Population Pharmacokinetics and Bayesian Estimators for Refined Dose Adjustment of a New Tacrolimus Formulation in Kidney and Liver Transplant Patients

A new once-daily formulation of tacrolimus (Envarsus(A (R))) has recently been developed, with alleged different pharmacokinetics from previous tacrolimus formulations. The objectives of this study were to develop population pharmacokinetic models and Bayesian estimators based on limited sampling strategies for Envarsus(A (R)) in kidney and liver transplant recipients. Full tacrolimus concentration-time profiles (13 samples) were drawn from 57 liver (113 profiles) and 49 kidney (97 profiles) graft recipients transplanted for at least 6 months and switched from Prograf(A (R)) to Envarsus(A (R)). The two databases were split into a development (75%) and a validation (25%) dataset. Pharmacokinetic models characterised by a single compartment with first-order elimination and absorption in two phases described by a sum of two gamma distributions were developed using non-parametric (Pmetrics) and parametric (ITSIM) approaches in parallel. The best limited sampling strategy for each patient group was determined using the multiple model optimal algorithm. The performance of the models and derived Bayesian estimators was evaluated in the validation set. The best limited sampling strategy was 0, 8 and 12 h post-dose, leading to a relative bias +/- standard deviation (root-mean-square error) between observed and modelled inter-dose area under the curve in the validation dataset of: 0.32 +/- 6.86% (6.87%) for ITSIM and 3.4 +/- 13.4% (13.2%) for Pmetrics in kidney transplantation; and 0.89 +/- 7.32% (7.38%) for ITSIM and -2.62 +/- 8.65% (8.89%) for Pmetrics in liver transplantation. Population pharmacokinetic models and Bayesian estimators for Envarsus(A (R)) in kidney and liver transplantation were developed and are now available online for area under the curve-based tacrolimus dose adjustment.