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
Tilade Pharmacology, Pharmacokinetics, Studies, Metabolism - Nedocromil (inhalation)
Tilade Pharmacology, Pharmacokinetics, Studies, Metabolism - Nedocromil (inhalation)
CLINICAL PHARMACOLOGY
General
Nedocromil sodium has
been shown to inhibit the in vitro activation of, and mediator
release from, a variety
of inflammatory
cell types associated with
asthma, including eosinophils,
neutrophils, macrophages, mast cells, monocytes, and platelets.
In vitro studies on cells obtained by bronchoalveolar lavage
from antigen-sensitized macaque monkeys show
that nedocromil sodium
inhibits the release
of mediators including histamine, leukotriene C4, and
prostaglandin
D2. Similar studies with human
bronchoalveolar
cells showed inhibition
of histamine release
from mast cells and beta-glucuronidase release
from macrophages.
Nedocromil sodium has
been tested in experimental models of asthma
using allergic animals and shown to inhibit the development
of early and late bronchoconstriction responses to inhaled antigen.
The development
of airway hyper-responsiveness to nonspecific
bronchoconstrictors was also inhibited. Nedocromil sodium
reduced antigen-induced increases in airway
microvasculature leakage when administered intravenously in a model
system.
In humans, nedocromil sodium
has been shown to inhibit acutely the bronchoconstrictor response
to several kinds of challenge. Pretreatment with single doses of
nedocromil sodium inhibited
the bronchoconstriction
caused by sulfur dioxide, inhaled neurokinin A, various antigens,
exercise, cold air, fog,
and adenosine monophosphate.
Nedocromil sodium has
no bronchodilator, antihistamine,
or corticosteroid activity.
Nedocromil sodium, when
delivered by inhalation
at the recommended dose, has no
known systemic activity.
Pharmacokinetics and Bioavailability
Systemic bioavailability
of nedocromil sodium
administered as an inhaled aerosol is low. In
a single dose study involving
20 healthy adult
subjects who were administered a 3.5 mg
dose of nedocromil sodium
(2 actuations of 1.75 mg
each), the mean AUC
was 5.0 ng-hr/mL and the mean Cmax was 1.6 ng/mL attained
about 28 minutes after dosing. The mean half-life
was 3.3 hours. Urinary excretion
over 12 hours averaged 3.4% of the administered dose, of which approximately
75% was excreted in the first six hours of dosing.
In a multiple dose
study, six healthy adult
volunteers (3 males and 3 females) received a 3.5 mg
single dose followed by
3.5 mg four times a day for
seven consecutive days. Accumulation of the drug
was not observed. Following single and multiple
dose inhalations, urinary
excretion of nedocromil
accounted for 5.6% and 12% of the drug
administered, respectively. After intravenous administration
to healthy adults, urinary
excretion of nedocromil
was approximately 70%. The absolute
bioavailability
of nedocromil was thus 8% (5.6/70) for single and 17% (12/70) for
multiple inhaled doses.
Similarly, in a multiple
dose study of 12 asthmatic
adult patients, each given
a 3.5 mg single dose
followed by 3.5 mg four times
a day for one month, both single dose
and multiple dose
inhalations gave a mean
high plasma concentration
of 2.8 ng/mL between 5 and 90 minutes, mean
AUC of 5.6 ng-hr/mL, and
a mean terminal
half-life of 1.5 hours.
The mean 24-hour urinary
excretion after either
single or multiple
dose administration
represented approximately 5% of the administered dose.
Studies involving very high oral
doses of nedocromil (600 mg
single dose, and subsequently 200 mg
three times a day for seven days) showed an absolute
bioavailability
of less than 2%. In a radiolabeled
(14C) nedocromil intravenous
study involving two healthy
adult males, urinary excretion
accounted for 64% of the dose, fecal excretion
for 36%.
Although minimal pharmacokinetic
data are available in children between the ages of 6 and 11 years,
the nedocromil sodium
levels obtained at 1 hour after chronic
dosing in this age group
appear to be similar to those observed in adults.
Protein Binding: Nedocromil is approximately 89%
protein bound in human
plasma over a concentration
range of 0.5 to 50 µg/mL.
This binding is reversible.
Metabolism: Nedocromil is not metabolized after IV
administration and is excreted unchanged.
CLINICAL STUDIES
The worldwide clinical
trial experience
with Tilade comprises 6,469 patients, including 993 pediatric
patients 6 through 11 years of age. Studies have been conducted
both at twice daily and at four times daily dosage regimens. Evidence
from these studies indicates that the four times daily regimen has
been more effective than the twice daily regimen. Less frequent
administration can be considered in patients under good control
on the four times daily regimen. (See DOSAGE
AND ADMINISTRATION.)
Adult Studies
Tilade vs. Placebo: The effectiveness
of Tilade given four times daily was examined in a 14-week, double-blind,
placebo-controlled, parallel-group trial in five centers in 120
patients (60/treatment). To be eligible for entry, the asthmatic
patients had to be controlled using only sustained-release theophylline
(SRT) and beta2-agonists. Two weeks after the test
therapies were begun the SRT was discontinued and four weeks after
that oral beta2-agonists
were stopped. Beta2-agonist metered dose
inhalers could still be used after 6 weeks. Efficacy was assessed
by symptom scores recorded
on diary cards completed on a daily basis
by the patients. Each morning the patient
recorded nighttime asthma
on a 0-2 scale, (0=slept well, no
asthma; 1=woke once because of asthma; 2=woke more than once because
of asthma). Before bedtime the patients recorded daytime asthma
and cough on a 0-5 scale
(0=no symptoms of asthma/cough today; 5=asthma/cough symptoms were
noticed most of the day and caused a lot of trouble). At
the end of the treatment
phase, patients and clinicians were asked for their opinions on
the effectiveness
of the treatment based on a five point
scale (1=very effective;
5=made condition worse). The results of these evaluations are shown
in Table 1; Tilade was significantly superior
to placebo for all measurements.
Table 1
|
Variable
|
Time Period
|
Tilade Mean
|
Placebo Mean
|
| Daytime Asthma1 |
Weeks 7-14 |
1.26 |
2.08 |
| Nighttime Asthma2 |
Weeks 7-14 |
0.67 |
0.96 |
| Cough1 |
Weeks 7-14 |
0.68 |
1.49 |
| Patient’s Opinion2 |
Week 14 |
2.27 |
3.55 |
| Clinician’s Opinion2 |
Week 14 |
2.13 |
3.48 |
| FEV12 (liters) |
Week 2 |
2.69 |
2.18 |
| FEV12 (liters) |
Week 6 |
2.65 |
2.15 |
| FEV12 (liters) |
Week 10 |
2.55 |
2.15 |
| FEV12 (liters) |
Week 14 |
2.59 |
2.10 |
The FEV1 percentage change relative to baseline
is shown in Figure 1; these also favored Tilade over placebo
throughout the study, with an effect
seen first at the two week measurement.
This study shows that Tilade improves symptom
control and pulmonary
function when it is added to an as-needed inhaled beta2-adrenergic
bronchodilator regimen
and that a beneficial effect
could be detected within two weeks.
Tilade vs. Cromolyn Sodium vs. Placebo: The effectiveness
of Tilade was compared to cromolyn sodium
and placebo in an eight-week,
double-blind, parallel-group,
12-center trial during which medication
was given four times daily. Three hundred and six patients were
randomized to treatment
(103/Tilade; 104/cromolyn sodium; 99/placebo). All patients were
SRT dependent and this drug
was stopped prior to starting the test
treatment. Efficacy was assessed on the basis
of diary card symptom
scores and FEV1. The diary scores were the same as used
in the 14-week study except that nighttime symptoms were recorded
on a 0-3 scale. The primary
efficacy variable
was a summary symptom score
derived by averaging the scores for daytime asthma,
nighttime asthma, and cough. The results of the study are shown
in Table 2.
Table 2
|
Variable
|
Time Period
|
Tilade Mean
|
Placebo Mean
|
Cromolyn Sodium Mean
|
| Summary Score1 |
Weeks 3-8 |
1.30 |
1.76 |
1.13 |
| Daytime Asthma1 |
Weeks 3-8 |
1.59 |
2.05 |
1.41 |
| Nighttime Asthma2 |
Weeks 3-8 |
0.91 |
1.23 |
0.77 |
| Cough3 |
Weeks 3-8 |
1.11 |
1.58 |
0.93 |
| FEV12 |
Weeks 3-8 |
2.46 |
2.23 |
2.56 |
| Patient’s Opinion1 |
Week 8 |
2.54 |
3.39 |
2.22 |
| Clinician’s Opinion1 |
Week 8 |
2.60 |
3.43 |
2.39 |
1Tilade significantly better than
Placebo, p<0.001
2Tilade significantly better than Placebo, p<0.01,
cromolyn sodium significantly better than Tilade, p<0.05
3Tilade significantly better than Placebo, p<0.05
This study corroborates the findings of the 14-week study, showing
that Tilade is effective in the management of symptoms and pulmonary
function in primarily atopic
mild to moderate asthmatics. Both active treatments were statistically
significantly better than placebo
for the primary efficacy
variable (summary symptom
score); Tilade and cromolyn sodium
were not significantly different for this parameter. A statistically
significant difference
favoring cromolyn sodium
w.s. however, seen for
nighttime asthma and
FEV1.
In allergic asthmatics
who are well controlled on cromolyn sodium,
there is no evidence
that the substitution
of Tilade for cromolyn sodium
would confer additional benefit
to the patient.
Available data on the relative efficacy
of Tilade and cromolyn sodium are inconclusive and efficacy
with one agent is not
known to be predictive of efficacy
with the other.
Pediatric Studies
Tilade vs. Placebo in Pediatric Patients: The effectiveness
of Tilade in minimizing the anticipated seasonal increase in asthmatic
symptoms in pediatric
patients 6 through 11 years of age
with mild seasonal ragweed-induced asthma
was examined in an eight-week, double-blind, placebo-controlled,
parallel-group trial in nine centers in 146 patients (75/Tilade;
71/placebo). These patients had a mean
baseline FEV1
that was 85% of predicted normal and a mean
baseline beta2-agonist
requirement of less than 2 inhalations of albuterol from a metered
dose inhaler
per day. Study medication
was given four times a day. Efficacy was assessed on the basis of
diary card symptom scores
(daytime asthma, sleep
disturbance, daytime cough, and morning asthma,
all rated on a six point
scale: 0=no symptoms; 5=severe symptoms) and as-needed bronchodilator
use. The primary efficacy
variable was based on both the summary symptom
score (total of daytime
asthma, daytime cough, and sleep
disturbance) and as-needed bronchodilator usage. At
the end of the treatment
phase, parents and clinicians assessed treatment effectiveness
on a five-point scale: 1=very effective; 5=made condition worse.
After a two-week baseline,
patients were randomized to eight weeks of double-blind treatment.
The results of these evaluations are shown in Table 3.
Table 3
|
Comparison of Scores for Tilade and
Placebo During the Primary
Time Period of Evaluation
|
|
Variable
|
Time Period
|
Tilade Mean
|
Vehicle Placebo Mean
|
| Summary Symptom Score1,3,4 |
Weeks 3-8 |
1.38 |
1.99 |
| Bronchodilator Use2,3,4 |
Weeks 3-8 |
0.43 |
0.84 |
| Parent’s Opinion4 |
Week 8 |
2.13 |
2.75 |
| Clinician’s Opinion4 |
Week 8 |
2.16 |
2.74 |
1Daytime asthma,
daytime cough, and sleep
disturbance due to asthma
(0-15)
2One unit
for every two inhalations
3Adjusted for baseline
4Tilade significantly better than Placebo, p<0.05
This study shows that Tilade, when used prophylactically in asthmatics
with known seasonal exacerbations, can attenuate
an increase in symptoms of asthma
and reduce the need
for rescue bronchodilator
treatment.
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