Tadalafil nonclinical toxicology

Tadalafil
ADCIRCA (tadalafil) tablet ® FDA Package Insert
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Pratik Bahekar, MBBS [2]

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Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis — Tadalafil was not carcinogenic to rats or mice when administered daily for 2 years at doses up to 400 mg/kg/day. Systemic drug exposures, as measured by AUC of unbound tadalafil, were approximately 5–fold for mice, and 7– and 14–fold for male and female rats, respectively, the exposures at the maximum recommended human dose (MRHD) of 40 mg.

Mutagenesis — Tadalafil was not mutagenic in the in vitro bacterial Ames assays or the forward mutation test in mouse lymphoma cells. Tadalafil was not clastogenic in the in vitrochromosomal aberration test in human lymphocytes or the in vivo rat micronucleus assays.

Impairment of Fertility — There were no effects on fertility, reproductive performance or reproductive organ morphology in male or female rats given oral doses of tadalafil up to 400 mg/kg/day, a dose producing AUCs for unbound tadalafil of 6–fold for males or 17–fold for females the exposures at the MRHD of 40 mg. In beagle dogs given tadalafil daily for 3 to 12 months, there was treatment–related non–reversible degeneration and atrophy of the seminiferous tubular epithelium in the testes in 20–100% of the dogs that resulted in a decrease in spermatogenesis in 40–75% of the dogs at doses of ≥10 mg/kg/day. Systemic exposure (based on AUC) at no–observed–adverse-effect–level (NOAEL) (10 mg/kg/day) for unbound tadalafil was similar to that expected in humans at the MRHD of 40 mg.

There were no treatment–related testicular findings in rats or mice treated with doses up to 400 mg/kg/day for 2 years.

13.2 Animal Toxicology and/or Pharmacology

Animal studies showed vascular inflammation in tadalafil–treated mice, rats, and dogs. In mice and rats, lymphoid necrosis and hemorrhage were seen in the spleen, thymus, and mesenteric lymph nodes at unbound tadalafil exposure of 1– to 17–fold the human exposure (AUCs) at the MRHD of 40 mg. In dogs, an increased incidence of disseminated arteritis was observed in 1– and 6-month studies at unbound tadalafil exposure of 0.5– to 38–fold the human exposure (AUC) at the MRHD of 40 mg. In a 12–month dog study, no disseminated arteritis was observed, but 2 dogs exhibited marked decreases in white blood cells (neutrophils) and moderate decreases in platelets with inflammatory signs at unbound tadalafil exposures of approximately 4– to 10–fold the human exposure at the MRHD of 40 mg. The abnormal blood–cell findings were reversible within 2 weeks upon removal of the drug.

13.3 Reproductive Toxicology Studies

Reproduction studies have been performed in rats and mice at exposures up to 17 times the MRHD of 40 mg and have revealed no evidence of impaired fertility or harm to the fetus because of tadalafil. In addition, there was no evidence of teratogenicity, embryotoxicity, or fetotoxicity when tadalafil was given to pregnant rats or mice at exposures up to 7 times the MRHD during the period of major organ development.

In a rat prenatal and postnatal development study at doses of 60, 200, and 1000 mg/kg, a reduction in postnatal survival of pups was observed. The no-observed-effect-level (NOEL) for maternal toxicity was 200 mg/kg/day and for developmental toxicity was 30 mg/kg/day. This gives approximately 8- and 5-fold exposure multiples, respectively, of the human AUC for the MRHD of 40 mg. Tadalafil and/or its metabolites cross the placenta, resulting in fetal exposure in rats.

Tadalafil and/or its metabolites were secreted into the milk in lactating rats at concentrations approximately 2.4–fold greater than found in the plasma.