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
Flomax Pharmacology, Pharmacokinetics, Studies, Metabolism - Tamsulosin
Flomax Pharmacology, Pharmacokinetics, Studies, Metabolism - Tamsulosin
CLINICAL PHARMACOLOGY
The symptoms associated with benign
prostatic hyperplasia
(BPH) are related to bladder
outlet obstruction,
which is comprised of two underlying components: static
and dynamic. The static
component is related
to an increase in prostate
size caused, in part, by a proliferation
of smooth muscle cells
in the prostatic stroma.
However, the severity of BPH
symptoms and the degree of urethral
obstruction do not
correlate well with the size of the prostate. The dynamic
component is a function
of an increase in smooth muscle tone
in the prostate and
bladder neck
leading to constriction
of the bladder outlet.
Smooth muscle tone
is mediated by the sympathetic
nervous stimulation of alpha1 adrenoceptors, which are abundant
in the prostate, prostatic capsule,
prostatic urethra,
and bladder neck. Blockade
of these adrenoceptors can cause
smooth muscles in the bladder
neck and prostate to relax,
resulting in an improvement in urine
flow rate
and a reduction in symptoms of BPH.
Tamsulosin, an alpha1 adrenoceptor blocking
agent, exhibits selectivity
for alpha1 receptors in the human
prostate. At least three
discrete alpha1 -adrenoceptor
subtypes have been identified: alpha1 A, alpha1 B and alpha1 their
distribution differs
between human organs and
tissue. Approximately 70% of the alpha1- receptors in human
prostate are of the
alpha1A subtype. FLOMAX capsules are not intended for use as an
antihypertensive
drug.
Pharmacokinetics
The pharmacokinetics
of tamsulosin HCl have been evaluated in adult healthy volunteers
and patients with BPH after
single and/or multiple
administration with doses ranging from 0.1 mg
to 1 mg.
Absorption: Absorption of tamsulosin HCl from FLOMAX capsules
0.4 mg is essentially complete
(> 90%) following oral
administration under fasting
conditions. Tamsulosin HCl exhibits linear
kinetics following
single and multiple
dosing, with achievement of steady- state
concentrations by the fifth day of once-a-day dosing..
Effect of Food: The time
to maximum concentration
(Tmax) is reached by four to five hours under fasting
conditions and by six to seven hours when FLOMAX capsules are administered
with food. Taking FLOMAX capsules under fasted conditions results
in a 30% increase in bioavailability (AUC) and 40% to 70% increase
in peak concentrations (Cmax) compared to fed conditions.
The effects of food on
the pharmacokinetics
of tamsulosin HCl are consistent regardless of whether a FLOMAX
capsule is taken with
a light breakfast or a
high- fat breakfast (Table
1).
TABLE 1: Mean (± S. D.) Pharmacokinetic
Parameters Following FLOMAX capsules 0.4 mg
Once Daily or
0.8 mg
Once Daily with a Light Breakfast, High- Fat Breakfast or Fasted
|
Pharmacokinetic
Parameter
|
0.4 mg
q. d. to healthy
volunteers; n= 23
(age range
18- 32 years)
|
0.8 mg
q. d. to healthy
volunteers; n= 22
(age range
55- 75 years)
|
| |
Light
Breakfast
|
Fasted
|
Light
Breakfast
|
High- Fat
Breakfast
|
Fasted
|
| Cmin (ng/ mL) |
4.0 ± 2.6
|
3.8 ± 2.5
|
12.3 ± 6.7
|
13.5 ± 7.6
|
13.3 ± 13.3
|
| Cmax (ng/ mL) |
10.1 ± 4.8
|
17.1 ± 17.1
|
29.8 ± 10.3
|
29.1 ± 11.0
|
41.6 ± 15.6
|
| Cmax/ Cmin Ratio
|
3.1 ± 1.0
|
5.3 ± 2.2
|
2.7 ± 0.7
|
2.5 ± 0.8
|
3.6 ± 1.1
|
| Tmax (hours) |
6.0
|
4.0
|
7.0
|
6.6
|
5.0
|
| T1/2 (hours) |
-
|
-
|
-
|
-
|
14.9 ± 3.9
|
| AUC • C (ng • hr/
mL) |
151 ± 81.5
|
199 ± 94.1
|
440 ± 195
|
449 ± 217
|
557 ± 257
|
- Cmin = observed minimum
concentration
- Cmax = observed maximum
tamsulosin HCl plasma
concentration
- Tmax = median
time-to-maximum concentration
- T1/2 = observed half-life
.
- AUC-C = Area under the tamsulosin HCl plasma
time curve over the dosing
interval
Distribution: The mean
steady-state apparent
volume of distribution
of tamsulosin HCl after intravenous
administration
to ten healthy male
adults was 1.6L, which is suggestive
of distribution
into extracellular fluids in the body. Additionally, whole body
autoradiographic studies in mice and rats and tissue
distribution in
rats and dogs indicate that tamsulosin HCl is widely distributed
to most tissues including kidney,
prostate, liver, gall
bladder, heart,
aorta, and brown fat, and minimally distributed to the brain,
spinal cord, and testes.
Tamsulosin HCl is extensively bound
to human plasma
proteins (94% to 99%), primarily alpha-1 acid
glycoprotein (AAG),
with linear binding over
a wide concentration
range (20 to 600 ng/ mL).
The results of two-way in vitro studies indicate that the
binding of tamsulosin HCl to human plasma proteins is not affected
by amitriptyline, diclofenac, glyburide, simvastatin plus simvastatin-
hydroxy acid metabolite,
warfarin, diazepam, propranolol, trichlormethiazide, or chlormadinone.
Likewise, tamsulosin HCl had no
effect on the extent
of binding of these drugs.
Metabolism: There is no
enantiometric bioconversion from tamsulosin HCl [R(-) isomer] to
the S(+) isomer in humans.
Tamsulosin HCl is extensively metabolized by cytochrome
P450 enzymes in the liver
and less than 10% of the dose
is excreted in urine unchanged.
However, the pharmacokinetic profile of the metabolites in humans
has not been established. Additionally, the cytochrome
P450 enzymes that primarily catalyze
the Phase I metabolism
of tamsulosin HCl have not been conclusively identified. Therefore,
possible interactions with other cytochrome
P450 metabolized compounds cannot be discerned with current
information. The metabolites of tamsulosin HCl undergo extensive
conjugation to glucuronide
or sulfate prior to renal
excretion.
Incubations with human
liver microsomes showed
no evidence
of clinically significant metabolic interactions between tamsulosin
HCl and amitriptyline, albuterol (beta agonist), glyburide
(glibenclamide) and finasteride
(5alpha- reductase inhibitor
for treatment of BPH).
However, results of the in vitro testing of the tamsulosin
HCl interaction with diclofenac and warfarin were equivocal.
Excretion: On administration
of the radiolabeled dose
of tamsulosin HCl to four healthy
volunteers, 97% of the administered radioactivity
was recovered, with unne (76%) representing the primary
route of excretion compared to feces
(21 %) over 168 hours. Following intravenous
or oral administration of an immediate- release
formulation, the elimination
half-life of tamsulosin HCl is in plasma
range from five to seven
hours. Because of absorption
rate- controlled pharmacokinetics
with FLOMAX capsules, the apparent half- life
of tamsulosin HCl is approximately 9 to 13 hours in healthy volunteers
and 14 to 15 hours in the target
population. Tamsulosin HCl undergoes restrictive clearance
in humans, with a relatively low systemic clearance (2.88 L/h).
Special Populations:
Geriatrics (Age): Cross-study comparison of FLOMAX
capsules overall exposure
(AUC) and half- life indicate
that the pharmacokinetic disposition of tamsulosin HCl may be slightly
prolonged in geriatric males compared to young, healthy
male volunteers. Intrinsic
clearance is independent
of tamsulosin HCl binding to AAG, but diminishes with age, resulting
in a 40% overall higher exposure
(AUC) in subjects of age
55 to 75 years compared to subjects of age
20 to 32 years.
Renal Dysfunction: The pharmacokinetics
of tamsulosin HCl have been compared in 6 subjects with mild - moderate
(30 CLcr< 70 mL/min/1 .73m2) or moderate- severe (10
CLcr< 30 mL/min/ 1.73m2) renal
impairment and 6
normal subjects (CLcr
< 90 mL/min/1.73m2). While a change in the overall
plasma concentration
of tamsulosin HCl was observed as the result of altered binding
to AAG, the unbound (active) concentration
of tamsulosin HCl, as well as the intrinsic clearance, remained
relatively constant. Therefore, patients with renal impairment do
not require an adjustment
in FLOMAX capsules dosing. However, patients with endstage renal
disease (CLcr < 1
0 mL/min/ l .73m2) have not been studied.
Hepatic Dysfunction: The pharmacokinetics
of tamsulosin HCl have been compared in 8 subjects with moderate
hepatic dysfunction
(Child- Pugh’s classification: Grades A and B) and 8 normal
subjects. While a change in the overall plasma
concentration
of tamsulosin HCl was observed as the result of altered binding
to AAG, the unbound (active) concentration of tamsulosin HCl does
not change significantly with only a modest (32%) change in intrinsic
clearance of unbound
tamsulosin HCl. Therefore, patients with moderate hepatic
dysfunction do not
require an adjustment
in FLOMAX capsules dosage.
Clinical Studies
Four placebo-controlled clinical
studies and one active-controlled clinical study enrolled a total
of 2296 patients (1003 received FLOMAX capsules 0.4 mg
once daily, 491 received FLOMAX capsules 0.8 mg
once daily, and 802 were control
patients) in the U.S. and Europe.
In the two U. S. placebo-controlled, double-blind, 13-week, multicenter
studies [Study1 (US92- 03A) and Study 2 (US93- 01 )], 1486 men with
the signs and symptoms of BPH
were enrolled. In both studies,
patients were randomized to either placebo,
FLOMAX capsules 0.4 mg once
daily, or FLOMAX capsules 0.8 mg
once daily. Patients in FLOMAX capsules 0.8-mg once daily treatment
groups received a dose
of 0.4 mg once daily for
one week before increasing to the 0.8-mg once daily dose. The primary
efficacy assessments
included: 1) total American Urological Association (AUA) Symptom
Score questionnaire, which evaluated irritative
(frequency, urgency, and nocturia), any obstructive (hesitancy,
incomplete emptying, intermittency, and weak stream) symptoms, where
a decrease in score is
consistent with improvement in symptoms; and 2) peak urine
flow rate, where an increased
peak urine flow rate value
over baseline is consistent
with decreased urinary
obstruction.
Mean changes from baseline
to week 13 in total AUA Symptom Score were significantly greater
for groups treated with FLOMAX capsules 0.4 mg
and 0.8 mg once daily compared
to placebo in both U.S.
studies (Table 2). The changes from baseline
to week 13 in peak urine
flow rate
were also significantly greater for the FLOMAX capsules 0.4-mg and
0.8-mg once daily groups compared to placebo
in Study 1, and for the FLOMAX capsules 0.8-mg once daily group
in Study 2 (Table 2). Overall there were no
significant differences
in improvement observed in total AUA Symptom Scores or peak urine
flow rates between the
0.4-mg and the 0.8-mg dose
groups with the exception that the 0.8- mg
dose in Study 1 had a significantly
greater improvement in total AUA Symptom Score compared to the 0.4-mg
dose.
TABLE 2: M.A.
(± S. D.) CHANGES FROM BASELINE TO
WEEK 13 IN TOTAL AUA
SYMPTOM SCORE ** AND P.A.
URINE FLOW RATE (ML/SEC)
| |
Total AUA Symptom Score
|
Peak Urine Flow Rate
|
|
Mean Baseline Value
|
Mean Change
|
Mean Baseline Value
|
Mean Change
|
| Study l t
|
| FLOMAX
capsules
0.8 mg
once daily
|
19.9 ± 4.9
n= 247
|
-9.6* ± 6.7
n= 237
|
9.57 ± 2.51
n= 247
|
1.78* ± 3.35
n= 247
|
| FLOMAX
capsules
0.4 mg
once daily
|
19.8 ± 5.0
n= 254
|
-8.3* ± 6.5
n= 246
|
9.46 ± 2.49
n= 254
|
1.75* ± 3.57
n= 254
|
| Placebo
|
19.6 ± 4.9
n= 254
|
-5.5 ± 6.6
n= 246
|
9.75 ± 2.54
n= 254
|
0.52 ± 3.39
n= 253
|
| Study2 S
|
| FLOMAX
capsules
0.8 mg
once daily
|
18.2 ± 5.6
n= 244
|
-5.8* ± 6.4
n= 238
|
9.96 ± 3.16
n= 244
|
1.79* ± 3.36
n= 237
|
| FLOMAX
capsules
0.4 mg
once daily
|
17.9 ± 5.8
n= 248
|
-5.1* ± 6.4
n= 244
|
9.94 ± 3.14
n= 248
|
1.52 ± 3.64
n= 244
|
| Placebo
|
19.2 ± 6.0
n= 239
|
-3.6 ± 5.7
n= 235
|
9.95 ± 3.12
n= 239
|
0.93 ± 3.28
n= 235
|
*Statistically significant
difference from placebo
(p-value 0.050; Bonferroni-Hoim multiple
test procedure);
**TotaI AUA Symptom Scores ranged from 0 to 35
t-Peak urine
flow rate
measured 4 to 8 hours post
dose at week 13
S-Peak urine
flow rate
measured 24 to 27 hours post
dose at week 13
Week 13: For patients not completing the 13 week
study the last observation was carried forward.
Mean total AUA Symptom Scores for both FLOMAX capsules 0.4-mg and
0.8-mg once daily groups showed a rapid decrease starting at one
week after dosing and remained decreased through 13 weeks in both
studies. In Study 1, 400
patients (53% of the originally randomized group) elected to continue
in their originally assigned treatment
groups in a double- b.i.d.
placebo controlled, 40 week extension
trial (138 patients on 0.4 mg, 135 patients on 0.8 mg
and 127 patients on placebo). Three hundred and twenty- three patients
(43% of the originally randomized group) completed one year. Of
these, 81% (97 patients) on 0.4 mg, 74% (75 patients) on 0.8 mg
and 56% (57 patients) on placebo
had a response 25%
above baseline in total
AUA Symptom Score at one year.
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