free asthma guide

The empirical formula is: C 31 H 33 N 3 O 6 S

Zafirlukast, a fine white to pale yellow amorphous powder, is practically insolublein water free asthma guide. It is slightly soluble in methanol and freely soluble in tetrahydrofuran,dimethylsulfoxide, and acetone free asthma guide.

ACCOLATE is supplied as 10 and 20 mg tablets for oral administration free asthma guide.

Inactive Ingredients: Film-coated tablets containing croscarmellose sodium,lactose, magnesium stearate, microcrystalline cellulose, povidone, hypromellose,and titanium dioxide free asthma guide.

CLINICAL PHARMACOLOGY
Mechanism of Action
Zafirlukast is a selective and competitive receptor antagonist of leukotrieneD 4 and E 4 (LTD 4 and LTE 4 ), components of slow-reacting substance of anaphylaxis(SRSA) free asthma guide. Cysteinyl leukotriene production and receptor occupation have been correlatedwith the pathophysiology of asthma, including airway edema, smooth muscle constriction,and altered cellular activity associated with the inflammatory process, whichcontribute to the signs and symptoms of asthma free asthma guide. Patients with asthma were foundin one study to be 25-100 times more sensitive to the bronchoconstricting activityof inhaled LTD 4 than nonasthmatic subjects free asthma guide.

In vitro studies demonstrated that zafirlukast antagonized the contractileactivity of three leukotrienes (LTC 4 , LTD 4 and LTE 4 ) in conducting airwaysmooth muscle from laboratory animals and humans free asthma guide. Zafirlukast prevented intradermalLTD 4 -induced increases in cutaneous vascular permeability and inhibited inhaledLTD 4 -induced influx of eosinophils into animal lungs free asthma guide. Inhalational challengestudies in sensitized sheep showed that zafirlukast suppressed the airway responsesto antigen; this included both the early- and late-phase response and the nonspecifichyperresponsiveness free asthma guide.

In humans, zafirlukast inhibited bronchoconstriction caused by several kindsof inhalational challenges free asthma guide. Pretreatment with single oral doses of zafirlukastinhibited the bronchoconstriction caused by sulfur dioxide and cold air in patientswith asthma free asthma guide. 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 free asthma guide. Zafirlukastalso attenuated the increase in bronchial hyperresponsiveness to inhaled histaminethat followed inhaled allergen challenge free asthma guide.

Clinical Pharmacokinetics and Bioavailability:
Absorption
Zafirlukast is rapidly absorbed following oral administration free asthma guide. Peak plasma concentrationsare generally achieved 3 hours after oral administration free asthma guide. The absolute bioavailabilityof zafirlukast is unknown free asthma guide. In two separate studies, one using a high fat andthe other a high protein meal, administration of zafirlukast with food reducedthe mean bioavailability by approximately 40% free asthma guide.

Distribution
Zafirlukast is more than 99% bound to plasma proteins, predominantly albumin free asthma guide. The degree of binding was independent of concentration in the clinically relevantrange free asthma guide. The apparent steady-state volume of distribution (V SS /F) is approximately70 L, suggesting moderate distribution into tissues free asthma guide. Studies in rats using radiolabeledzafirlukast indicate minimal distribution across the blood-brain barrier free asthma guide.

Metabolism
Zafirlukast is extensively metabolized free asthma guide. The most common metabolic products arehydroxylated metabolites which are excreted in the feces free asthma guide. The metabolites ofzafirlukast identified in plasma are at least 90 times less potent as LTD 4receptor antagonists than zafirlukast in a standard in vitro test of activity free asthma guide. In vitro studies using human liver microsomes showed that the hydroxylated metabolitesof zafirlukast excreted in the feces are formed through the cytochrome P4502C9 (CYP2C9) pathway free asthma guide. Additional in vitro studies utilizing human liver microsomesshow that zafirlukast inhibits the cytochrome P450 CYP3A4 and CYP2C9 isoenzymesat concentrations close to the clinically achieved total plasma concentrations(see Drug Interactions ) free asthma guide.

Excretion
The apparent oral clearance (CL/f) of zafirlukast is approximately 20 L/h free asthma guide. Studiesin the rat and dog suggest that biliary excretion is the primary route of excretion free asthma guide. Following oral administration of radiolabeled zafirlukast to volunteers, urinaryexcretion accounts for approximately 10% of the dose and the remainder is excretedin feces free asthma guide. Zafirlukast is not detected in urine free asthma guide.

In the pivotal bioequivalence study, the mean terminal half-life of zafirlukastis approximately 10 hours in both normal adult subjects and patients with asthma free asthma guide. In other studies, the mean plasma half-life of zafirlukast ranged from approximately8 to 16 hours in both normal subjects and patients with asthma free asthma guide. The pharmacokineticsof zafirlukast are approximately linear over the range from 5 mg to 80 mg free asthma guide. Steady-stateplasma concentrations of zafirlukast are proportional to the dose and predictablefrom single-dose pharmacokinetic data free asthma guide. Accumulation of zafirlukast in the plasmafollowing twice-daily dosing is approximately 45% free asthma guide.

The pharmacokinetic parameters of zafirlukast 20 mg administered as a singledose to 36 male volunteers are shown with the table below free asthma guide.

Mean (% Coefficient of Variation) pharmacokinetic
parameters of zafirlukast following single 20 mg
oral dose administration to male volunteers (n=36) C max
ng/mL t max h AUC
ng·h/mL t 1/2
h CL/f
L/h
326 (31.0) 2 (0.5-5.0) 1137 (34) 13.3 (75.6) 19.4 (32)
1 Median and range

Special Populations
Gender: The pharmacokinetics of zafirlukast are similar in males and females free asthma guide. Weight-adjusted apparent oral clearance does not differ due to gender free asthma guide.

Race: No differences in the pharmacokinetics of zafirlukast due to race havebeen observed free asthma guide.

Elderly: The apparent oral clearance of zafirlukast decreases with age free asthma guide. Inpatients above 65 years of age, there is an approximately 2-3 fold greater Cmax and AUC compared to young adult patients free asthma guide.

Children: Following administration of a single 20 mg dose of zafirlukast to20 boys and girls between 7 and 11 years of age, and in a second study, to 29boys and girls between 5 and 6 years of age, the following pharmacokinetic parameterswere obtained:

Parameter Children age
5-6 years
Mean (% Coefficient
of Variation) Children age
7-11 years
Mean (% Coefficient
of Variation)
C max (ng/mL) 756 (39%) 601 (45%)
AUC (ng·h/mL) 2458 (34%) 2027 (38%)
t max (h) 2.1 (61%) 2.5 (55%)
CL/f (L/h) 9.2 (37%) 11.4 (42%)

Weight unadjusted apparent clearance was 11.4 L/h (42%) in the 7-11 year oldchildren and 9.2 L/h (37%) in the 5-6 year old children, which resulted in greatersystemic drug exposures than that obtained in adults for an identical dose free asthma guide. To maintain similar exposure levels in children compared to adults, a dose of10 mg twice daily is recommended in children 5-11 years of age (see DOSAGE ANDADMINISTRATION ) free asthma guide.

Zafirlukast disposition was unchanged after multiple dosing (20 mg twice daily)in children and the degree of accumulation in plasma was similar to that observedin adults free asthma guide.

Hepatic Insufficiency: In a study of patients with hepatic impairment (biopsy-provencirrhosis), there was a reduced clearance of zafirlukast resulting in a 50-60%greater C max and AUC compared to normal subjects free asthma guide.

Renal Insufficiency: Based on a cross-study comparison, there are no apparentdifferences in the pharmacokinetics of zafirlukast between renally-impairedpatients and normal subjects free asthma guide.

Drug-Drug Interactions
The following drug interaction studies have been conducted with zafirlukast(see PRECAUTIONS , Drug Interactions ) free asthma guide.

Coadministration of multiple doses of zafirlukast (160 mg/day) to steady-statewith a single 25 mg dose of warfarin (a substrate of CYP2C9) resulted in a significantincrease in the mean AUC (+63%) and half-life (+36%) of S-warfarin free asthma guide. The meanprothrombin time increased by approximately 35% free asthma guide. The pharmacokinetics of zafirlukastwere unaffected by coadministration with warfarin free asthma guide.
Coadministration of zafirlukast (80 mg/day) at steady-state with a single doseof a liquid theophylline preparation (6 mg/kg) in 13 asthmatic patients, 18to 44 years of age, resulted in decreased mean plasma concentrations of zafirlukastby approximately 30%, but no effect on plasma theophylline concentrations wasobserved free asthma guide.
Coadministration of zafirlukast (20 mg/day) or placebo at steady-state witha single dose of sustained release theophylline preparation (16 mg/kg) in 16healthy boys and girls (6 through 11 years of age) resulted in no significantdifferences in the pharmacokinetic parameters of theophylline free asthma guide.
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 concentrationsor contraceptive efficacy free asthma guide.
Coadministration of zafirlukast (40 mg/day) with aspirin (650 mg four timesdaily) resulted in mean increased plasma concentrations of zafirlukast by approximately45% free asthma guide.
Coadministration of a single dose of zafirlukast (40 mg) with erythromycin (500mg three times daily for 5 days) to steady-state in 11 asthmatic patients resultedin decreased mean plasma concentrations of zafirlukast by approximately 40%due to a decrease in zafirlukast bioavailability free asthma guide.

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