A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Casodex Pharmacology, Pharmacokinetics, Studies, Metabolism - Bicalutamide
Casodex Pharmacology, Pharmacokinetics, Studies, Metabolism - Bicalutamide
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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