THE PRECLINICAL DEVELOPMENT OF BICALUTAMIDE - PHARMACODYNAMICS AND MECHANISM OF ACTION

Objectives. To describe the preclinical development of bicalutamide an d clarify its pharmacodynamics and mechanism of action. Bicalutamide w as developed from a series of nonsteroidal compounds related to flutam ide that showed a range of pharmacologic activity from full androgen a gonist to pure antiandrogen, including progestational and antiprogesta tional properties. Methods and Results. Bicalutamide is a pure antiand rogen that binds to rat, dog, and human prostate; the affinity compare d with the natural ligand 5 alpha-dihydrotestosterone is low, but bica lutamide has an affinity for the rat androgen receptor approximately f our times higher than hydroxyflutamide, the active metabolite of fluta mide. Bicalutamide also binds to androgen receptors found in the LNCaP human prostate tumor and the Shionogi S115 mouse mammary tumor cell l ine, as well as androgen receptors transfected into CV-1 and HeLa cell s. In all cases, bicalutamide behaves as a pure antiandrogen and inhib its gene expression and cell growth stimulated by androgen. Studies wi th the LNCaP cell line are particularly interesting, as these cells co ntain a mutated androgen receptor (codon 868, Thr --> Ala), which beha ves idiosyncratically with other antiandrogens (cyproterone acetate an d flutamide): both these antiandrogens act as agonists in this cell li ne 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 p rofound inhibition of accessory sex organ (ventral prostate and semina l vesicles) growth at oral doses as low as 0.25 mg/kg; it is more acti ve in this test than flutamide or cyproterone acetate. In mature male rats, daily oral doses of bicalutamide produce a dose-related reductio n in weights of the ventral prostate glands and seminal vesicles: in t his 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 eff ect on serum LH and testosterone; i.e., it is peripherally selective. The peripheral selectivity of bicalutamide in the rat is not due to di fferences between the prostate versus hypothalamic or pituitary recept ors, as bicalutamide reverses the suppressive effect of testosterone o n luteinizing hormone-releasing hormone (LHRH) secretion from hypothal amic slices in vitro and is as effective as flutamide at sensitizing t he pituitary gland to secrete LH in response to administered LHRH. The peripheral selectivity of bicalutamide has now been shown to be due t o poor penetration across the blood-brain barrier: tissue distribution studies with [H-3]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 hypothal amus and the central nervous system (CNS) are much lower than in blood . Indeed, it is probable that levels found in the CNS reflect levels o f blood contamination. In dogs, bicalutamide has exquisite potency and causes dose-related atrophy of the prostate gland and epididymides; w ith an oral ED(50) of 0.1 mg/kg, it is around 50 times as potent as fl utamide in this species and also more potent than the steroidal antian drogen WIN49596 and the 5 alpha-reductase inhibitor MK-906. Even at su bstantial multiples of the active dose (up to 100 mg/kg orally), bical utamide failed to increase serum testosterone, so it is also periphera lly selective in the dog. Magnetic resonance imaging studies have show n that bicalutamide is also a potent antiandrogen in the monkey; oral doses of 1 and 5 mg/kg produced significant reductions in seminal vesi cle and ventral prostate size. At a daily oral dose of 25 mg/kg, bical utamide effected a highly significant reduction in growth of Dunning R 3227H transplantable rat prostate tumors that was equivalent to that a chieved by either surgical castration or medical castration with the L HRH agonist goserelin acetate. In a comparative study, flutamide was s hown 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 do g, 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 i diosyncratic finding is of no toxicologic consequence. Conclusions. Bi calutamide was shown to be a pure antiandrogen and specifically did no t possess estrogenic or anestrogenic, progestational or antiprogestati onal, glucocorticoid or antiglucocorticoid, or mineralocorticoid or an timineralocorticoid activity in classic endocrine tests. Bicalutamide also showed no androgenic activity and did not inhibit steroid 5 alpha -reductase.