12 CLINICAL PHARMACOLOGY12.1 Mechanism of Action
Alfuzosin is a selective antagonist of post-synaptic alpha1-adrenoreceptors, which are located in the prostate, bladder
base, bladder neck, prostatic capsule, and prostatic urethra.
12.2 Pharmacodynamics
The symptoms associated with benign prostatic hyperplasia (BPH)
such as urinary frequency, nocturia, weak stream, hesitancy and incomplete
emptying are related to two components, anatomical (static) and functional
(dynamic). The static component is related to the prostate size. Prostate size
alone does not correlate with symptom severity. The dynamic component is a
function of the smooth muscle tone in the prostate and its capsule, the bladder
neck, and the bladder base as well as the prostatic urethra. The smooth muscle
tone is regulated by alpha-adrenergic receptors. Alfuzosin exhibits selectivity
for alpha1-adrenergic receptors in the lower urinary
tract. Blockade of these adrenoreceptors can cause smooth muscle in the bladder
neck and prostate to relax, resulting in an improvement in urine flow and a
reduction in symptoms of BPH.
Cardiac Electrophysiology
The effect of 10 mg and 40 mg alfuzosin on QT interval was evaluated in a
double-blind, randomized, placebo and active-controlled (moxifloxacin 400 mg),
4-way crossover single dose study in 45 healthy white male subjects aged 19 to
45 years. The QT interval was measured at the time of peak alfuzosin plasma
concentrations. The 40 mg dose of alfuzosin was chosen because this dose
achieves higher blood levels than those achieved with the co-administration of
UROXATRAL and ketoconazole 400 mg. Table 3 summarizes the effect on uncorrected
QT and mean corrected QT interval (QTc) with different methods of correction
(Fridericia, population-specific and subject-specific correction methods) at the
time of peak alfuzosin plasma concentrations. No single one of these correction
methodologies is known to be more valid. The mean change of heart rate
associated with a 10 mg dose of alfuzosin in this study was 5.2 beats/minute and
5.8 beats/minute with 40 mg alfuzosin. The change in heart rate with
moxifloxacin was 2.8 beats/minute.
Table 3. Mean QT and QTc changes in msec (95% CI) from baseline at
Tmax (relative to placebo) with different methodologies
to correct for effect of heart rate.| Drug/Dose | QT | Fridericia method | Population-specific method | Subject-specific method |
|---|
| Active control |
Alfuzosin
10 mg | -5.8
(-10.2, -1.4) | 4.9
(0.9, 8.8) | 1.8
(-1.4, 5.0) | 1.8
(-1.3, 5.0) |
Alfuzosin
40 mg | -4.2
(-8.5, 0.2) | 7.7
(1.9, 13.5) | 4.2
(-0.6, 9.0) | 4.3
(-0.5, 9.2) |
Moxifloxacin
400 mg | 6.9
(2.3, 11.5) | 12.7
(8.6, 16.8) | 11.0
(7.0, 15.0) | 11.1
(7.2, 15.0) |
The QT effect appeared greater for 40 mg compared to 10 mg alfuzosin. The
effect of the highest alfuzosin dose (four times the therapeutic dose) studied
did not appear as large as that of the active control moxifloxacin at its
therapeutic dose. This study, however, was not designed to make direct
statistical comparisons between the drugs or the dose levels. There has been no
signal of Torsade de Pointes in the extensive post-marketing experience with
alfuzosin outside the United States.
A separate post-marketing QT study evaluated the effect of the
co-administration of 10 mg alfuzosin with a drug of similar QT effect size. In
this study, the mean placebo-subtracted QTcF increase of alfuzosin 10 mg alone
was 1.9 msec (upperbound 95% CI, 5.5 msec). The concomitant administration of
the two drugs showed an increased QT effect when compared with either drug
alone. This QTcF increase [5.9 msec (UB 95% CI, 9.4 msec)] was not more than
additive. Although this study was not designed to make direct statistical
comparisons between drugs, the QT increase with both drugs given together
appeared to be lower than the QTcF increase seen with the positive control
moxifloxacin 400 mg [10.2 msec (UB 95% CI, 13.8 msec)]. The clinical impact of
these QTc changes is unknown.
12.3 PharmacokineticsThe pharmacokinetics of UROXATRAL have been evaluated in adult
healthy male volunteers after single and/or multiple administration with daily
doses ranging from 7.5 mg to 30 mg, and in patients with BPH at doses from 7.5
mg to 15 mg.
Absorption
The absolute bioavailability of UROXATRAL 10 mg tablets under fed conditions
is 49%. Following multiple dosing of 10 mg UROXATRAL under fed conditions, the
time to maximum concentration is 8 hours. Cmax and
AUC0–24 are 13.6 (SD = 5.6) ng/mL and 194 (SD = 75)
ng∙h/mL, respectively. UROXATRAL exhibits linear kinetics following single and
multiple dosing up to 30 mg. Steady-state plasma levels are reached with the
second dose of UROXATRAL administration. Steady-state alfuzosin plasma
concentrations are 1.2- to 1.6-fold higher than those observed after a single
administration.
Effect of Food
As illustrated in Figure 1, the extent of absorption is 50% lower under
fasting conditions. Therefore, UROXATRAL should be taken immediately following a
meal [see Dosage and Administration
(2)].
Figure 1 Image (Uroxatral Fig1)
Figure 1 – Mean (SEM) Alfuzosin Plasma
Concentration-Time Profiles after a Single Administration of UROXATRAL 10 mg
tablets to 8 Healthy Middle-Aged Male Volunteers in Fed and Fasted States
Distribution
The volume of distribution following intravenous administration in healthy
male middle-aged volunteers was 3.2 L/kg. Results of in
vitro studies indicate that alfuzosin is moderately bound to human plasma
proteins (82% to 90%), with linear binding over a wide concentration range (5 to
5,000 ng/mL).
Metabolism
Alfuzosin undergoes extensive metabolism by the liver, with only 11% of the
administered dose excreted unchanged in the urine. Alfuzosin is metabolized by
three metabolic pathways: oxidation, O-demethylation, and N-dealkylation. The
metabolites are not pharmacologically active. CYP3A4 is the principal hepatic
enzyme isoform involved in its metabolism.
Excretion
Following oral administration of 14C-labeled alfuzosin
solution, the recovery of radioactivity after 7 days (expressed as a percentage
of the administered dose) was 69% in feces and 24% in urine. Following oral
administration of UROXATRAL 10 mg tablets, the apparent elimination half-life is
10 hours.
Specific Populations
Elderly: In a pharmacokinetic
assessment during phase 3 clinical studies in patients with BPH, there was no
relationship between peak plasma concentrations of alfuzosin and age. However,
trough levels were positively correlated with age. The concentrations in
subjects ≥75 years of age were approximately 35% greater than in those below 65
years of age.
Renal Impairment: The Pharmacokinetic
profiles of UROXATRAL 10 mg tablets in subjects with normal renal function
(CLCR>80 mL/min), mild impairment (CLCR 60 to 80 mL/min), moderate impairment (CLCR 30 to 59 mL/min), and severe impairment (CLCR less than 30 mL/min) were compared. These clearances were
calculated by the Cockcroft-Gault formula. Relative to subjects with normal
renal function, the mean Cmax and AUC values were
increased by approximately 50% in patients with mild, moderate, or severe renal
impairment [see Warnings and Precautions
(5.2) and Use in Specific Populations
(8.6)].
Hepatic Impairment: The
pharmacokinetics of UROXATRAL have not been studied in patients with mild
hepatic impairment. In patients with moderate or severe hepatic insufficiency
(Child-Pugh categories B and C), the plasma apparent clearance (CL/F) was
reduced to approximately one-third to one-fourth that observed in healthy
subjects. This reduction in clearance results in three to four-fold higher
plasma concentrations of alfuzosin in these patients compared to healthy
subjects. Therefore, UROXATRAL is contraindicated in patients with moderate to
severe hepatic impairment [see Contraindications (4), Warnings and Precautions
(5.3) and Use in Specific Populations (8.7)].
Drug-Drug Interactions
Metabolic Interactions
CYP3A4 is the principal hepatic enzyme isoform involved in the metabolism of
alfuzosin.
Potent CYP3A4 Inhibitors
Repeated oral administration of 400 mg/day of ketoconazole, a potent
inhibitor of CYP3A4, increased alfuzosin Cmax by 2.3-fold
and AUClast by 3.2-fold, following a single 10 mg dose of
alfuzosin.
In another study, repeated oral administration of a lower (200 mg/day) dose
of ketoconazole increased alfuzosin Cmax by 2.1-fold and AUClast by 2.5-fold, following a single 10 mg dose of alfusion.
Therefore, UROXATRAL is contraindicated for co-administration with potent
inhibitors of CYP3A4 because exposure is increased, (e.g., ketoconazole,
itraconazole, or ritonavir) [see Contraindications (4), Warnings and Precautions
(5.5) and Drug Interactions (7.1)].
Moderate CYP3A4 Inhibitors
Diltiazem: Repeated co-administration
of 240 mg/day of diltiazem, a moderately-potent inhibitor of CYP3A4, with 7.5
mg/day (2.5 mg three times daily) alfuzosin (equivalent to the exposure with
UROXATRAL) increased the Cmax and AUC0–24 of alfuzosin 1.5- and 1.3-fold, respectively. Alfuzosin
increased the Cmax and AUC0–12 of
diltiazem 1.4-fold. Although no changes in blood pressure were observed in this
study, diltiazem is an antihypertensive medication and the combination of
UROXATRAL and antihypertensive medications has the potential to cause
hypotension in some patients [see Warnings
and Precautions (5.1)].
In human liver microsomes, at concentrations that are achieved at the
therapeutic dose, alfuzosin did not inhibit CYP1A2, 2A6, 2C9, 2C19, 2D6 or 3A4
isoenzymes. In primary culture of human hepatocytes, alfuzosin did not induce
CYP1A, 2A6 or 3A4 isoenzymes.
Other Interactions
Warfarin: Multiple dose administration
of an immediate release tablet formulation of alfuzosin 5 mg twice daily for six
days to six healthy male volunteers did not affect the pharmacological response
to a single 25 mg oral dose of warfarin.
Digoxin: Repeated co-administration of
UROXATRAL 10 mg tablets and digoxin 0.25 mg/day for 7 days did not influence the
steady-state pharmacokinetics of either drug.
Cimetidine: Repeated administration of
1 g/day cimetidine increased both alfuzosin Cmax and AUC
values by 20%.
Atenolol: Single administration of 100
mg atenolol with a single dose of 2.5 mg of an immediate release alfuzosin
tablet in eight healthy young male volunteers increased alfuzosin Cmax and AUC values by 28% and 21%, respectively. Alfuzosin
increased atenolol Cmax and AUC values by 26% and 14%,
respectively. In this study, the combination of alfuzosin with atenolol caused
significant reductions in mean blood pressure and in mean heart rate. [see Warnings and Precautions (5.1)].
Hydrochlorothiazide: Single
administration of 25 mg hydrochlorothiazide did not modify the pharmacokinetic
parameters of alfuzosin. There was no evidence of pharmacodynamic interaction
between alfuzosin and hydrochlorothiazide in the 8 patients in this study.
