Title |
Bicalutamide
|
---|---|
Published in |
Clinical Pharmacokinetics, September 2012
|
DOI | 10.2165/00003088-200443130-00003 |
Pubmed ID | |
Authors |
Ian D. Cockshott |
Abstract |
Bicalutamide is a nonsteroidal pure antiandrogen given at a dosage of 150 mg once daily as monotherapy for the treatment of early (localised or locally advanced) nonmetastatic prostate cancer. It is used at a dosage of 50 mg 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 (1 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 (Css) of (R)-bicalutamide are 100-fold higher than those of (S)-bicalutamide. Css increases linearly with doses up to 50 mg, but nonlinearly at higher doses, reaching a plateau above 300 mg. Css 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 clinically relevant inhibition is observed in vivo with bicalutamide 150mg. Although bicalutamide is a CYP inducer in laboratory animals, dosages < or = 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 < or = 150 mg/day. However, little relationship is observed between median PSA reduction and (R)-bicalutamide Css. |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Japan | 1 | 1% |
Denmark | 1 | 1% |
Slovenia | 1 | 1% |
Unknown | 82 | 96% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 15 | 18% |
Student > Bachelor | 13 | 15% |
Researcher | 10 | 12% |
Student > Master | 8 | 9% |
Other | 7 | 8% |
Other | 11 | 13% |
Unknown | 21 | 25% |
Readers by discipline | Count | As % |
---|---|---|
Medicine and Dentistry | 19 | 22% |
Pharmacology, Toxicology and Pharmaceutical Science | 12 | 14% |
Chemistry | 11 | 13% |
Biochemistry, Genetics and Molecular Biology | 8 | 9% |
Agricultural and Biological Sciences | 4 | 5% |
Other | 9 | 11% |
Unknown | 22 | 26% |