TY - JOUR
T1 - A Semi-Physiological Population Model to Quantify the Effect of Hematocrit on Everolimus Pharmacokinetics and Pharmacodynamics in Cancer Patients
AU - van Erp, Nielka P.
AU - van Herpen, Carla M.
AU - de Wit, Djoeke
AU - Willemsen, Annelieke
AU - Burger, David M.
AU - Huitema, Alwin D.R.
AU - Kapiteijn, Ellen
AU - ter Heine, Rob
N1 - Publisher Copyright:
© 2016, The Author(s).
PY - 2016/11/1
Y1 - 2016/11/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84974856147&partnerID=8YFLogxK
U2 - 10.1007/s40262-016-0414-3
DO - 10.1007/s40262-016-0414-3
M3 - Article
C2 - 27299325
AN - SCOPUS:84974856147
SN - 0312-5963
VL - 55
SP - 1447
EP - 1456
JO - Clinical Pharmacokinetics
JF - Clinical Pharmacokinetics
IS - 11
ER -