Pharmacodynamics and pharmacokinetics of bicalutamide: defining an active dosing regimen

Bicalutamide, a potent nonsteroidal antiandrogenic drug devoid of hormonal agonist activity, is considered to be a pure antiandrogen. Binding of bicalutamide to the androgen receptor results in regression of prostate tumors. The antiandrogenic activity resides exclusively in the R-enantiomer. The S-enantiomer of bicalutamide is rapidly cleared, but the R-enantiomer has a plasma elimination half-life of about 1 week, with a tenfold plasma accumulation at all dose levels, making it suitable for a once-daily administration. It has been shown that plasma concentrations increase linearly with dose after either single or multiple dosing. These pharmacokinetics are not affected by age, impairment of renal function, or mild-to-moderate hepatic impairment. Following daily administration of single doses of 50 mg/day for 12 weeks result in steady-state plasma concentrations for the R-enantiomer of +/- 9 micrograms/mL. A single dose of 50 mg/day was preferred because this dose resulted in a 50% decrease of prostatic acid phosphate (PAP) in 83% of the treated patients. Subsequent studies focused on the decrease of prostate-specific antigen (PSA) as a surrogate endpoint. Decreases of PSA of > or = 90% were noted with daily doses of 100-200 mg. The excellent safety profile allows further investigations of doses up to 450 mg daily. Studies are ongoing to establish the most efficient dose with acceptable levels of toxicity in order to maximize the effect of bicalutamide on clinical response, time to progression, mortality, and quality of life.