Program 1

In vivo HDL-c and LDL-c kinetics using radiotracers, and development of a dyslipidemic hamster model based on a nutritional approach

In view of the crucial importance of cholesterol management in dyslypidemic and diabetic populations, in 2004 we initiated a research program focusing on in vivo lipoprotein flux measurements and on developing predictive animal nutritional models.

Lipoprotein and cholesterol kinetics platform

Recent drug failures in the late clinical development stage clear illustrate the difficulty of anticipating the benefit/risk ratio of a new class of drug affecting lipoprotein metabolism. Circulating HDL-c and LDL-c levels alone do not always accurately predict functional drug efficacy or the impact on physiological equilibrium (indirect safety concerns).
This project is studying the in vivo kinetics of LDL-cholesterol, HDL-cholesterol, and apoproteins apoB100 and apoA1. This will be useful for precisely evaluating the mechanisms involved in production, clearance and tissue uptake. Unlike plasma variables, the mechanistic information provided by cholesterol and apolipoprotein kinetics provides:

1. Robust in vivo proof of concept
2. Prediction of in vivo safety issues by studying the consequences of biomarker changes on the global physiological balance and on individual organs.

This platform could be used for example to evaluate the liver toxicity of a drug candidate targeting reverse cholesterol transport, by detecting subnormal fecal cholesterol elimination that may be associated with severe hepatic steatosis.

Predictive dyslipidemic animal nutritional model

Contrary to classical model mice and rats, hamsters, like humans, have natural CETP activity. This project is aimed at developing a specific diet for generating a dyslipidemic hamster model displaying hypertriglyceridemia associated with high LDl-c and low HDl-c levels. This model will be assessed for its clinical and pharmacological relevance by using already marketed drugs. 
This 3-year 1.5-M€ program was funded by the French government in 2006 (ANR grant).
The first results on the dyslipidemic hamster and LDL and HDL-C kinetics are already available. More data are expected in September 2008.