CLINICAL PHARMACOLOGY
Pharmacodynamics
Benign Prostatic Hyperplasia (BPH)
Benign prostatic hyperplasia (BPH) is a common cause
of urinary outflow obstruction in aging males. Severe
BPH may lead to urinary retention and renal damage. A
static and a dynamic component contribute to the symptoms
and reduced urinary wflow rate associated with BPH. 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 of BPH is associated with an increase
in smooth muscle tone in the prostate and bladder neck.
The degree of tone in this area is mediated by the alpha1
adrenoceptor, which is present in high density in the
prostatic stroma, prostatic capsule and bladder neck.
Blockade of the alpha1 receptor decreases urethral resistance
and may relieve the obstruction and BPH symptoms. In the
human prostate, doxazosin mesylate antagonizes phenylephrine
(alpha1 agonist)-induced contractions, in vitro, and binds
with high affinity to the alpha1c adrenoceptor. The receptor
subtype is thought to be the predominant functional type
in the prostate. Doxazosin mesylate acts within 1-2 weeks
to decrease the severity of BPH symptoms and improve urinary
wflow rate. Since alpha1 adrenoceptors are of low density
in the urinary bladder (apart from the bladder neck),
doxazosin mesylate should maintain bladder contractility.
The efficacy of doxazosin mesylate was evaluated extensively
in over 900 patients with BPH in double-blind, placebo-controlled
trials. Doxazosin mesylate treatment was superior to placebo
in improving patient symptoms and urinary wflow rate.
Significant relief with doxazosin mesylate was seen as
early as one week into the treatment regimen, with doxazosin
mesylate treated patients (N=173) showing a significant
(p<0.01) increase in maximum wflow rate of 0.8 ml/sec
compared to a decrease of 0.5 ml/sec in the placebo group
(N=41). In long-term studies improvement was maintained
for up to 2 years of treatment. In 66-71% of patients,
improvements above baseline were seen in both symptoms
and maximum urinary wflow rate.
In three placebo-controlled studies of 14-16 weeks duration
obstructive symptoms (hesitation, intermittency, dribbling,
weak urinary stream, incomplete emptying of the bladder)
and irritative symptoms (nocturia, daytime frequency,
urgency, burning) of BPH were evaluated at each visit
by patient-assessed symptom questionnaires. The bothersomeness
of symptoms was measured with a modified Boyarsky questionnaire.
Symptom severity/frequency was assessed using a modified
Boyarsky questionnaire or an AUA-based questionnaire.
Uroflowmetric evaluations were performed at times of peak
(2-6 hours post-dose) and/or trough (24 hours post-dose)
plasma concentrations of doxazosin mesylate.
The results from the three placebo-controlled studies
(N=609) showing significant efficacy with 4 mg and 8 mg
doxazosin are summarized in TABLE 1. In all three studies,
doxazosin mesylate resulted in statistically significant
relief of obstructive and irritative symptoms compared
to placebo. Statistically significant improvements of
2.3-3.3 ml/sec in maximum wflow rate were seen with doxazosin
mesylate in Studies 1 and 2, compared to 0.1-0.7 ml/sec
with placebo.
| TABLE 1
Summary of Effectiveness Data in Placebo-Controlled
Trials |
| |
Symptom Scorea |
Maximum Flow
Rate (ml/sec) |
| |
N |
Mean Baseline |
Mean* Change |
N |
Mean Baseline |
Mean†Change |
| Study
1 (Titration to maximum dose of 8 mg)† |
|
|
47 |
15.6 |
-2.3 |
41 |
9.7 |
+0.7 |
|
|
49 |
14.5 |
-4.9|| |
41 |
9.8 |
+2.9|| |
| Study
2 (Titration to fixed dose-14 weeks)‡ |
|
|
37 |
20.7 |
-2.5 |
30 |
10.6 |
+0.1 |
|
|
38 |
21.2 |
-5.0|| |
32 |
9.8 |
+2.3|| |
|
|
42 |
19.9 |
-4.2|| |
36 |
10.5 |
+3.3|| |
| Study
3 (Titration to fixed dose-12 weeks) |
|
|
47 |
14.9 |
-4.7 |
44 |
9.9 |
+2.1 |
|
|
46 |
16.6 |
-6.1|| |
46 |
9.6 |
+2.6 |
| a AUA
questionnaire (range 0-30) in studies 1 and 3. Modified
Boyarsky Questionnaire (range 7-39) in study 2. |
| * Change
is to endpoint. |
| † Change
is to fixed-dose efficacy phase, 22-26 hours post-dose
for studies 1 and 3 and 2-6 hours post-dose for
study 2. |
| ‡ Study
in hypertensives with BPH. |
| §
36 patients received a dose of 8 mg doxazosin mesylate. |
| || p <
0.05 (0.01) compared to placebo mean change. |
In one fixed dose study (study 2) doxazosin mesylate therapy
(4-8 mg, once daily) resulted in a significant and sustained
improvement in maximum urinary flow rate of 2.3-3.3 ml/sec
(TABLE 1) compared to placebo (0.1 ml/sec). In this study,
the only study in which weekly evaluations were made, significant
improvement with doxazosin mesylate vs. placebo was seen
after one week. The proportion of patients who responded
with a maximum wflow rate improvement of ³ 3 ml/sec
was significantly larger with doxazosin mesylate (34-42%)
than placebo (13-17%). A significantly greater improvement
was also seen in average wflow rate with doxazosin mesylate
(1.6 ml/sec) than with placebo (0.2 ml/sec).
In BPH patients (N=450) treated for up to 2 years in
open-label studies, doxazosin mesylate therapy resulted
in significant improvement above baseline in urinary wflow
rates and BPH symptoms. The significant effects of doxazosin
mesylate were maintained over the entire treatment period.
Although blockade of alpha1 adrenoceptors also lowers
blood pressure in hypertensive patients with increased
peripheral vascular resistance, doxazosin mesylate treatment
of normotensive men with BPH did not result in a clinically
significant blood pressure lowering effect (TABLE 2).
The proportion of normotensive patients with a sitting
systolic blood pressure less than 90 mmHg and/or diastolic
blood pressure less than 60 mmHg at any time during treatment
with doxazosin mesylate 1-8 mg once daily was 6.7% with
doxazosin and not significantly different (statistically)
from that with placebo (5%).
| TABLE 2
Mean Changes in Blood Pressure from Baseline to
the Mean of the Final Efficacy Phase in Normotensives
(Diastolic BP <90 mmHg) in Two Double-Blind,
Placebo-Controlled U.S. Studies with Doxazosin Mesylate
1-8 mg Once Daily |
| |
Placebo (N=85) |
Doxazosin Mesylate
(N=183) |
| |
Baseline |
Change |
Baseline |
Change |
| Sitting
BP (mmHg) |
|
|
128.4 |
-1.4 |
128.8 |
-4.9* |
|
|
79.2 |
-1.2 |
79.6 |
-2.4* |
| Standing
BP (mmHg) |
|
|
128.5 |
-0.6 |
128.5 |
-5.3* |
|
|
80.5 |
-0.7 |
80.4 |
-2.6* |
| * p £
0.05 compared to placebo. |
Hypertension
The mechanism of action of doxazosin mesylate is selective
blockade of the alpha1 (postjunctional) subtype of adrenergic
receptors. Studies in normal human subjects have shown
that doxazosin competitively antagonized the pressor effects
of phenylephrine (an alpha1 agonist) and the systolic
pressor effect of norepinephrine. Doxazosin and prazosin
have similar abilities to antagonize phenylephrine. The
antihypertensive effect of doxazosin mesylate results
from a decrease in systemic vascular resistance. The parent
compound doxazosin is primarily responsible for the antihypertensive
activity. The low plasma concentrations of known active
and inactive metabolites of doxazosin (2-piperazinyl,
6¢- and 7¢-hydroxy and 6- and 7-O-desmethyl
compounds) compared to parent drug indicate that the contribution
of even the most potent compound (6¢-hydroxy) to
the antihypertensive effect of doxazosin in man is probably
small. The 6¢- and 7¢-hydroxy metabolites have
demonstrated antioxidant properties at concentrations
of 5 mcM, in vitro.
Administration of doxazosin mesylate results in a reduction
in systemic vascular resistance. In patients with hypertension
there is little change in cardiac output. Maximum reductions
in blood pressure usually occur 2-6 hours after dosing
and are associated with a small increase in standing heart
rate. Like other alpha1-adrenergic blocking agents, doxazosin
has a greater effect on blood pressure and heart rate
in the standing position.
In a pooled analysis of placebo-controlled hypertension
studies with about 300 hypertensive patients per treatment
group, doxazosin, at doses of 1-16 mg given once daily,
lowered blood pressure at 24 hours by about 10/8 mmHg
compared to placebo in the standing position and about
9/5 mmHg in the supine position. Peak blood pressure effects
(1-6 hours) were larger by about 50-75% (i.e., trough
values were about 55-70% of peak effect), with the larger
peak-trough differences seen in systolic pressures. There
was no apparent difference in the blood pressure response
of Caucasians and blacks or of patients above and below
age 65. In these predominantly normocholesterolemic patients
doxazosin produced small reductions in total serum cholesterol
(2-3%), LDL cholesterol (4%), and a similarly small increase
in HDL/total cholesterol ratio (4%). The clinical significance
of these findings is uncertain. In the same patient population,
patients receiving doxazosin mesylate gained a mean of
0.6 kg compared to a mean loss of 0.1 kg for placebo patients.
Pharmacokinetics
After oral administration of therapeutic doses, peak
plasma levels of doxazosin mesylate occur at about 2-3
hours. Bioavailability is approximately 65%, reflecting
first pass metabolism of doxazosin by the liver. The effect
of food on the pharmacokinetics of doxazosin mesylate
was examined in a crossover study with twelve hypertensive
subjects. Reductions of 18% in mean maximum plasma concentration
and 12% in the area under the concentration-time curve
occurred when doxazosin mesylate was administered with
food. Neither of these differences was statistically or
clinically significant.
Doxazosin mesylate is extensively metabolized in the
liver, mainly by O-demethylation of the quinazoline nucleus
or hydroxylation of the benzodioxan moiety. Although several
active metabolites of doxazosin have been identified,
the pharmacokinetics of these metabolites have not been
characterized. In a study of two subjects administered
radiolabelled doxazosin 2 mg orally and 1 mg intravenously
on two separate occasions, approximately 63% of the dose
was eliminated in the feces and 9% of the dose was found
in the urine. On average only 4.8% of the dose was excreted
as unchanged drug in the feces and only a trace of the
total radioactivity in the urine was attributed to unchanged
drug. At the plasma concentrations achieved by therapeutic
doses approximately 98% of the circulating drug is bound
to plasma proteins.
Plasma elimination of doxazosin is biphasic, with a terminal
elimination half-life of about 22 hours. Steady-state
studies in hypertensive patients given doxazosin doses
of 2-16 mg once daily showed linear kinetics and dose
proportionality. In two studies, following the administration
of 2 mg orally once daily, the mean accumulation ratios
(steady-state AUC vs. first dose AUC) were 1.2 and 1.7.
Enterohepatic recycling is suggested by secondary peaking
of plasma doxazosin concentrations.
In a crossover study in 24 normotensive subjects, the
pharmacokinetics and safety of doxazosin were shown to
be similar with morning and evening dosing regimens. The
area under the curve after morning dosing was, however,
11% less than that after evening dosing and the time to
peak concentration after evening dosing occurred significantly
later than that after morning dosing (5.6 hr vs. 3.5 hr).
The pharmacokinetics of doxazosin mesylate in young (<65
years) and elderly (³ 65 years) subjects were similar
for plasma half-life values and oral clearance. Pharmacokinetic
studies in elderly patients and patients with renal impairment
have shown no significant alterations compared to younger
patients with normal renal function. Administration of
a single 2 mg dose to patients with cirrhosis (Child-Pugh
Class A) showed a 40% increase in exposure to doxazosin.
There are only limited data on the effects of drugs known
to influence the hepatic metabolism of doxazosin [e.g.,
cimetidine (see DRUG INTERACTIONS)]. As with any drug
wholly metabolized by the liver, use of doxazosin mesylate
in patients with altered liver function should be undertaken
with caution.
In two placebo-controlled studies, of normotensive and hypertensive
BPH patients, in which doxazosin was administered in the
morning and the titration interval was two weeks and one
week, respectively, trough plasma concentrations of doxazosin
mesylate were similar in the two populations. Linear kinetics
and dose proportionality were observed.
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