Preclinical and clinical pharmacology of cerivastatin

• Published in: The American journal of cardiology Vol. 82; no. 4; pp. 18J - 25J
• Main Authors: Bischoff, Hilmar, Heller, Allen H
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27-08-1998; Elsevier Limited
• Subjects: Animals; Arteriosclerosis - drug therapy; Arteriosclerosis - metabolism; Cardiovascular disease; Cholesterol; Clinical Trials, Phase I as Topic; Dogs; Drug Evaluation, Preclinical; Drug therapy; Enzymes; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacokinetics; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Lovastatin - pharmacokinetics; Lovastatin - pharmacology; Male; Pharmacology; Pyridines - pharmacokinetics; Pyridines - pharmacology; Rabbits; Rats; Safety
• ISSN: 0002-9149; 1879-1913
• DOI: 10.1016/S0002-9149(98)00433-0

Cerivastatin, a new, entirely synthetic, and enantiomerically pure 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, is pharmacologically potent and hepatically selective, with an uncomplicated pharmacokinetic profile. In vitro and acute in vivo studies in animals demonstrated that cerivastatin is markedly more pharmacologically potent than other statins. In rats and dogs, cerivastatin inhibited hepatic cholesterol synthesis at concentrations 100–150 times lower than lovastatin. Cerivastatin’s potent inhibition of HMG-CoA reductase (the rate-limiting step in cholesterol biosynthesis) is confirmed by its cholesterol-lowering properties, combined with significant triglyceride-decreasing effects, and dose-dependent increases in low-density lipoprotein (LDL) receptor binding in the liver. The antiatherogenic effects of cerivastatin extend beyond serum lipid and lipoprotein reductions to potent inhibition of migration of smooth muscle cells in vitro and reductions in the accumulation of cholesterol ester in the arterial tissue of rabbits. The high pharmacologic potency of cerivastatin, coupled with high liver selectivity, enable cerivastatin to be administered at 1–5% of the dose of currently available HMG-CoA reductase inhibitors. At ultra-low doses in the range 0.01–0.8 mg/day, cerivastatin proved to be both safe and well tolerated when administered to healthy volunteers in a series of ascending single- and multiple-dose studies. Cerivastatin has an uncomplicated pharmacokinetic profile; it can be administered to both young and elderly patients, male and female, without the need for dosage adjustments. Because no clinically significant pharmacokinetic drug interactions occur with cerivastatin, it may be the preferred HMG-CoA reductase inhibitor for patients on multiple-drug therapy including warfarin and digoxin.