The Safety Evaluation of Fluvastatin, an HMG–CoA Reductase Inhibitor, in Beagle Dogs and Rhesus Monkeys

Abstract

Fluvastatin is a potent synthetic competitive inhibitor of beta-hydroxy-beta-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in the biosynthetic pathway for hepatic cholesterol synthesis. The therapeutic indication is reduction of elevated total and low-density lipoprotein cholesterol levels. Results from four toxicity studies in beagle dogs and one study in rhesus monkeys following oral administration of fluvastatin are reported. In two 26-week dog studies, doses were 0, 1, 8, or 48 mg/kg/day (reduced to 36 mg/kg/day in Week 7) and 0, 6, 24, or 36 mg/kg/day (reduced to 30 mg/kg/day in Week 2). In a 2-year dog study, doses were 0, 1, 8, or 16 mg/kg/day. Dose levels in the 26-week monkey study were 0, 0.6, 12, and 48 mg/kg/day (raised to 84 mg/kg/day in Week 17 and to 108 mg/kg/day in Week 22). In these studies, evaluations included clinical and physical examinations, body weight and food consumption, electrocardiography, ophthalmoscopy, hematology and clinical chemistries, urinalysis, blood drug concentration, and macroscopic and microscopic examinations of observed lesions and representative tissues. In the 26- and 52-week dog studies and the monkey study, lenticular biochemistry, the HMG-CoA reductase activity of liver microsomes, and serum lipid concentrations were investigated. The fourth dog study was a single-dose toxicokinetic study in which 48 mg/kg [3H]-fluvastatin was monitored for up to 2 weeks. Sampling was limited to ocular tissues for enzyme analysis. Doses of > or = 24 mg/kg/day were lethal in dogs. At lethal doses, ataxia, convulsions, fecal blood, multifocal congestion and hemorrhage, isolated foci of malacia in the medulla oblongata, and liver necrosis were observed. Reduced weight gain, emesis, cataracts, elevated liver enzymes, reduced cholesterol, and gallbladder inflammation with mucosal hyperplasia occurred at > or = 8 mg/kg/day. In contrast to other HMG-CoA reductase inhibitors, fluvastatin did not cause significant central nervous system hemorrhage or testicular changes in dogs. Monkeys tolerated exposure to fluvastatin well with only mild gallbladder changes observed. Reduced serum cholesterol and slight hyperplasia of the gallbladder mucosa occurred in the 12 and 48/84/108 mg/kg/day groups.

The Toxicology of HMG—CoA Reductase Inhibitors: Prediction of Human Risk

“…At high dosage levels in dogs treated with some HMG-CoA reductase inhibitors, significant evidence of liver pathology is observed (Walsh and Rockwell, 1999;Hartman et al, 1996). With other reductase inhibitors, elevations in serum transaminase activity were observed in dogs in the absence of any morphologic abnormalities in the liver or other tissues Gerson et al, 1989;Gerson et al, 1991).…”

“…High doses of the HMG-CoA reductase inhibitors atorvastatin or fluvastatin given to beagle dogs can result in hepatocellular degeneration or necrosis, inflammation and necrosis of gallbladder epithelium and evidence of bile duct hyper- plasia (Corsini et al, 1966;Hartman et al, 1996;Walsh et al, 1996). With other statins, administration to dogs for extended periods of time (up to 2 years) with high doses results in significant elevations of serum transaminase activity in the absence of evidence of hepatic morphologic changes detected either by light or electron microscopy Gerson et al, 1989Gerson et al, , 1991.…”

“…Although no similar direct evidence is available from pharmacologic intervention studies with mevalonate, fluvastatin and atorvastatin produce similar effects in dog gallbladder epithelium (Corsini et al, 1996;Hartman et al, 1996;Walsh et al, 1996) and can be presumed to have similar etiology.…”

Hepatic Effects in Beagle Dogs Administered Atorvastatin, a 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitor, for 2 Years

“…These changes could be due to relatively increased concentrations of AT in bile and gallbladder, since AT is excreted primarily via bile. It is also possible that low cholesterol levels affected bile composition, since cholesterol is the immediate precursor to bile acids (20,25 (10).…”

“…Full details of this study will be reported elsewhere. Briefly, beagle dogs were given 0, 10, 40, or 120 mg/kg of AT in gelatin capsules daily (10 (23), and procedures and results of semen and sperm analyses will be reported separately (6).…”