Bicalutamide is a nonsteroidal pure antiandrogen-given at a dosage of 150mg once daily as monotherapy for the treatment, of early (localised or locally advanced) nonmetastatic prostate cancer. It is used at a dosage of 50mg once daily in combination with a luteinising hormone-releasing hormone analogue or surgical castration for the treatment of advanced prostate cancer. Bicalutamide is a racemate and its antiandrogenic, activity resides almost exclusively in the (R)-enantiomer, with little, if any, activity in the (S)-enantiomer. (R),-Bicalutamide is slowly and saturably absorbed, but absorption is unaffected by food. It has a long plasma elimination half-life (I week) and accumulates about 10-fold in, plasma during daily administration. (S)Bicalutamide is much more rapidly absorbed and cleared from plasma; steady-state concentrations (C-ss) of (R)-bicalutamide are 100-fold higher than those of (S)-bicalutamide. Css increases linearly with doses up to 50mg, but nonlinearly at higher doses, reaching a plateau above 300mg. C-ss is higher in Japanese than in Caucasians, but no relationship with degree of renal impairment, bodyweight or age exists. Although mild-to-moderate hepatic impairment does not affect pharmacokinetics, there is evidence for slower elimination of (R)-bicalutamide in subjects with severe hepatic impairment. Bicalutamide metabolites are excreted almost equally in urine and faeces with little or no unchanged drug excreted in urine; conversely, unchanged drug predominates in plasma. Bicalutamide in faeces is thought to arise from hydrolysis of bicalutamide glucuronide and from unabsorbed drug. Bicalutamide-appears to be cleared almost exclusively by metabolism; this is largely mediated by cytochrome P450 (CYP) for (R)-bicalutamide,but glucuronidation is the predominant metabolic route for (S)-bicalutamide. (S)-Bicalutamide is metabolised in vitro by CYP3A4, and it is probable that this isoenzyme is also responsible for the metabolism of (R)-bicalutamide. In vitro data suggest that (R)-bicalutamide has the potential to inhibit CYP3A4 and, to a lesser extent, CYP2C9, 2C19 and 2D6. However, using midazolam as a specific CYP3A4 marker, no c1inically relevant inhibition is observed in vivo with bicalutamide. 150mg. Although bicalutamide is a CYP inducer in laboratory animals, dosages less than or equal to 150 mg/day have shown no evidence of enzyme induction in humans. Daily administration of bicalutamide increases circulating levels of gonadotrophins and sex hormones; although testosterone increases by up to 80%, concentrations in most patients remain within. the normal range. Bicalutamide produces a dose-related decrease in prostate-specific antigen (PSA) at dosages less than or equal to 150 mg/day. However, little relationship is observed between median PSA reduction and (R)bicalutamide C-ss.
