title: 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 Cerivastatin was withdrawn from the market for myotoxicity safety concerns.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 [{(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 ED(50) 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.
authors.affiliation: Department of Atherosclerosis, Bristol-Myers Squibb Co., 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA. cort.madsen@bms.com
authors.forename: Cort S
authors.initials: CS
authors.lastname: Madsen
authors.forename: Evan
authors.initials: E
authors.lastname: Janovitz
authors.forename: Rongan
authors.initials: R
authors.lastname: Zhang
authors.forename: Van
authors.initials: V
authors.lastname: Nguyen-Tran
authors.forename: Carol S
authors.initials: CS
authors.lastname: Ryan
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Yin
authors.forename: Hossain
authors.initials: H
authors.lastname: Monshizadegan
authors.forename: Ming
authors.initials: M
authors.lastname: Chang
authors.forename: Celia
authors.initials: C
authors.lastname: D'Arienzo
authors.forename: Susan
authors.initials: S
authors.lastname: Scheer
authors.forename: Robert
authors.initials: R
authors.lastname: Setters
authors.forename: Debra
authors.initials: D
authors.lastname: Search
authors.forename: Xing
authors.initials: X
authors.lastname: Chen
authors.forename: Shaobin
authors.initials: S
authors.lastname: Zhuang
authors.forename: Lori
authors.initials: L
authors.lastname: Kunselman
authors.forename: Andrew
authors.initials: A
authors.lastname: Peters
authors.forename: Thomas
authors.initials: T
authors.lastname: Harrity
authors.forename: Atsu
authors.initials: A
authors.lastname: Apedo
authors.forename: Christine
authors.initials: C
authors.lastname: Huang
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Cuff
authors.forename: Mark C
authors.initials: MC
authors.lastname: Kowala
authors.forename: Michael A
authors.initials: MA
authors.lastname: Blanar
authors.forename: Chong-Qing
authors.initials: CQ
authors.lastname: Sun
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Robl
authors.forename: Philip D
authors.initials: PD
authors.lastname: Stein
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006168:Guinea Pigs / Q000097:blood / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects*; D008297:Male; D023421:Models, Animal; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors