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 urine.

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. Steady-state 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 approximately 45%.

The pharmacokinetic parameters of zafirlukast 20 mg administered as a single dose to 36 male volunteers are shown with the table below.

Mean (% Coefficient of Variation) pharmacokinetic parameters of zafirlukast following single 20 mg oral dose administration to male volunteers (n=36)

Special Populations

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 11years of age, and in a second study, to 29 boys and girls between 5 and 6 years of age, the following pharmacoki-netic parameters were obtained:

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.

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