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

Clin Pharmacokinet. 2016 Nov;55(11):1447-1456. doi: 10.1007/s40262-016-0414-3.

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.

Publication types

  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / pharmacokinetics*
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Dose-Response Relationship, Drug
  • Everolimus / pharmacokinetics*
  • Everolimus / pharmacology
  • Everolimus / therapeutic use*
  • Female
  • Hematocrit*
  • Humans
  • Male
  • Middle Aged
  • Models, Biological
  • Neoplasms / drug therapy*
  • Neoplasms / pathology
  • Ribosomal Protein S6 Kinases, 70-kDa / antagonists & inhibitors

Substances

  • Antineoplastic Agents
  • Everolimus
  • Ribosomal Protein S6 Kinases, 70-kDa
  • ribosomal protein S6 kinase, 70kD, polypeptide 1