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Clinical Pharmacokinetics

, Volume 57, Issue 11, pp 1459–1469 | Cite as

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
  • Jean Debord
  • Anders Åsberg
  • Pierre Marquet
  • Jean-Baptiste Woillard
Original Research Article

Abstract

Background and Objective

Intracellular exposure of everolimus may be a better marker of therapeutic effect than trough whole blood concentrations. We aimed to develop pharmacokinetic population models and Bayesian estimators 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 haplotype, 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.

Notes

Acknowledgements

The authors thank Mrs Karen Poole of the Department of Pharmacology, Toxicology and Pharmacovigilance, CHU Limoges for manuscript editing.

Compliance with Ethical Standards

Funding

The authors did not receive any funding for this project.

Conflict of interest

I. Robertsen, J. Debord, A. Åsberg, K. Midtvedt, P. Marquet, and J.-B. Woillard declare that they have no conflicts of interest.

Research involving human participants

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Supplementary material

40262_2018_646_MOESM1_ESM.docx (55 kb)
Supplementary material 1 (DOCX 56 kb)
40262_2018_646_MOESM2_ESM.docx (529 kb)
Supplementary material 2 (DOCX 529 kb)
40262_2018_646_MOESM3_ESM.docx (947 kb)
Supplementary material 3 (DOCX 947 kb)

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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Pharmaceutical Biosciences, School of PharmacyUniversity of OsloOsloNorway
  2. 2.Department of Pharmacology, Toxicology and PharmacovigilanceCHU LimogesLimogesFrance
  3. 3.INSERM, UMR 1248, University of LimogesLimogesFrance
  4. 4.Department of Transplantation Medicine, Clinic for Surgery, Inflammatory Medicine and TransplantationOslo University Hospital-RikshospitaletOsloNorway

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