Elimination of zileuton is predominantly via metabolism with a mean terminal half-life of 2.5 hours. Apparent oral clearance of zileuton is 7.0 mL/min/kg. ZYFLO activity is primarily due to the parent drug. Studies with radiolabeled drug demonstrated that orally administered zileuton is well absorbed into the systemic circulation with 94.5% and 2.2% of the radiolabeled dose recovered in urine and feces, respectively. Several zileuton metabolites have been identified in human plasma and urine. These include two diastereomeric O-glucuronide conjugates (major metabolites) and an N-dehydroxylated metabolite of zileuton. The urinary excretion of the inactive N-dehydroxylated metabolite and unchanged zileuton each accounted for less than 0.5% of the dose. In vitro studies utilizing human liver microsomes have shown that zileuton and its N-dehydroxylated metabolite can be oxidatively metabolized by the cytochrome P450 isoenzymes 1A2, 2C9 and 3A4 (CYP1A2, CYP2C9 and CYP3A4).

Special Populations

Effect of age: The pharmacokinetics of zileuton were investigated in healthy elderly volunteers (ages 65 to 81 years, 9 Males and 4 Females) and healthy young volunteers (ages 20 to 40 years, 5 Males and 4 Females) after single and multiple oral doses of 600 mg every 6 hours of zileuton. Zileuton pharmacokinetics were similar in healthy elderly subjects (³ 65 years) compared to healthy younger adults (18 to 40 years).

Effect of gender: Across several studies, no significant gender effects were observed on the pharmacokinetics of zileuton.

Renal insufficiency: The pharmacokinetics of zileuton were similar in healthy subjects and in subjects with mild, moderate, and severe renal insufficiency. In subjects with renal failure requiring hemodialysis, zileuton pharmacokinetics were not altered by hemodialysis and a very small percentage of the administered zileuton dose (<0.5%) was removed by hemodialysis. Hence, dosing adjustment in patients with renal dysfunction or undergoing hemodialysis is not necessary.

Hepatic insufficiency: ZYFLO is contraindicated in patients with active liver disease (see CONTRAINDICATIONS and PRECAUTIONS, Hepatic).

CLINICAL STUDIES

Two double-blind, parallel, placebo-controlled, multi-center studies have established the efficacy of ZYFLO in the treatment of asthma. Three hundred seventy-three (373) patients were enrolled in the 6-month, double-blind phase of Study 1, and 401 patients were enrolled in the 3-month double-blind phase of Study 2. In these studies, the patients were mild-to-moderate asthmatics who had a mean baseline FEV₁ of approximately 2.3 liters and who used inhaled beta-agonists as needed, the mean being approximately 6 puffs of albuterol per day from a metered-dose inhaler. In each study, patients were randomized to receive either ZYFLO 400 mg four times daily, ZYFLO 600 mg four times daily, or placebo. Only the ZYFLO 600 mg four times daily dosage regimen was shown to be efficacious by demonstrating statistically significant improvement across several parameters.

Efficacy endpoints measured in Study 1 are shown in Table 1 below as mean change from baseline to the end of the study (six months). Statistically significant differences from placebo at the p<0.05 level are indicated by an asterisk(*). Similar results were observed after three months in Study 2.

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