CLINICAL PHARMACOLOGY
General
Zafirlukast is a selective and competitive receptor antagonist
of leukotriene D4 and E4(LTD4 and LTE4), components of
slow-reacting substance of anaphylaxis (SRSA). Cysteinyl
leukotriene production and receptor occupation have been
correlated with the pathophysiology of asthma, including
airway edema, smooth muscle constriction, and altered
cellular activity associated with the inflammatory process,
which contribute to the signs and symptoms of asthma.
Patients with asthma were found in one study to be 25-100
times more sensitive to the bronchoconstricting activity
of inhaled LTD4 than nonasthmatic subjects.
In vitro studies demonstrated that zafirlukast antagonized
the contractile activity of three leukotrienes (LTC4,
LTD4 and LTE4) in conducting airway smooth muscle from
laboratory animals and humans. Zafirlukast prevented intradermal
LTD4-induced increases in cutaneous vascular permeability
and inhibited inhaled LTD4-induced influx of eosinophils
into animal lungs. Inhalational challenge studies in sensitized
sheep showed that zafirlukast suppressed the airway responses
to antigen; this included both the early- and late-phase
response and the nonspecific hyperresponsiveness.
In humans, zafirlukast inhibited bronchoconstriction
caused by several kinds of inhalational challenges. Pretreatment
with single oral doses of zafirlukast inhibited the bronchoconstriction
caused by sulfur dioxide and cold air in patients with
asthma. Pretreatment with single doses of zafirlukast
attenuated the early- and late-phase reaction caused by
inhalation of various antigens such as grass, cat dander,
ragweed, and mixed antigens in patients with asthma. Zafirlukast
also attenuated the increase in bronchial hyperresponsiveness
to inhaled histamine that followed inhaled allergen challenge.
Clinical Pharmacokinetics and Bioavailability
Zafirlukast is rapidly absorbed following oral administration.
The absolute bioavailability of zafirlukast is unknown.
Peak plasma concentrations are achieved 3 hours after
dosing.
The mean terminal elimination half-life of zafirlukast
is approximately 10 hours in both normal subjects and
patients with asthma. Steady-state plasma concentrations
of zafirlukast are proportional to the dose and predictable
from single-dose pharmacokinetic data.
Zafirlukast is extensively metabolized. Following oral
administration of a radiolabeled dose, urinary excretion
accounts for approximately 10% of the dose and the remainder
is excreted in feces. Unmetabolized zafirlukast is not
detected in urine. In vitro studies using human liver
microsomes showed that the hydroxylated metabolites of
zafirlukast are formed through the cytochrome P450 2C9
(CYP2C9) enzyme pathway. Additional in vitro studies utilizing
human liver microsomes wshow that zafirlukast inhibits
the cytochrome P450 CYP3A4 and CYP2C9 isoenzymes at concentrations
close to the clinically achieved plasma concentrations.
The metabolites of zafirlukast found in plasma are at
least 90 times less potent as LTD4 receptor antagonists
than zafirlukast in a standard in vitro test of activity.
Cross-study comparisons in patients ranging from 7 years
to greater than 65 years of age wshow that mean dose (mg/kg)
normalized AUC and Cmax increase and plasma clearance
(CL) decreases with increasing age. In patients above
65 years of age, there is an approximately 2-3 fold greater
Cmax and AUC compared to young adult patients.
In a study of patients with hepatic impairment (biopsy-proven
cirrhosis), there was a 50-60% greater Cmax and AUC compared
to normal subjects.
Based on a cross-study comparison, there are no apparent
differences in the pharmacokinetics of zafirlukast between
renally impaired patients and normal subjects.
In two separate studies, one using a high fat and the
other a high protein meal, administration of zafirlukast
with food reduced the mean bioavailability by approximately
40%.
In the concentration range of 0.25-10 mcg/ml, zafirlukast
is >99% bound to plasma proteins, predominantly albumin.
CLINICAL STUDIES
Three U.S. double-blind, randomized, placebo-controlled,
13-week clinical trials in 1380 patients with mild-to-moderate
asthma demonstrated that zafirlukast improved daytime
asthma symptoms, nighttime awakenings, mornings with asthma
symptoms, rescue beta2-agonist use, FEV1, and morning
peak expiratory wflow rate. In these studies, the patients
had a mean baseline FEV1 of approximately 75% of predicted
normal and a mean baseline beta-agonist requirement of
approximately 4-5 puffs of albuterol per day. The results
of the largest of the trials are shown in TABLE 1.
| TABLE 1
Mean Change from Baseline at Study Endpoint |
| |
Zafirlukast 20 mg
twice daily |
Placebo |
| |
N=514 |
N=248 |
| Daytime Asthma symptom
score (0-3 scale) |
-0.44* |
-0.25 |
| Nighttime Awakenings
(number per week) |
-1.27* |
-0.43 |
| Mornings with Asthma
Symptoms (days per week) |
-1.32* |
-0.75 |
| Rescue b2-agonist
use (puffs per day) |
-1.15* |
-0.24 |
| FEV1 (L) |
+0.15* |
+0.05 |
| Morning PEFR (L/min) |
+22.06* |
+7.63 |
| Evening PEFR (L/min) |
+13.12 |
+10.14 |
| * p<0.05,
compared to placebo |
In a second and smaller study, the effect of zafirlukast
on most efficacy parameters was comparable to the active
control (inhaled cromolyn sodium 1600 mcg 4 times per
day) and superior to placebo at endpoint for decreasing
rescue beta-agonist use.
In these trials, improvement in asthma symptoms occurred
within one week of initiating treatment with zafirlukast.
The role of zafirlukast in the management of patients
with more severe asthma, patients receiving antiasthma
therapy other than as-needed, inhaled beta2-agonists,
or as an oral or inhaled corticosteroid-sparing agent
remains to be fully characterized.
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