Information on the pharmacokinetics of zileuton following the administration of zileuton immediate-release tablets is available in healthy subjects. The results of two clinical pharmacology studies using Zileuton Extended-Release Tablets are described below.

Absorption

A three-way crossover study was conducted in healthy male and female subjects (n=23) with a mean age of 33 (range 20-55) following single dose of 1200 mg (2 × 600 mg) Zileuton Extended-Release Tablets under fasted and fed conditions, and two doses of 600 mg zileuton immediate-release tablets every 6 hours under fasted conditions. Food increased the peak mean plasma concentrations (C﻿max) and the mean extent of absorption (AUC) of Zileuton Extended-Release Tablets by 18 and 34%, respectively, and prolonged T﻿max from 2.1 hours to 4.3 hours. The relative bioavailability of Zileuton Extended-Release Tablets to zileuton immediate-release tablets with respect to C﻿max and AUC under fasted conditions were 0.39 (90% CI: 0.36, 0.43) and 0.57 (90% CI: 0.52, 0.62), respectively. Similarly, relative bioavailability of Zileuton Extended-Release Tablets to zileuton immediate-release tablets with respect to C﻿max and AUC under fed conditions were 0.45 (90% CI: 0.41, 0.49) and 0.76 (90% CI: 0.70, 0.83), respectively.

A three-way crossover study was conducted in healthy male and female subjects (n=24) with a mean age of 35 (range 19-56) following multiple doses of 1200 mg (2 × 600 mg) Zileuton Extended-Release Tablets administered every 12 hours under fasted and fed conditions, and 600 mg zileuton immediate-release tablets every 6 hours under fed conditions until steady state zileuton levels were achieved. Food increased AUC and C﻿min of Zileuton Extended-Release Tablets by 43% and 170%, respectively, but had no effect on C﻿max. Therefore, Zileuton Extended-Release Tablets is recommended to be administered with food [see Dosage and Administration (2)]. At steady state, relative bioavailability of Zileuton Extended-Release Tablets to zileuton immediate-release tablets with respect to C﻿max, C﻿min, and AUC were 0.65 (90% CI: 0.60, 0.71), 1.05 (90% CI: 0.88, 1.25) and 0.85 (90% CI: 0.78, 0.92) respectively. These data indicate that at steady state under fed conditions the Cmax of Zileuton Extended-Release Tablets is about 35% lower than that of zileuton immediate-release tablets but the C﻿minand AUC are similar for both formulations.

Distribution

The apparent volume of distribution (V/F) of zileuton is approximately 1.2 L/kg. Zileuton is 93% bound to plasma proteins, primarily to albumin, with minor binding to ﻿α1–acid glycoprotein. 

Elimination

Elimination of zileuton is predominantly via metabolism with a mean terminal half-life of 3.2 hours. Apparent oral clearance (CL/F) of zileuton is 669 mL/min. Zileuton activity is primarily due to the parent drug. Studies with radiolabeled drug have 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.

Metabolism

In vitro studies utilizing human liver microsomes have shown that zileuton and its N-dehydroxylated metabolite can be oxidatively metabolized by CYP1A2, CYP2C9 and CYP3A4.

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 (A-66193) of zileuton. The urinary excretion of the inactive A-66193 metabolite and unchanged zileuton each accounted for less than 0.5% of the single radiolabeled dose. Multiple doses of 1200 mg Zileuton Extended-Release Tablets twice daily resulted in peak plasma levels of 4.9 μg/mL of the inactive metabolite A-66193 with an AUC of 93 μg hr/mL, showing large inter-subject variability. This inactive metabolite has been shown to be formed by the gastrointestinal microflora prior to the absorption of zileuton and its formation increases with delayed absorption of zileuton.

Renal Impairment

The pharmacokinetics of zileuton immediate-release tablets 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 Impairment

The pharmacokinetics of zileuton immediate-release tablets were compared between subjects with mild and moderate chronic hepatic insufficiency. The mean apparent plasma clearance of total zileuton in subjects with hepatic impairment was approximately half the value of the healthy subjects. The percent binding of zileuton to plasma proteins after multiple dosing was significantly reduced in patients with moderate hepatic impairment. Zileuton Extended-Release Tablets is contraindicated in patients with active liver disease or persistent ALT elevations ≥3×ULN [see Warnings and Precautions (5)].

Geriatric Use

The pharmacokinetics of zileuton immediate-release tablets were investigated in healthy elderly subjects (ages 65 to 81 years, 9 males, 9 females) and healthy young subjects (ages 20 to 40 years, 5 males, 4 females) after single and multiple oral doses of 600 mg zileuton every 6 hours. Zileuton pharmacokinetics were similar in healthy elderly subjects (≥65 years) compared to healthy younger adults (20 to 40 years).