) study.
In this study, we prospectively enrolled de novo kidney transplant recipients at our center between july of 2016 and july of 2017. Inclusion criteria were non-sensitized, ABO compatible, first time kidney transplant recipient, age 18 or older. Patients received an induction with antithymocyte globulin (ATG or Grafalon©), steroids and tacrolimus (once daily, envarsus©) together with everolimus from day 1 post-transplantation. Targeted trough level over the first month were 5-7 μg/l for tacrolimus and 4-6 μg/l for everolimus, then 4-5 for tacrolimus and 5-7 for everolimus.
We evaluated tacrolimus and everolimus AUC at day 7 post-transplant, then after 1 and 3 months.
We included 55 patients with an initial AUC at day 7. Among these patients, 36 had a follow-up measurement at month 1 or 3, and 19 had 3 measurements on day 7 and at month 1 and 3.
Taking into account all measurements, correlations between trough levels and the AUC were 0.79 (p for non-nullity < 0.001) for tacrolimus and 0.661 (p for non-nullity < 0.001) for everolimus. Figure 1 depicts the association of AUC and trough levels for both tacrolimus and everolimus. These correlations are depicted in figure 1.
Evolution of tacrolimus and everolimus trough levels are represented on figure 2.
A linear model of tacrolimus AUC predicted by tacrolimus trough level and sampling occasion does not show a significant effect of the sampling occasion on the link between trough levels and AUC (p=0.269 for nullity of the interaction coefficient). This shows that changing everolimus concentrations do not change this link. We can therefore still rely on tacrolimus trough levels for AUC estimations, when using tacrolimus together with everolimus.