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
Serevent Diskus Pharmacology, Pharmacokinetics, Studies, Metabolism - Salmeterol Xinafoate (inhalation powder)
Serevent Diskus Pharmacology, Pharmacokinetics, Studies, Metabolism - Salmeterol Xinafoate (inhalation powder)
CLINICAL PHARMACOLOGY
Mechanism of Action
Salmeterol is a long-acting beta-adrenergic agonist. In vitro
studies and in vivo pharmacologic studies demonstrate that salmeterol
is selective for beta2-adrenoceptors compared with isoproterenol,
which has approximately equal agonist
activity on beta1-
and beta2-adrenoceptors. In vitro studies show
salmeterol to be at least 50 times more selective for beta2-adrenoceptors
than albuterol. Although beta2-adrenoceptors are the
predominant adrenergic
receptors in bronchial
smooth muscle and beta1-adrenoceptors
are the predominant receptors in the heart, there are also beta2-adrenoceptors
in the human heart
comprising 10% to 50% of the total beta-adrenoceptors. The precise
function of these receptors
has not been established, but they raise the possibility that even
highly selective beta2-agonists may have cardiac
effects.
The pharmacologic effects of beta2-adrenoceptor agonist
drugs, including salmeterol, are at least in proof
attributable to stimulation of intracellular
adenyl cyclase, the enzyme
that catalyzes the conversion of adenosine
triphosphate (ATP) to cyclic-3',5'-adenosine monophosphate (cyclic
AMP). Increased cyclic
AMP levels cause
relaxation of bronchial
smooth muscle and inhibition
of release of mediators
of immediate hypersensitivity
from cells, especially from mast cells.
In vitro tests show
that salmeterol is a potent
and long-lasting inhibitor of the release
of mast cell mediators,
such as histamine, leukotrienes,
and prostaglandin
D2, from human
lung. Salmeterol inhibits histamine-induced plasma protein
extravasation
and inhibits platelet
activating factor-induced eosinophil accumulation in the lungs of
guinea pigs when administered by the inhaled route. In
humans, single doses of salmeterol administered via inhalation aerosol
attenuate allergen-induced
bronchial hyper-responsiveness.
Pharmacokinetics
Salmeterol acts locally in the lung; plasma
levels therefore do not predict therapeutic
effect. Because of the low therapeutic
dose, systemic levels of salmeterol inhalation
powder are low or undetectable
after inhalation of recommended doses (50 mcg
twice daily). Following chronic
administration of an inhaled dose
of 50 mcg of salmeterol
inhalation powder
twice daily, salmeterol was detected in plasma
within 5 to 45 minutes in seven asthmatic patients; plasma
concentrations were very low, with mean
peak concentrations of 167 ± 75 pg/mL and no
accumulation with repeated doses. Oral administration of 1 mg
of radiolabeled salmeterol (as salmeterol xinafoate) to two healthy
subjects gave peak plasma
salmeterol concentrations of about 650 pg/mL at about 45 minutes;
the terminal elimination
half-life was about
5.5 hours (one volunteer only).
Salmeterol xinafoate, an ionic
salt, dissociates in solution
so that the salmeterol and 1-hydroxy-2-
naphthoic acid (xinafoate)
moieties are absorbed, distributed, metabolized, and excreted independently.
Salmeterol base is extensively
metabolized by hydroxylation, with subsequent elimination
predominantly in the feces. In two healthy
subjects who received 1 mg
of radiolabeled salmeterol (as salmeterol xinafoate) orally, approximately
25% and 60% of the radiolabeled salmeterol was eliminated in urine
and feces, respectively, over a period of 7 days. No
significant amount
of unchanged salmeterol base
was detected in either urine
or feces.
Salmeterol is 94% to 98% bound
to human plasma
proteins in vitro over the concentration
range of 8 to 7,722 ng
of base per
milliliter, much higher concentrations than those achieved following
therapeutic doses
of salmeterol.
The xinafoate moiety
has no apparent
pharmacologic activity, is highly protein bound
(>99%), and has a long elimination
half-life of 11 days.
The pharmacokinetics
of salmeterol base has
not been studied in elderly patients nor in patients with hepatic
or renal impairment. Since
salmeterol is predominantly cleared by hepatic
metabolism, liver
function impairment
may lead to accumulation
of salmeterol in plasma. Therefore, patients with hepatic disease
should be closely monitored.
Pharmacodynamics
Inhaled salmeterol, like other beta-adrenergic agonist
drugs, can in some patients produce cardiovascular
effects (see PRECAUTIONS).
The cardiovascular
effects (heart rate, blood
pressure) associated with salmeterol inhalation
aerosol occur with similar
frequency, and are of similar type
and severity, as those noted following albuterol administration.
The effects of rising doses of salmeterol and standard
inhaled doses of albuterol were studied in
volunteers and in patients with asthma. Salmeterol doses up to 84
mcg administered as inhalation
aerosol resulted in
heart rate
increases of 3 to 16 beats/min, about the same as albuterol dosed
at 180 mcg by inhalation
aerosol (4 to 10 beats/min).
Adolescent and adult patients
receiving 50-mcg doses of salmeterol inhalation
powder (n = 60) underwent
continuous electrocardiographic monitoring during two 12-hour periods
after the first dose and
after 1 month of therapy,
and no clinically significant
dysrhythmias were noted. Also, pediatric
patients receiving 50-mcg doses of salmeterol
inhalation powder (n =
67) underwent continuous electrocardiographic monitoring during
two 12-hour periods after the first dose
and after 3 months of therapy,
and no clinically significant
dysrhythmias were noted.
Studies in laboratory
animals (minipigs, rodents, and dogs) have demonstrated the occurrence
of cardiac arrhythmias
and sudden death (with
histologic evidence of myocardial
necrosis) when beta-agonists and methylxanthines are administered
concurrently. The clinical
significance of these findings is unknown.
Clinical Trials
During the initial
treatment day in several
multiple-dose clinical
trials with salmeterol inhalation
powder in patients with
asthma, the median
time to onset of clinically significant
bronchodilatation (³15%improvement
in FEV1) ranged from 30 to 48 minutes after a 50-mcg
dose.
One hour after a single dose
of 50 mcg of salmeterol
inhalation powder,
the majority of patients had ³15%
improvement in FEV1. Maximum improvement in FEV1
generally occurred within 180 minutes, and clinically significant
improvement continued for 12 hours in most patients.
In two large, randomized, double-blind studies, salmeterol inhalation
powder was compared with albuterol inhalation
aerosol and placebo
in adolescent and adult
patients with mild-to-moderate asthma
(protocol defined as 50% to 80% predicted FEV1, actual
mean of 67.7% at baseline),
including patients who did and who did not receive concurrent inhaled
corticosteroids. The efficacy
of salmeterol inhalation
powder was demonstrated
over the 12-week period
with no change in effectiveness
over this time period.
There were no gender- or
age-related differences in safety or efficacy. No
development of tachyphylaxis
to the bronchodilator
effect has been noted
in these studies.
During daily treatment
with salmeterol inhalation
powder for 12 weeks in
adolescent and adult
patients with mild-to-moderate asthma,
the following treatment effects were seen:
Table 1: Daily Efficacy Measurements in Two Large 12-Week
Clinical Trials (Combined Data)
| Parameter |
Time
|
Placebo
|
SEREVENT
|
Albuterol
|
| No. of randomized
subjects |
|
152
|
149
|
148
|
| Mean AM
peak expiratory
flow
rate (L/ min)
|
baseline
|
394
|
395
|
394
|
|
12 weeks
|
396
|
427*
|
394
|
| Mean %
days with no asthma
symptoms
|
baseline
|
14
|
13
|
12
|
|
12 weeks
|
20
|
33
|
21
|
| Mean %
nights with no
awakenings
|
baseline
|
70
|
63
|
68
|
|
12 weeks
|
73
|
85*
|
71
|
| Rescue
medications (mean no.
of inhalations per
day)
|
baseline
|
4.2
|
4.3
|
4.3
|
|
12 weeks
|
3.3
|
1.6 †
|
2.2
|
| Asthma exacerbations
|
|
14%
|
15%
|
16%
|
* Statistically superior
to placebo and albuterol (P<0.001).
† Statistically superior to
placebo (P<0.001).
Safe usage with maintenance of efficacy
for periods up to 1 year has been documented.
Salmeterol inhalation
powder and salmeterol
aerosol were compared
to placebo in two additional
randomized, double-blind clinical
trials in adolescent
and adult patients with
mild-to-moderate asthma. Salmeterol inhalation
powder 50 mcg
administered via the DISKUS and salmeterol inhalation
aerosol 42 mcg, both
administered twice daily, produced significant
improvements in pulmonary
function compared with
placebo over the 12-week
period. While no statistically
significant differences were observed between the active treatments
for any of the efficacy assessments or safety evaluations performed,
there were some efficacy measures on which the metered-dose inhaler
appeared to provide better results. Similar findings were noted
in two randomized, single-dose, crossover
comparisons of salmeterol inhalation
powder and salmeterol aerosol
for the prevention
of exercise-induced bronchospasm. Therefore, while SEREVENT DISKUS
was comparable to SEREVENT® salmeterol xinafoate)
Inhalation Aerosol in clinical
trials in mild-to-moderate asthmatics, it should not be assumed
that the SEREVENT Inhalation Aerosol and SEREVENT DISKUS drug
products will produce clinically
equivalent outcomes
in all patients.
In a large, randomized, double-blind, controlled study (n = 449),
50 mcg of salmeterol inhalation
powder, via the SEREVENT
DISKUS, was administered twice daily to pediatric
asthma patients who did
and who did not receive concurrent inhaled corticosteroids. The
efficacy of salmeterol inhalation
powder was demonstrated
over the 12-week treatment
period with respect to
periodic serial peak expiratory
flow (36% to 39% postdose
increase from baseline) and FEV1 (32% to 33% postdose
increase from baseline). Salmeterol was effective in demographic
subgroup analyses (gender and age) and was effective when coadministered
with other inhaled asthma
medications such as short-acting bronchodilators and inhaled corticosteroids.
A second large, randomized, double-blind, placebo-controlled study
(n = 207) with 50 mcg of salmeterol inhalation
powder via an alternate
device supported the
findings of the trial with SEREVENT DISKUS.
In two randomized, single-dose, crossover
studies in adolescents and adults with exercise-induced
bronchospasm (EIB) (n = 53), 50 mcg
of salmeterol inhalation
powdersalmeterol powder significantly prevented EIB when dosed 30
minutes prior to exercise. For many patients, this protective
effect against EIB was
still apparent up to 8.5 hours following a single dose.
Table 2:
Results of Two Exercise-Induced Bronchospasm Studies in Adolescents
and Adults
|
|
Placebo
(n = 52)
n % Total
|
SEREVENT DISKUS
(n = 52)
n % Total
|
| 0.5 Hour
postdose exercise
challenge |
% Fall in FEV1
|
|
|
<10%
|
15
|
29
|
31
|
60
|
|
=10%, <20%
|
3
|
6
|
11
|
21
|
|
=20%,
|
34
|
65
|
10
|
19
|
| Mean maximal
% fall in FEV1
(SE) |
-25% (1.8)
|
-11% (1.9)
|
| 8.5 Hour
postdose exercise
challenge |
% Fall in FEV1
|
|
|
<10%
|
12
|
23
|
26
|
50
|
|
=10%, <20%
|
7
|
13
|
12
|
23
|
|
=20%,
|
33
|
63
|
14
|
27
|
| Mean maximal
% fall in FEV1
(SE) |
-27% (1.5)
|
-16% (2.0)
|
In two randomized studies in children 4 to 11 years old with asthma
and EIB (n = 50), a single 50-mcg dose
of salmeterol inhalation powder
prevented EIB when dosed 30 minutes prior to exercise, with
protection lasting up to 11.5 hours in repeat testing following
this single dose in many
patients.
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