Mechanism Of Action
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. Peak plasma concentrations are generally achieved 3 hours after
oral administration. The absolute bioavailability of zafirlukast is unknown. 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
Zafirlukast is more than 99% bound to plasma proteins,
predominantly albumin. The degree of binding was independent of concentration
in the clinically relevant range. The apparent steady-state volume of distribution
(Vss/F) is approximately 70 L, suggesting moderate distribution into tissues.
Studies in rats using radiolabeled zafirlukast indicate minimal distribution
across the blood-brain barrier.
Zafirlukast is extensively metabolized. The most common
metabolic products are hydroxylated metabolites which are excreted in the
feces. The metabolites of zafirlukast identified in plasma are at least 90
times less potent as LTD4 receptor antagonists than zafirlukast in a standard in
vitro test of activity. In vitro studies using human liver microsomes showed
that the hydroxylated metabolites of zafirlukast excreted in the feces are
formed through the cytochrome P450 2C9 (CYP2C9) pathway. Additional in vitro studies
utilizing human liver microsomes show that zafirlukast inhibits the cytochrome P450
CYP3A4 and CYP2C9 isoenzymes at concentrations close to the clinically achieved
total plasma concentrations (see DRUG INTERACTIONS).
The apparent oral clearance (CL/f) of zafirlukast is
approximately 20 L/h. Studies in the rat and dog suggest that biliary excretion
is the primary route of excretion. Following oral administration of radiolabeled
zafirlukast to volunteers, urinary excretion accounts for approximately 10% of
the dose and the remainder is excreted in feces. Zafirlukast is not detected in
In the pivotal bioequivalence study, the mean terminal
half-life of zafirlukast is approximately 10 hours in both normal adult
subjects and patients with asthma. In other studies, the mean plasma half-life
of zafirlukast ranged from approximately 8 to 16 hours in both normal subjects
and patients with asthma. The pharmacokinetics of zafirlukast are approximately
linear over the range from 5 mg to 80 mg. Steadystate plasma concentrations of
zafirlukast are proportional to the dose and predictable from single-dose pharmacokinetic
data. Accumulation of zafirlukast in the plasma following twice-daily dosing is
The pharmacokinetic parameters of zafirlukast 20 mg
administered as a single dose to 36 male volunteers are shown with the table
Mean (% Coefficient of Variation) pharmacokinetic
parameters of zafirlukast following single 20 mg oral dose administration to
male volunteers (n=36)
||2 (0.5 - 5.0)
|1. Median and range
Gender: The pharmacokinetics of zafirlukast are
similar in males and females. Weight-adjusted apparent oral clearance does not
differ due to gender.
Race: No differences in the pharmacokinetics of
zafirlukast due to race have been observed.
Elderly: The apparent oral clearance of
zafirlukast decreases with age. In patients above 65 years of age, there is an
approximately 2-3 fold greater Cmax and AUC compared to young adult patients.
Children: Following administration of a single 20
mg dose of zafirlukast to 20 boys and girls between 7 and 11 years of age, and
in a second study, to 29 boys and girls between 5 and 6 years of age, the following
pharmacokinetic parameters were obtained:
||Children age 5-6 years Mean (% Coefficient of Variation)
||Children age 7-11 years Mean (% Coefficient of Variation)
Weight unadjusted apparent clearance was 11.4 L/h (42%)
in the 7-11 year old children and 9.2 L/h (37%) in the 5-6 year old children,
which resulted in greater systemic drug exposures than that obtained in adults
for an identical dose. To maintain similar exposure levels in children compared
to adults, a dose of 10 mg twice daily is recommended in children 5-11 years of
age (see DOSAGE AND ADMINISTRATION).
Zafirlukast disposition was unchanged after multiple
dosing (20 mg twice daily) in children and the degree of accumulation in plasma
was similar to that observed in adults.
Hepatic Insufficiency: In a study of patients with
hepatic impairment (biopsy-proven cirrhosis), there was a reduced clearance of
zafirlukast resulting in a 50-60% greater Cmax and AUC compared to normal subjects.
Renal Insufficiency: Based on a cross-study
comparison, there are no apparent differences in the pharmacokinetics of
zafirlukast between renally-impaired patients and normal subjects.
The following drug interaction studies have been
conducted with zafirlukast (see PRECAUTIONS: DRUG INTERACTIONS).
- Coadministration of multiple doses of zafirlukast (160
mg/day) to steady-state with a single 25 mg dose of warfarin (a substrate of
CYP2C9) resulted in a significant increase in the mean AUC (+63%) and half-life
(+36%) of S-warfarin. The mean prothrombin time increased by approximately 35%.
The pharmacokinetics of zafirlukast were unaffected by coadministration with
- Coadministration of zafirlukast (80 mg/day) at
steady-state with a single dose of a liquid theophylline preparation (6 mg/kg)
in 13 asthmatic patients, 18 to 44 years of age, resulted in decreased mean plasma
concentrations of zafirlukast by approximately 30%, but no effect on plasma
theophylline concentrations was observed.
- Coadministration of zafirlukast (20 mg/day) or placebo at
steady-state with a single dose of sustained release theophylline preparation
(16 mg/kg) in 16 healthy boys and girls (6 through 11 years of age) resulted in
no significant differences in the pharmacokinetic parameters of theophylline.
- Coadministration of zafirlukast dosed at 40 mg twice
daily in a single-blind, parallel-group, 3-week study in 39 healthy female
subjects taking oral contraceptives, resulted in no significant effect on ethinyl
estradiol plasma concentrations or contraceptive efficacy.
- Coadministration of zafirlukast (40 mg/day) with aspirin
(650 mg four times daily) resulted in mean increased plasma concentrations of
zafirlukast by approximately 45%.
- Coadministration of a single dose of zafirlukast (40 mg)
with erythromycin (500 mg three times daily for 5 days) to steady-state in 11
asthmatic patients resulted in decreased mean plasma concentrations of
zafirlukast by approximately 40% due to a decrease in zafirlukast
- Coadministration of zafirlukast with fluconazole, a
moderate CYP2C9 inhibitor, resulted in increased plasma levels of zafirlukast,
by approximately 58% (90% CI:28, 95). The clinical significance of this interaction
is unknown. Zafirlukast exposure is likely to be increased by other moderate
and strong CYP2C9 inhibitors. Coadministration of zafirlukast with
itraconazole, a strong CYP3A4 inhibitor, caused no change in plasma levels of
Three U.S. double-blind, randomized, placebo-controlled,
13-week clinical trials in 1380 adults and children 12 years of age and older
with mild-to-moderate asthma demonstrated that ACCOLATE improved daytime asthma
symptoms, nighttime awakenings, mornings with asthma symptoms, rescue beta2-agonist
use, FEV1, and morning peak expiratory flow rate. In these studies, the
patients had a mean baseline FEV1 of approximately 75% of predicted normal and
a mean baseline beta2-agonist requirement of approximately 4-5 puffs of
albuterol per day. The results of the largest of the trials are shown in the table
Mean Change from Baseline at Study End Point
||ACCOLATE 20 mg twice daily
|Daytime Asthma symptom score (0-3 scale)
|Nightime Awakenings (number per week)
|Mornings with Asthma Symptoms (days per week)
|Rescue β2-agonist use (puffs per day)
|Morning PEFR (L/min)
|Evening PEFR (L/min)
|1. p < 0.05, compared to placebo
In a second and smaller study, the effect of ACCOLATE on
most efficacy parameters was comparable to the active control (inhaled cromolyn
sodium 1600 mcg four times per day) and superior to placebo at end point for
decreasing rescue beta2-agonist use (figure below).
Â In these trials, improvement in asthma symptoms occurred
within one week of initiating treatment with ACCOLATE. The role of ACCOLATE 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.