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 Cerivastatin was withdrawn from the market for myotoxicity safety concerns.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 ,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.

Human Skeletal Muscle Drug Transporters Determine Local Exposure and Toxicity of Statins

“…In the guinea pig, skeletal muscle concentrations of rosuvastatin and atorvastatin are less than 10% of that found in plasma, suggesting that the balance is tipped toward higher efflux than uptake activity. 60 In our evaluation of the literature, the plasma-to-skeletal muscle concentration ratio of statins in humans is not known, but this value will undoubtedly be dependent on the relative expression and intrinsic activities of the attendant uptake (OATP2B1) and efflux (MRP1, MRP4, MRP5) transporters. The present results would also suggest that drug-statin interactions occurring not only at the level of the hepatocyte cell membrane but also in skeletal muscle fibers could contribute to myopathy.…”

Spruce Needle Polyprenols Protect Against Atorvastatin-Induced Muscle Weakness and do not Influence Central Nervous System Functions in Rats

“…In our study, we chose similar doses (10 and 20 mg/kg) and a lower dose (1 mg/kg) of PPs. The atorvastatin dose of 80 mg/kg and the treatment regimen for 16 days were in the mid range of values in the literature (Madsen et al, 2008).…”

Hypocholesterolaemic Effects of Probiotics

“…Probiotics are beneficial bacteria that influence the health of the host by improving their microbial balance. Modifications of intestinal flora have been shown to be beneficial on lipid metabolism in mice [2][3][4][5][6], rats [7][8][9][10][11], guinea pigs [12] and pigs [13]. In contrast, studies in humans [14,15] indicated that the role of fermented milk products as hypocholesterolaemic agents were inconsistent but more reliable effects were documented in the recent clinical studies [16][17][18][19].…”