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Pharmacology: Pharmacodynamics: Mechanism of action: Bicalutamide is a non-steroidal antiandrogen, devoid of other endocrine activity. It binds to androgen receptors without activating gene expression, and thus inhibits the androgen stimulus. Regression of prostatic tumours results from this inhibition. Clinically, discontinuation of bicalutamide can result in antiandrogen withdrawal syndrome in a subset of patients.
Bicalutamide is a racemate with its antiandrogenic activity being almost exclusively in the (R)-enantiomer.
Clinical efficacy and safety: Bicalutamide 150 mg was studied as a treatment for patients with localised (T1-T2, N0 or NX, M0) or locally advanced (T3-T4, any N, M0; T1-T2, N+, M0) non metastatic prostate cancer in a combined analysis of three placebo controlled, double-blind studies in 8,113 patients, where bicalutamide 150 mg was given as immediate hormonal therapy or as adjuvant to radical prostatectomy or radiotherapy, (primarily external beam radiation). At 7.4 years median follow up, 27.4% and 30.7% of all bicalutamide and placebo treated patients, respectively, had experienced objective disease progression.
A reduction in risk of objective disease progression was seen across most patient groups but was most evident in those at highest risk of disease progression. Therefore, clinicians may decide that the optimum medical strategy for a patient at low risk of disease progression, particularly in the adjuvant setting following radical prostatectomy, may be to defer hormonal therapy until signs that the disease is progressing.
No overall survival difference was seen at 7.4 years median follow up with 22.9% mortality (HR=0.99; 95% CI 0.91 to 1.09). However, some trends were apparent in exploratory subgroup analyses.
Progression-free survival and overall survival data for patients with locally advanced disease are summarised in the following tables: See Tables 1 and 2.
Click on icon to see table/diagram/image
Click on icon to see table/diagram/imageFor patients with localised disease receiving bicalutamide alone, there was no significant difference in progression free survival. In these patients there was also a trend toward decreased survival compared with placebo patients (HR=1.16; 95% CI 0.99 to 1.37). In view of this, the benefit-risk profile for the use of bicalutamide is not considered favourable in this group of patients.
Pharmacokinetics: Absorption: Bicalutamide is well absorbed following oral administration. There is no evidence of any clinically relevant effect of food on bioavailability.
Distribution: The (S)-enantiomer is rapidly cleared relative to the (R)-enantiomer, the latter having a plasma elimination half-life of about 1 week.
On daily administration of bicalutamide, the (R)-enantiomer accumulates about 10 fold in plasma as a consequence of its long half-life.
Steady state plasma concentrations of the (R)-enantiomer of approximately 9 μg/mL are observed during daily administration of 50 mg doses of bicalutamide.
At steady state the predominantly active (R)-enantiomer accounts for 99% of the total circulating enantiomers.
The pharmacokinetics of the (R)-enantiomer are unaffected by age, renal impairment or mild to moderate hepatic impairment. There is evidence that for subjects with severe hepatic impairment, the (R)-enantiomer is more slowly eliminated from plasma.
Biotransformation and elimination: Bicalutamide is highly protein bound (racemate 96%, R-bicalutamide 99.6%) and extensively metabolised (via oxidation and glucuronidation): Its metabolites are eliminated via the kidneys and bile in approximately equal proportions.
After excretion in the bile, hydrolysis of the glucuronides takes place. In the urine scarcely altered bicalutamide is found.
In a clinical study the mean concentration of (R)-bicalutamide in semen of men receiving bicalutamide 150 mg was 4.9 μg/mL. The amount of bicalutamide potentially delivered to a female partner during intercourse is low and equates to approximately 0.3 μg/kg. This is below that required to induce changes in offspring of laboratory animals.
Toxicology: Preclinical safety data: Bicalutamide is a potent antiandrogen and a mixed function oxidase enzyme inducer in animals.
Target organ changes, including tumour induction, in animals, are related to these activities. None of the findings in the preclinical testing is considered to have relevance to the treatment of advanced prostate cancer patients.
