CLINICAL PHARMACOLOGY
Mechanism of Action: CASODEX is a non-steroidal antiandrogen.
It competitively inhibits the action of androgens by binding
to cytosol androgen receptors in the target tissue. Prostatic
carcinoma is known to be androgen sensitive and responds
to treatment that counteracts the effect of androgen and/or
removes the source of androgen.
When CASODEX is combined with luteinizing hormone-releasing
hormone (LHRH) analogue therapy, the suppression of serum
testosterone induced by the LHRH analogue is not affected.
However, in clinical trials with CASODEX as a single agent
for prostate cancer, rises in serum testosterone and estradiol
have been noted.
Pharmacokinetics
Absorption: Bicalutamide is well-absorbed following oral
administration, although the absolute bioavailability
is unknown. Co-administration of bicalutamide with food
has no clinically significant effect on rate or extent
of absorption.
Distribution: Bicalutamide is highly
protein-bound (96%). See Drug-Drug Interactions
below.
Metabolism/ Elimination: Bicalutamide
undergoes stereo specific metabolism. The S (inactive)
isomer is metabolized primarily by glucuronidation. The
R (active) isomer also undergoes glucuronidation but is
predominantly oxidized to an inactive metabolite followed
by glucuronidation. Both the parent and metabolite glucuronides
are eliminated in the urine and feces. The S-enantiomer
is rapidly cleared relative to the R-enantiomer, with
the R-enantiomer accounting for about 99% of total steady-state
plasma levels.
Special Populations
Geriatric: In two studies in patients
given 50 or 150 mg daily, no significant relationship
between age and steady-state levels of total bicalutamide
or the active R-enantiomer has been shown.
Hepatic Insufficiency: No clinically
significant difference in the pharmacokinetics of either
enantiomer of bicalutamide was noted in patients with
mild-to-moderate hepatic disease as compared to healthy
controls. However, the half-life of the R-enantiomer was
increased apprpximately 76% (5.9 and 10.4 days for normal
and impaired patients, respectively) in patients with
severe liver disease (n= 4).
Renal Inefficiency: Renal impairment (as measured by
creatinine clearance) had no significant effect on the
elimination of total bicalutamide or the active R-enantiomer.
Women, Pediatrics: Bicalutamide has
not been studied in women or pediatric subjects.
Drug-Drug Interactions: Clinical studies
have not shown any drug interactions between bicalutamide
and LHRH analogues (goserelin or leuprolide). There is
no evidence that bicalutamide induces hepatiç enzymes.
In vitro protein-binding studies have shown that bicalutamide
can displace coumarin anticoagulants from binding sites.
Prothrombin times should be closely monitored in patients
already receiving coumarin anticoagulants who are started
on CASODEX.
Pharmacokinetics of the active enantiomer of CASODEX
in normal males and patients with prostate cancer are
presented in Table 1.
Table 1.
|
Parameter
|
Mean
|
Standard
Deviation
|
| Normal
Males (n=30) |
| Apparent Oral Clearance
(L/hr) |
0.320 |
0.103 |
| Single Dose Peak Concentration
(mg/mL) |
0.768 |
0.178 |
| Single Dose Time to
Peak Concentration (hours) |
31.3 |
14.6 |
| Half-Life (days) |
5.8 |
2.29 |
| Patients
with Prostate Cancer (n=40) |
| Css (µg/mL) |
8.939 |
3.504 |
Css= Mean Steady-State Concentration
Clinical Studies
In a multicenter, double-blind, controlled clinical trial,
813 patients with previously untreated advanced prostate
cancer were randomized to receive CASODEX 50 mg once daily
(404 patients) or flutamide 250 mg (409 patients) three
times a day, each in combination with LHRH analogues (either
goserelin acetate implant or leuprolide acetate depot).
In an analysis conducted after a median follow-up of
160 weeks was reached, 213 (52.7%) patients treated with
CASODEX-LHRH analogue therapy and 235 (57.5%) patients
treated with flutamide-LHRH analogue therapy had died.
There was no significant difference in survival between
treatment groups. The hazard ratio for time to death (survival)
was 0.87 (95% confidence interval 0.72 to 1.05).
There was no significant difference in time to objective
tumor progression between treatment groups. Objective
tumor progression was defined as the appearance of any
bone metastases or the worsening of any existing bone
metastases on bones can attributable to metastatic disease,
or an increase by 25% or more of any existing measurable
extra skeletal metastases. The hazard ratio for time to
progression of CASODEX plus LHRH analogue to that of flutamide
plus LHRH analogue was 0.93 (95% confidence interval,
0.79 to 1.10).
Quality of life was assessed with self-administered patient
questionnaires on pain, social functioning, emotional well-being,
vitality, activity limitation, bed disability, overall health,
physical capacity, general symptoms, and treatment related
symptoms. Assessment of the Quality of Life questionnaires
did not indicate consistent significant differences between
the two treatment groups.
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