Flutamide

Flutamide is a non-steroidal, highly specific, orally active anti-androgenic agent. It has been demonstrated to reduce prostate and seminal vesicle weights in intact immature rats and to prevent androgen-stimulated hypertrophy of these organs in castrated immature rats. Prostate weights in dogs and baboons were also reduced by flutamide treatment. The biological activity of oral flutamide is attributable to its pharmacologically active metabolite, hydroxyflutamide, which is believed to exert an anti-androgenic effect directly on the target tissues, either by inhibiting androgen uptake or by blocking cytoplasmic and nuclear binding of androgen.

Flutamide is indicated for the treatment of advanced prostatic carcinoma in which suppression of testosterone effects is indicated.

Absorption

Flutamide is rapidly and extensively absorbed and almost completely metabolised following oral administration.

Distribution

A high proportion of flutamide binds to plasma proteins (94-96%) as does its active metabolite (92-94%). The peak plasma concentration of hydroxyflutamide at steady state at the recommended therapeutic dose (250 mg t.i.d.) is approximately 1700 µg/L.

Biotransformation

The major metabolite is hydroxyflutamide, which has been demonstrated to possess potent anti-androgenic activity. Radiolabelled flutamide studies reveal a rapid and extensive conversion to its metabolites; at least 6 have been identified in the plasma up to 8 hours after administration.

Elimination

Approximately 45% of the administered dose is excreted in the urine and 2% in faeces during the first two days. The excretion and metabolism is essentially complete within two days. The elimination half-life in plasma is 5 to 6 hours in adults for flutamide and its main metabolite hydroxyflutamide and 8 hours in older people. The elimination half-life at steady-state is approximately 10 hours.

The effects observed in oral repeat dose toxicology studies in the rat, dog and monkey were as expected for a potent anti-androgenic agent.

Studies have been performed in animals to determine the tolerance after repeated oral administration for a period of up to 6, 52 and 78 weeks in monkeys, rats and dogs, respectively. The oral doses administered daily reached 90 mg/kg in monkeys, 40 mg/kg in dogs and 180 mg/kg in rats, which corresponded to 1.5 to 18 times the dose used in humans. In addition to weight loss and anorexia, which occurred in all of the animal species, vomiting was observed in dogs and monkeys. The rest of the clinical observations did not reveal any anomalies.

Reductions in prostate gland and seminal vesicle weights were observed in all species and reduced testicular weights were observed in the rat and monkey. Histological changes characteristic of anti-androgenic activity were observed in all species and there was evidence of suppression of spermatogenesis.

In addition, an increase in the weight of the liver in rats and dogs and elevated transaminase levels in dogs without the corresponding morphological changes were observed. In rats only, the emergence of adenomas of the interstitial testicular cells linked to the medicinal product were observed (although they were not dose-dependent). This effect is related to the mechanism of action of flutamide and is species-specific. In a long-term study in rats, increases were found in the rate of occurrence of adenomas or carcinomas of the mammary gland related to the dose.

Mutagenicity

No mutagenic potential was observed with flutamide in a variety of screening tests.

Reproductive toxicity

The influence of flutamide on fertility and the development of the progeny has been studied in rats. Additional teratogenicity studies have been performed in rabbits. The effects were related to the anti-androgenic actions of flutamide. These effects are not relevant to the clinical use of flutamide in the treatment of prostate cancer.