RT Journal Article
SR Electronic
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
FD American Society for Pharmacology and Experimental Therapeutics
SP 576
OP 586
DO 10.1124/jpet.107.131615
VO 324
IS 2
A1 Cort S. Madsen
A1 Evan Janovitz
A1 Rongan Zhang
A1 Van Nguyen-Tran
A1 Carol S. Ryan
A1 Xiaohong Yin
A1 Hossain Monshizadegan
A1 Ming Chang
A1 Celia D'Arienzo
A1 Susan Scheer
A1 Robert Setters
A1 Debra Search
A1 Xing Chen
A1 Shaobin Zhuang
A1 Lori Kunselman
A1 Andrew Peters
A1 Thomas Harrity
A1 Atsu Apedo
A1 Christine Huang
A1 Carolyn A. Cuff
A1 Mark C. Kowala
A1 Michael A. Blanar
A1 Chong-qing Sun
A1 Jeffrey A. Robl
A1 Philip D. Stein
YR 2008
UL http://jpet.aspetjournals.org/content/324/2/576.abstract
AB 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 Cerivastatin was withdrawn from the market for myotoxicity safety concerns.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