The preclinical development of bicalutamide: pharmacodynamics and mechanism of action

Abstract

Objectives. To describe the preclinical development of bicalutamide and clarify its pharmacodynamics and mechanism of action. Bicalutamide was developed from a series of nonsteroidal compounds related to flutamide that showed a range of pharmacologic activity from full androgen agonist to pure antiandrogen, including progestational and antiprogestational properties. Methods and Results. Bicalutamide is a pure antiandrogen that binds to rat, dog, and human prostate; the affinity compared with the natural ligand 5α-dihydrotestosterone is low, but bicalutamide has an affinity for the rat androgen receptor approximately four times higher than hydroxyflutamide, the active metabolite of flutamide. Bicalutamide also binds to androgen receptors found in the LNCaP human prostate tumor and the Shionogi S115 mouse mammary tumor cell line, as well as androgen receptors transfected into CV-1 and HeLa cells. In all cases, bicalutamide behaves as a pure antiandrogen and inhibits gene expression and cell growth stimulated by androgen. Studies with the LNCaP cell line are particularly interesting, as these cells contain a mutated androgen receptor (codon 868, Thr → Ala), which behaves idiosyncratically with other antiandrogens (cyproterone acetate and flutamide): both these antiandrogens act as agonists in this cell line and stimulate proliferation. Studies in vivo show that bicalutamide is a potent antiandrogen in the rat. In immature, castrated male rats treated daily with testosterone propionate, bicalutamide produces a profound inhibition of accessory sex organ (ventral prostate and seminal vesicles) growth at oral doses as low as 0.25 mg/kg; it is more active in this test than flutamide or cyproterone acetate. In mature male rats, daily oral doses of bicalutamide produce a dose-related reduction in weights of the ventral prostate glands and seminal vesicles: in this test, bicalutamide is around five times as potent as flutamide. In contrast to flutamide, which produces dose-related, marked increases in serum luteinizing hormone (LH) and testosterone as a consequence of the central inhibition of the negative feedback effects of androgens on the hypothalamic—pituitary—testes axis, bicalutamide has little effect on serum LH and testosterone; i.e., it is peripherally selective. The peripheral selectivity of bicalutamide in the rat is not due to differences between the prostate versus hypothalamic or pituitary receptors, as bicalutamide reverses the suppressive effect of testosterone on luteinizing hormone-releasing hormone (LHRH) secretion from hypothalamic slices in vitro and is as effective as flutamide at sensitizing the pituitary gland to secrete LH in response to administered LHRH. The peripheral selectivity of bicalutamide has now been shown to be due to poor penetration across the blood—brain barrier: tissue distribution studies with [ 3H]bicalutamide show that although it is concentrated in the organs of metabolism and secretion as well as in the prostate, the pituitary glands, and the seminal vesicles, levels in the hypothalamus and the central nervous system (CNS) are much lower than in blood. Indeed, it is probable that levels found in the CNS reflect levels of blood contamination. In dogs, bicalutamide has exquisite potency and causes dose-related atrophy of the prostate gland and epididymides; with an oral ED 50 of 0.1 mg/kg, it is around 50 times as potent as flutamide in this species and also more potent than the steroidal antiandrogen WIN49596 and the 5α-reductase inhibitor MK-906. Even at substantial multiples of the active dose (up to 100 mg/kg orally), bicalutamide failed to increase serum testosterone, so it is also peripherally selective in the dog. Magnetic resonance imaging studies have shown that bicalutamide is also a potent antiandrogen in the monkey; oral doses of 1 and 5 mg/kg produced significant reductions in seminal vesicle and ventral prostate size. At a daily oral dose of 25 mg/kg, bicalutamide effected a highly significant reduction in growth of Dunning R3227H transplantable rat prostate tumors that was equivalent to that achieved by either surgical castration or medical castration with the LHRH agonist goserelin acetate. In a comparative study, flutamide was shown to be both less potent and less active than bicalutamide. In all these preclinical studies, bicalutamide was well tolerated. It had no significant effects in any general pharmacology tests except in the dog, in which, on chronic administration, it caused a small increase in heart rate and a reduction in PR interval at doses of >25 times the ED 50 value for prostate atrophy. Because there was neither impairment of cardiac function nor pathologic observations when cardiac histology was examined in chronic toxicity studies, it is concluded that this idiosyncratic finding is of no toxicologic consequence. Conclusions. Bicalutamide was shown to be a pure antiandrogen and specifically did not possess estrogenic or anestrogenic, progestational or antiprogestational, glucocorticoid or antiglucocorticoid, or mineralocorticoid or antimineralocorticoid activity in classic endocrine tests. Bicalutamide also showed no androgenic activity and did not inhibit steroid 5α-reductase.