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

Area of Science:

• Pharmacology
• Oncology
• Translational Medicine

Background:

• The mTOR inhibitor RAD001 (everolimus) is used in cancer therapy.
• Understanding species-specific pharmacokinetics (PK) is crucial for effective drug development and translation from preclinical models to humans.

Purpose of the Study:

• To conduct a comparative pharmacokinetic (PK) analysis of RAD001 in rats and mice.
• To evaluate the PK properties of RAD001 in blood, tissues, and tumors across different dosing regimens.
• To compare rodent PK profiles with known human PK data.

Main Methods:

• Determined blood cell partitioning, plasma protein binding, and PK parameters of RAD001 in rats and mice.
• Utilized PK modeling to predict drug levels in plasma, blood, and tumors.
• Employed DCE-MRI to assess tumor vascularity and in vitro/in vivo assays for anti-tumor activity.

Main Results:

• Significant differences in RAD001 PK were observed between mice and rats, affecting erythrocyte partitioning, bioavailability, and tissue penetration.
• Modeling indicated higher tumor drug accumulation in rats (7.9-fold) compared to mice (2-fold) with daily dosing.
• Rat tumors showed greater plasma content and permeability, contributing to higher drug uptake. Maximal anti-tumor effects were achieved with similar unbound drug concentrations in both species.
• Brain penetration of RAD001 was poor but dose-dependent, with rats showing over-proportional uptake.

Conclusions:

• The PK profile of RAD001 in rats more closely resembles that of humans than in mice.
• Findings suggest that high intermittent doses of RAD001 may be a more suitable strategy for treating brain tumors.