ORIGINAL RESEARCH ARTICLE A Limited Sampling Strategy to Estimate Exposure of Everolimus in Whole Blood and Peripheral Blood Mononuclear Cells in Renal Transplant Recipients Using Population Pharmacokinetic Modeling and Bayesian Estimators Ida Robertsen 1 • Jean Debord 2,3 • Anders A ˚ sberg 1,4 • Pierre Marquet 2,3 • Jean-Baptiste Woillard 2,3 Ó Springer International Publishing AG, part of Springer Nature 2018 Abstract Background and Objective Intracellular exposure of ever- olimus may be a better marker of therapeutic effect than trough whole blood concentrations. We aimed to develop pharmacokinetic population models and Bayesian estima- tors based on a limited sampling strategy for estimation of dose interval exposures of everolimus in whole blood and peripheral blood mononuclear cells (PBMCs) in renal transplant recipients. Methods Full whole blood and PBMC concentration–time profiles of everolimus were obtained from 12 stable renal transplant recipients on two different occasions, 4 weeks apart. The dataset was treated as 24 individual profiles and split into a development dataset (n = 20) and a validation dataset (n = 4). The pharmacokinetic model was developed using non-parametric modeling and its performances and those of the derived Bayesian estimator were evaluated in the validation set. Results A structural two-compartment model with first- order elimination and two absorption phases described by a sum of two gamma distributions were developed. None of the tested covariates (age, sex, albumin, hematocrit, fat-free mass and genetic variants such as CYP3A5*1, ABCB1 hap- lotype, PPARA*42, PPARA*48, and POR*28) were retained in the final model. A limited sampling schedule of two whole blood samples at 0 and 1.5 h and one PBMC sample at 1.5 h post dose provided accurate estimates of the area under the plasma concentration–time curve (AUC) in comparison with the trapezoidal reference AUC (relative bias ± standard deviation = - 3.9 ± 10.6 and 4.1 ± 12.3% for whole blood and PBMC concentrations, respectively). Conclusion The developed model allows simultaneous and accurate prediction of everolimus exposure in whole blood and PBMCs, and supplies a base for a feasible exploration of the relationships between intracellular exposure and therapeutic effects in prospective trials. Key Points A novel population pharmacokinetic model allowing a joint determination of everolimus in whole blood and peripheral blood mononuclear cells (PBMC) has been developed. Bayesian Estimators were developed based on a limited sampling strategy using only two whole blood and one PBMC sample to accurately predict whole blood and intracellular exposure of everolimus. The model offers an opportunity to explore the relationship between intracellular everolimus exposure and the clinical effect in prospective trials. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s40262-018-0646-5) contains supple- mentary material, which is available to authorized users. & Ida Robertsen ida.robertsen@farmasi.uio.no 1 Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, P.O. Box 1068 Blindern, 0316 Oslo, Norway 2 Department of Pharmacology, Toxicology and Pharmacovigilance, CHU Limoges, Limoges, France 3 INSERM, UMR 1248, University of Limoges, Limoges, France 4 Department of Transplantation Medicine, Clinic for Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital-Rikshospitalet, Oslo, Norway Clin Pharmacokinet https://doi.org/10.1007/s40262-018-0646-5