Received for publication September 14, 2007.
Revised November 2, 2007.
Accepted for publication November 5, 2007.

The Guinea Pig as a Preclinical Model for Demonstrating the Efficacy and Safety of Statins

Abstract

Statins, because of their excellent efficacy and manageable safety profile, represent a key component in the current armamentarium for the treatment of hypercholesterolemia. Nonetheless, myopathy remains a safety concern for this important drug class. Cerivastatin was withdrawn from the market for myotoxicity safety concerns. BMS-423526, similar to cerivastatin in potency and lipophilicity, was terminated in early clinical development due to an unacceptable myotoxicity profile. In this report, we describe the guinea pig as a model of statin-induced cholesterol lowering and myotoxicity, and show that this model can distinguish statins with unacceptable myotoxicity profiles from statins with acceptable safety profiles. In our guinea pig model, both cerivastatin and BMS-423526 induced mytoxicity at doses near the ED₅₀ for total cholesterol (TC) lowering in plasma. In contrast, wide differences between myotoxic and TC-lowering doses were established for the currently marketed, more hydrophilic statins, pravastatin, rosuvastatin, and atorvastatin. This in vivo model compared favorably to an in vitro model which utilized statin inhibition of cholesterol synthesis in rat hepatocytes and L6 myoblasts as surrogates of potential efficacy and toxicity, respectively. Our conclusion is that the guinea pig is a useful preclincal in vivo model for demonstrating whether a statin is likely to have an acceptable therapeutic safety margin.

Key words: Cholesterol, HMG-CoA Reductase, Hypercholesterolemia, Myotoxicity, Rhabdomyolysis, Statin