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Clinical Pharmacokinetics

, Volume 43, Issue 13, pp 855–878 | Cite as

Bicalutamide

Clinical Pharmacokinetics and Metabolism
  • Ian D. Cockshott
Review Article

Abstract

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 (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 50mg, but nonlinearly at higher doses, reaching a plateau above 300mg. 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 ≤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 ≤150 mg/day. However, little relationship is observed between median PSA reduction and (R)-bicalutamide Css.

Keywords

Prostate Cancer Flutamide Advanced Prostate Cancer Bicalutamide Cyproterone Acetate 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

The author would like to thank the many colleagues and clinical trialists for their contributions to the AstraZeneca data on file that have been included in this review.

At the time of writing this review, Dr Cockshott was a full-time employee of AstraZeneca; however he has since retired. No other financial support was received during the period of preparing this review.

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Copyright information

© Adis Data Information BV 2004

Authors and Affiliations

  • Ian D. Cockshott
    • 1
  1. 1.AstraZenecaMacclesfieldUK

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