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INSPRA® (eplerenone) Nonclinical Toxicology

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Eplerenone was non-genotoxic in a battery of assays including in vitro bacterial mutagenesis (Ames test in Salmonella spp. and E. Coli), in vitro mammalian cell mutagenesis (mouse lymphoma cells), in vitro chromosomal aberration (Chinese hamster ovary cells), in vivo rat bone marrow micronucleus formation, and in vivo/ex vivo unscheduled DNA synthesis in rat liver.

There was no drug-related tumor response in heterozygous P53 deficient mice when tested for 6 months at dosages up to 1000 mg/kg/day (systemic AUC exposures up to 9 times the exposure in humans receiving the 100 mg/day therapeutic dose). Statistically significant increases in benign thyroid tumors were observed after 2 years in both male and female rats when administered eplerenone 250 mg/kg/day (highest dose tested) and in male rats only at 75 mg/kg/day. These dosages provided systemic AUC exposures approximately 2 to 12 times higher than the average human therapeutic exposure at 100 mg/day. Repeat dose administration of eplerenone to rats increases the hepatic conjugation and clearance of thyroxin, which results in increased levels of TSH by a compensatory mechanism. Drugs that have produced thyroid tumors by this rodent-specific mechanism have not shown a similar effect in humans.

Male rats treated with eplerenone at 1000 mg/kg/day for 10 weeks (AUC 17 times that at the 100 mg/day human therapeutic dose) had decreased weights of seminal vesicles and epididymides and slightly decreased fertility. Dogs administered eplerenone at dosages of 15 mg/kg/day and higher (AUC 5 times that at the 100 mg/day human therapeutic dose) had dose-related prostate atrophy. The prostate atrophy was reversible after daily treatment for 1 year at 100 mg/kg/day. Dogs with prostate atrophy showed no decline in libido, sexual performance, or semen quality. Testicular weight and histology were not affected by eplerenone in any test animal species at any dosage.

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