TY - JOUR T1 - The Guinea Pig as a Preclinical Model for Demonstrating the Efficacy and Safety of Statins JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 576 LP - 586 DO - 10.1124/jpet.107.131615 VL - 324 IS - 2 AU - Cort S. Madsen AU - Evan Janovitz AU - Rongan Zhang AU - Van Nguyen-Tran AU - Carol S. Ryan AU - Xiaohong Yin AU - Hossain Monshizadegan AU - Ming Chang AU - Celia D'Arienzo AU - Susan Scheer AU - Robert Setters AU - Debra Search AU - Xing Chen AU - Shaobin Zhuang AU - Lori Kunselman AU - Andrew Peters AU - Thomas Harrity AU - Atsu Apedo AU - Christine Huang AU - Carolyn A. Cuff AU - Mark C. Kowala AU - Michael A. Blanar AU - Chong-qing Sun AU - Jeffrey A. Robl AU - Philip D. Stein Y1 - 2008/02/01 UR - http://jpet.aspetjournals.org/content/324/2/576.abstract N2 - 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 Cerivastatin was withdrawn from the market for myotoxicity safety concerns.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 [{(3R,5S)-7-[4-(4-fluorophenyl)-6,7-dihydro-2-(1-methylethyl)-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-3-yl]-3,5-dihydroxy-heptenoic acid} sodium salt], 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 myotoxicity 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 used 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 preclinical in vivo model for demonstrating whether a statin is likely to have an acceptable therapeutic safety margin. The American Society for Pharmacology and Experimental Therapeutics ER -