Population pharmacokinetics of meltdose tacrolimus (EnvarsusⓇ) in stable adult liver transplant recipients

M. Biewenga, L.C. Martial, B.N. Ruijter, J.J. Swen, D.J.A.R. Moes, B. van Hoek

Thursday 5 march 2020

14:10 - 14:20h at Theaterzaal

Parallel session: Parallel sessie XII – Klinische en Basale abstracts

Background: Meltdose tacrolimus (Envarsus®) is a new tacrolimus formulation marketed as a tacrolimus formulation with a more consistent exposure. Due to the narrow therapeutic window of tacrolimus, therapeutic drug monitoring is essential to achieve adequate exposure. The area under the concentration-time-curve over 24 hours (AUC) is the best link between concentration and effect. The aim of this study was to develop a population pharmacokinetic (PK) model of Envarsus® in adult liver transplant and construct a limited sampling strategy (LSS) in order to predict the AUC.

Methods: Stable adult liver transplant patients were converted from prolonged release tacrolimus (Advagraf®) to Envarsus® and AUC measurement (8 time points) was performed 2 weeks after conversion. Nonlinear-mixed-effects-modelling (NONMEM) and R statistics were used for the analyses.

Results: 55 patients were converted to Envarsus® with a median dose of 2mg once daily (range:0.75-6mg) of which 53 (total 748 concentrations) could be included for PK analysis. 35% was female and the median age was 57 years (range 21-70), median body weight was 81 kg (range 54-135).

Envarsus® absorption varied widely between and within patients in terms of Cmax and Tmax. The PK was best described by a two compartmental model based on. Absorption was best described by 1,6 transit compartments with mean transit time of 3,4h. The PK parameters along with their % interindividual variability (IIV) were as follows: clearance (CL): 3,27 L/h (34%); intercompartmental clearance (Q): 9,6 L/h, volume of distribution of compartment 1: 95 L (141%); volume of distribution of compartment 2: 500 L.

Two LSS of 4 time points (t=0,4,8,12 & 0,1,3,6) resulted in adequate AUC prediction with a median(range) bias of 1,5% (-9,2 – 12,5) and 0% (-7,6 - 13,4). The best 3-point LSS was t=0,4,8 with a median bias of 1,8% (-12,5 – 12,5). A correlation coefficient (Pearson, r²) of 0,89 between trough concentrations and AUC was found.

Conclusions: The PK of Envarsus® in stable adult liver transplant patients was adequately described by a 2-compartmental model with transit compartments for absorption. The PK model was used to develop a 3-point LSS in order to predict the AUC with maximal 12,5% bias. A 4-point LSS (t=0,4,8,12 or 0,1,3,6), led to even lower bias. This LSS can be used in routine clinical care to adequately predict AUC in a patient-friendly way with reduced health-care costs.