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Clinical Pharmacokinetics
Published in: Clinical Pharmacokinetics 11/2016

Open Access 01-11-2016 | Original Research Article

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

Authors: Nielka P. van Erp, Carla M. van Herpen, Djoeke de Wit, Annelieke Willemsen, David M. Burger, Alwin D. R. Huitema, Ellen Kapiteijn, Rob ter Heine, PhD, PharmD

Published in: Clinical Pharmacokinetics | Issue 11/2016

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Abstract

Introduction and Objective

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.

Methods

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.

Results

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.

Conclusions

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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Metadata
Title
A Semi-Physiological Population Model to Quantify the Effect of Hematocrit on Everolimus Pharmacokinetics and Pharmacodynamics in Cancer Patients
Authors
Nielka P. van Erp
Carla M. van Herpen
Djoeke de Wit
Annelieke Willemsen
David M. Burger
Alwin D. R. Huitema
Ellen Kapiteijn
Rob ter Heine, PhD, PharmD
Publication date
01-11-2016
Publisher
Springer International Publishing
Published in
Clinical Pharmacokinetics / Issue 11/2016
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI
https://doi.org/10.1007/s40262-016-0414-3

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