Preclinical safety evaluation of cerivastatin, a novel HMG-CoA reductase inhibitor

Cerivastatin is a new but structurally distinct 8-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor ("statin"). It effectively decreases low-density lipoprotein (LDL) cholesteral at 1% of the doses of other currently available statins. The toxicology of cerivastatin was evaluated in a comprehensive program of studies including: (1) single- and multiple-dose toxicity studies in rats, mice, minipigs, dogs, and monkeys; (2) reproductive toxicity studies in rats and rabbits; (3) in vitro and in vivo mutagenicity assays in rats and mice; and (4) carcinagenicity studies in rats and mice. In addition, studies were undertaken to investigate the effects of cerivastatin on lens opacity, testicular tissue, and hemorrhage in dogs. Oral administration of single and multiple doses of cerivastatin over periods ranging from 4 weeks to 24 months was generally well tolerated. Adverse effects were similar to those observed with other statins and primarily involved the liver and muscle tissue. At the high doses used in the toxicologic studies, cerivastatin caused elevations in serum transaminases and creatine phasphokinase levels as well as some degeneration of muscle fibers in rats, mice, dogs, and minipigs. In dogs, the species most sensitive to statins, cerivastatin caused erosions and hemorrhages in the gastrointestinal tract, bleeding in the brain stem with fibroid degeneration of vessel walls in the choroid plexus, and lens opacity. Apart from minor morphologic changes in the testicular tissue of dogs-the only organ for which a comparably low margin of safety was observed- cerivastatin had no significant effects on the male or female reproductive system. Cerivastatin also caused no primary embryotoxic or teratogenic effects. With the exception of cerivastatin-induced effects on the eyes and testicles, administration of mevalanic acid reversed the toxicologic effects of cerivastatin, indicating that the toxic effects were related to its mode of action and nat to any intrinsic toxicity of the molecule itself. There was no evidence that cerivastatin had any mutagenic effects and, in contrast to other statins, high doses of cerivastatin did not induce rumors in rats. The main metabolite of cerivastatin was well tolerated systemically in all animals, including dogs. Overall, cerivastatin has a similar toxicolagic profile to other statins and is a well-tolerated HMG-CoA reductase inhibitor. (C) 1998 by Excerpta Medica, Inc.