A population pharmacokinetic model on the whole-blood to intracellular disposition of tacrolimus in renal transplant patients: a comparative study on formulations
Summary
Introduction and objective: Tacrolimus (Tac) is the cornerstone in follow-up care after organ transplantations and kept under review throughout therapy with therapeutic drug monitoring of whole-blood (WhB) concentrations. Though, rejection and drug related toxicity remains a problem. Dosing the drug on intracellular concentrations in peripheral blood mononuclear cells (PBMCs) might be a more suitable metric. To enable this, the disposition of Tac in PBMCs from WhB needs to be clarified. The study tries to create more insight in the pharmacokinetics of Tac with a population pharmacokinetic (PK) model, while also comparing two formulations (Prograf and Envarsus) with different release profiles (immediate versus extended release).
Methods: A post-hoc analysis was performed using non-linear mixed effects modelling software. Visual predictive checks, goodness-of-fit plots and bootstrapping was utilized to evaluate the final model.
Results: 36 full PK profiles were recorded of stable renal transplant patients, of which 35 were used for the model on Prograf and 31 for the model of Envarsus. A two-compartment model with delayed first order absorption, following gamma distribution, and first order elimination best described the data. The models showed good predictive performance. Tac-WhB to intracellular PBMC disposition was comparable for both formulations. Differences between the two formulations were demonstrated in the absorption phase and apparent volumes of distribution. CYP3A5*1 polymorphism was the only covariate included in the final model.
Discussion: In general, results seemed to be congruent and the PK behavior of Tac was further unraveled. Although, an extensive amount of improvements and future perspectives are identified. The low amount of included patients disables the ability to evaluate some covariates and decreases the representability of the study. Also, some physiological illogical results were generated by the final model. Although, theories are suggested as to how these results have been generated.