Population pharmacokinetics and pharmacogenetics of everolimus in renal transplant patients on a calcineurin inhibitor free regimen
D.J.A.R. Moes (1)(2), RR. Press (1)(2), J. den Hartigh (1), T. van der Straaten (1), Johan W. de Fijter (2), Henk-Jan Guchelaar (1)
(1)Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands; (2)Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands
Objectives: Everolimus is an immunosuppressant with a small therapeutic window. Its highly variable pharmacokinetics complicates prediction of the individual dose as to assure reaching adequate everolimus exposure in renal transplant patients. The aim of this study was to describe the population pharmacokinetics in renal transplant patients following oral administration of everolimus twice daily in absence of CNI's and to investigate whether demographic factors or polymorphisms in genes coding for ABCB1, CYP3A5, CYP2C8, Pregnane X receptor could explain the observed inter-individual variability.
Methods: A total of 779 blood samples obtained from 53 renal transplant patients who had been switched from cyclosporine to a calcineurin inhibitor free regimen of everolimus (3 mg twice daily) and prednisolone were collected over a 1.5 year period. Everolimus blood concentrations were analyzed using liquid chromatography tandem mass spectrometry during routine therapeutic drug monitoring. A population pharmacokinetic model using NONMEM was build and demographic factors and genetic polymorphisms in genes coding for ABCB1, CYP3A5, CYP2C8, Pregnane X receptor were included as covariates.
Results: The pharmacokinetics of everolimus was best described by an two compartment disposition model with first order absorption and lag-time. Parameter estimates of the final model were: Ka 7.55, CL/F 17.9 L/h, Vc/F 148 L, Q/F 55.7 L/h, Vp/F 498 L. A significant contribution was found for the demographic covariate Ideal Weight on everolimus distribution volume of the central compartment which explained 15.4 % of the inter-individual variability. None of the selected genetic polymorphisms contributed significantly in explaining the variability in everolimus pharmacokinetics. The remaining inter-individual variability in CL/F was 26.2% and inter-occasion variability of F was 25.9 %.
Conclusions: A two compartment pharmacokinetic model with lag-time describing the concentration time profile of oral everolimus in renal transplant patients has been developed. Ideal Body Weight significantly influences the apparent volume of distribution of everolimus, whereas polymorphisms in genes coding for ABCB1, CYP3A5, CYP2C8, Pregnane X receptor do not significantly influence everolimus pharmacokinetics.