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Clin Pharmacokinet. 2016 Nov;55(11):1447-1456.

A Semi-Physiological Population Model to Quantify the Effect of Hematocrit on Everolimus Pharmacokinetics and Pharmacodynamics in Cancer Patients.

Author information

Department of Pharmacy, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
Department of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands.
Department of Clinical Pharmacy and Toxicology, Leiden University Medical Centre, Leiden, The Netherlands.
Department of Pharmacy and Pharmacology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
Department of Medical Oncology, Leiden University Medical Centre, Leiden, The Netherlands.
Department of Pharmacy, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.



Everolimus (a drug from the class of mammalian target of rapamycin [mTOR] inhibitors) is associated with frequent toxicity-related dose reductions. Everolimus accumulates in erythrocytes, but the extent to which hematocrit affects everolimus plasma pharmacokinetics and pharmacodynamics is unknown. We aimed to investigate the everolimus pharmacokinetics/pharmacodynamics and the influence of hematocrit in cancer patients.


A semi-physiological pharmacokinetic model for everolimus was developed from pharmacokinetic data from 73 patients by non-linear mixed-effects modeling. Using a simulation study with a known pharmacodynamic model describing S6K1 (a downstream mTOR effector) inhibition, we investigated the impact of hematocrit.


The apparent volume of distribution of the central and peripheral compartment were estimated to be 207 L with a relative standard error (RSE) of 5.0 % and 485 L (RSE 4.2 %), respectively, with an inter-compartmental clearance of 72.1 L/h (RSE 3.2 %). The apparent intrinsic clearance was 198 L/h (RSE 4.3 %). A decrease in hematocrit from 45 % to 20 % resulted in a predicted reduction in whole-blood exposure of ~50 %, but everolimus plasma pharmacokinetics and pharmacodynamics were not affected. The predicted S6K1 inhibition was at a plateau level in the approved dose of 10 mg once daily.


A population pharmacokinetic model was developed for everolimus in cancer patients. Hematocrit influenced whole-blood pharmacokinetics, but not plasma pharmacokinetics or pharmacodynamics. Everolimus whole-blood concentrations should always be corrected for hematocrit. Since predicted mTOR inhibition was at a plateau level in the approved dose, dose reductions may have only a limited impact on mTOR inhibition.

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Conflict of interest statement

Compliance with Ethical StandardsAcknowledgmentsThe authors would like to acknowledge Elisabet Størset at the Oslo University Hospital in Norway for her helpful discussions on NONMEM® control stream coding for erythrocyte accumulation of everolimus. Jan den Hartigh from the Leiden University Medical Center and Karin Hoogtanders from the Maastricht University Medical Center are also greatly acknowledged for their help in bioanalysis of everolimus. Novartis is acknowledged for financially funding the clinical study with everolimus.Conflict of interestN. P. van Erp has received a research grant from Novartis to perform the presented study with everolimus. C. M. van Herpen, D. de Wit, A. E. C. A. B. Willemsen, D. M. Burger, A. D. R. Huitema, E. Kapiteijn, and R. ter Heine declare that they have no conflicts of interest.Ethical ApprovalAll 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.Informed consentInformed consent was obtained from all individual participants included in the study.

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