The Guinea pig as a preclinical model for demonstrating the efficacy and safety of statins.
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 Cerivastatin was withdrawn from the market for myotoxicity safety concerns.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.
Madsen
Cort S
CS
Department of Atherosclerosis, Bristol-Myers Squibb Co., 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, USA. cort.madsen@bms.com
Janovitz
Evan
E
Zhang
Rongan
R
Nguyen-Tran
Van
V
Ryan
Carol S
CS
Yin
Xiaohong
X
Monshizadegan
Hossain
H
Chang
Ming
M
D'Arienzo
Celia
C
Scheer
Susan
S
Setters
Robert
R
Search
Debra
D
Chen
Xing
X
Zhuang
Shaobin
S
Kunselman
Lori
L
Peters
Andrew
A
Harrity
Thomas
T
Apedo
Atsu
A
Huang
Christine
C
Cuff
Carolyn A
CA
Kowala
Mark C
MC
Blanar
Michael A
MA
Sun
Chong-Qing
CQ
Robl
Jeffrey A
JA
Stein
Philip D
PD
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
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors