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 Cerivastatin was withdrawn from the market for myotoxicity safety concerns.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 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.
Footnotes
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↵1 An ascending multiple-dose clinical study was conducted in healthy subjects to examine the safety, pharmacokinetics, and pharmacodynamics of BMS-423526 following once daily administration for 14 days. The mean percentage decrease in plasma levels of LDLc relative to baseline was 18 (0.5 mg), 34 (1 mg), 38 (2.5 mg), 54 (5 mg), 52 (10 mg), 57 (20 mg), and 56% (40 mg). Elevated plasma CK (>10 times the upper limit of normal) was noted in one subject (of six) at the 20-mg dose and also in four of six subjects treated with 40 mg, three of whom manifested reversible rhabdomyolysis.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.131615.
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ABBREVIATIONS: HMGR, 3-hydroxy-3-methylglutaryl-CoA reductase; atorvastatin, {(3R,5R)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-yl-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid} calcium salt; rosuvastatin, {(3R,5R)-7-[4-(4-fluorophenyl)-2-(methylmethylsulfonyl-amino)-6-propan-2-yl-pyrimidin-5-yl]-3,5-dihydroxy-heptanoic acid} calcium salt; 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; cerivastatin, {(3R,5S)-7-[4-(4-fluorophenyl)-5-(methoxymethyl)-2,6-dipropan-2-yl-pyridin-3-yl]-3,5-dihydroxy-heptanoic acid} sodium salt; pravastatin, {(3R,5R)-7-[(1S,2R,6S,8S,8aR)-6-hydroxy-2-methyl-8-[(2S)-2-methylbutanoyl]oxy-1,2,6,7,8,8a-hexahydronaphthalen-1-yl]-3,5-dihydroxyheptanoic acid} sodium salt; CK, creatine kinase; TC, total cholesterol; LC/MS/MS, liquid chromatography tandem mass spectroscopy; HPLC, high-performance liquid chromatography; LDLc, low-density lipoprotein cholesterol; KRB, Krebs-Ringer buffer.
- Received September 13, 2007.
- Accepted November 5, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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