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Nonclinical Toxicology Avanafil/

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis and Impairment of love and fertility

Carcinogenesis

Avanafil were carcinogenic to CD-1 mice when administered daily at doses of 100, 200, or 600 mg/kg/day orally by gavage for not less than 98 weeks (approximately 11 times the MRHD by using an AUC basis) so as to Sprague Dawley rats when administered daily at doses of 100, 300, or 1000 mg/kg/day orally by gavage for not less than 100 weeks (approximately 8 times for males and 34 times for females above the MRHD with an AUC basis).

Mutagenesis

Avanafil hasn't been genotoxic in the variety of tests. Avanafil had not been mutagenic in Ames assays. Avanafil hasn't been clastogenic in chromosome aberration assays using Chinese hamster ovary and lung cells, or perhaps vivo inside the mouse micronucleus assay. Avanafil still did not affect DNA repair when tested inside rat unscheduled DNA synthesis assay.

Impairment of love and fertility

In a rat fertility and early embryonic development study administered 100, 300, or 1000 mg/kg/day for 28 days ahead of paring and continued until euthanasia for males, and a couple of weeks previous to pairing to gestation day 7 for females, a decrease in fertility, no or reduced sperm motility, altered estrous cycles, and a greater percentage of abnormal sperm (broken sperm with detached heads) occurred at exposures in males approximately 11 times a person's beings exposure which includes a dose of 200 mg. The altered sperm effects were reversible to the end on the 9-week drug-free period. Systemic exposure for any NOAEL (300 mg/kg/day) was a lot like ones AUC for the MRHD of 200 mg.

Animal Toxicology and/or Pharmacology

Repeated oral administration of avanafil in multiple species triggered signs of centrally-mediated toxicity including ataxia, tremor, convulsion, hypoactivity, recumbency, and/or prostration at doses creating exposures approximately 5-8 times the MRHD based upon Cmax and 8-30 times the MRHD depending on AUC.