Cancer Chemotherapy and Pharmacology

, Volume 65, Issue 4, pp 625–639

Comparative pharmacokinetics of RAD001 (everolimus) in normal and tumor-bearing rodents

  • Terence O’Reilly
  • Paul M. J. McSheehy
  • R. Kawai
  • O. Kretz
  • L. McMahon
  • J. Brueggen
  • A. Bruelisauer
  • H.-P. Gschwind
  • P. R. Allegrini
  • H. A. Lane
Original Article

DOI: 10.1007/s00280-009-1068-8

Cite this article as:
O’Reilly, T., McSheehy, P.M.J., Kawai, R. et al. Cancer Chemother Pharmacol (2010) 65: 625. doi:10.1007/s00280-009-1068-8

Abstract

Purpose

Comparative pharmacokinetic (PK) analysis of the mTOR inhibitor RAD001 (everolimus) in rats and mice.

Methods

Blood cell partitioning, plasma protein binding and PK parameters of RAD001 in blood and tissues (including brain) of both mice and rats were determined. PK modeling predicted plasma/blood and tumor levels from a variety of regimens and these were compared with the known human PK profile. DCE-MRI was used to compare tumor vascularity between mice and rats. Estimation of IC50 values in vitro and ED50 values in vivo were used to provide an indication of anti-tumor activity.

Results

The PK properties of RAD001 differed between mice and rats, including erythrocyte partitioning, plasma protein binding, plasma/blood t1/2, oral bioavailability, volume of distribution, tissue/tumor penetration and elimination. Modeling of tumor and blood/plasma PK suggested that in mice, multiple daily administrations result in a ~2-fold increase in tumor levels of RAD001 at steady state, whereas in rats, a ~7.9-fold increase would occur. Weekly high-dose regimens were predicted not to facilitate tumor accumulation in either species. Total tumor levels of RAD001 were four- to eight-fold greater in rats than in mice. Rat tumors had a >2-fold greater plasma content and permeability compared to mouse tumors, which could contribute to differences in tumor drug uptake. Maximal antitumor effects (T/C of 0.04–0.35) were observed in both species after daily administration with similar Cmax and AUC values of unbound (free) RAD001. These free levels of RAD001 are exceeded in serum from cancer patients receiving clinically beneficial daily regimens. In rodents, brain penetration of RAD001 was poor, but was dose-dependent and showed over-proportional uptake in rats with a longer t1/2 compared to the systemic circulation.

Conclusions

The PK of RAD001 differed between mice and rats, with rats having a PK profile closer to that of humans. High intermittent doses of RAD001 may be more appropriate for treatment of brain tumors.

Keywords

Everolimus RAD001 Pharmacokinetics Mice Rat Tumor 

Supplementary material

280_2009_1068_MOESM1_ESM.doc (938 kb)
Supplementary material 1 (DOC 938 kb)

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Terence O’Reilly
    • 1
  • Paul M. J. McSheehy
    • 1
  • R. Kawai
    • 2
  • O. Kretz
    • 2
  • L. McMahon
    • 3
    • 6
  • J. Brueggen
    • 4
  • A. Bruelisauer
    • 2
  • H.-P. Gschwind
    • 2
  • P. R. Allegrini
    • 4
  • H. A. Lane
    • 5
  1. 1.Department of Oncology ResearchNovartis Institutes for BioMedical ResearchBaselSwitzerland
  2. 2.Department of Drug Metabolism and PharmacokineticsNovartis Pharma AGBaselSwitzerland
  3. 3.Department of Drug Metabolism and PharmacokineticsNovartis Institutes for BioMedical ResearchEast HanoverUSA
  4. 4.Department of Oncology ResearchNovartis Institutes for BioMedical ResearchBaselSwitzerland
  5. 5.Basilea Pharmaceutica International AGBaselSwitzerland
  6. 6.Wyeth Medica IrelandKildareIreland

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