Monday July 02, 2018 from 16:30 to 17:30
A Limited Sampling Strategy to Estimate Whole Blood and Intra-lymphocyte Exposure of Everolimus in Renal Transplant Recipients using Population Pharmacokinetic Modeling and Bayesian Estimators
Ida Robertsen1, Jean Debord2, Anders Åsberg1,3, Pierre Marquet2, Jean Baptiste Woillard2.
1Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway; 2Department of Pharmacology, Toxicology and Pharmacovigilance, CHU Limoges, Limoges, France; 3Department of Transplantation Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
Introduction: Intra-lymphocyte exposure of everolimus may be a better marker of therapeutic effect compared to trough whole blood concentrations. We aimed to develop pharmacokinetic population models and Bayesian estimators based on a limited sampling strategy for estimation of whole blood and intra-lymphocyte dose interval exposures of everolimus in renal transplants.
Methods: Full whole-blood and intra-lymphocyte concentration-time profiles of everolimus were obtained from 12 stable renal transplants 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 (Pmetrics) 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, gender, CYP3A5-genotype, hematocrit, fat-free mass) were retained in the final model. A limited sampling schedule of two whole blood samples at 0 and 1.5 hours and one intra-lymphocyte sample at 1.5 hours post dose provided accurate estimates of the area under the curve (AUC) in comparison with the trapezoidal reference AUC (relative bias ± SD = -3.9 ±10.6% and 4.1 ±12.3% for whole blood and intra-lymphocyte concentrations, respectively).
Conclusion: The developed model allows a simultaneous and accurate prediction of whole blood and intra-lymphocyte everolimus exposure based on two sample times and one intracellular concentrations determination. The model supplies a base for a feasible exploration of the relationships between intra-lymphocyte exposure and therapeutic effects in prospective trials.