Zileuton 600 mg (ER) · Tablets

Zileuton is an inhibitor of 5-lipoxygenase and thus inhibits leukotriene (LTB 4, LTC 4, LTD 4and LTE 4) formation. Both the R(+) and S(-) enantiomers are pharmacologically active as 5-lipoxygenase inhibitors in in vitroand in vivosystems. Leukotrienes are substances that induce numerous biological effects including augmentation of neutrophil and eosinophil migration, neutrophil and monocyte aggregation, leukocyte adhesion, increased capillary permeability, and smooth muscle contraction. These effects contribute to inflammation, edema, mucus secretion, and bronchoconstriction in the airways of asthmatic patients. LTB 4, a chemoattractant for neutrophils and eosinophils, and cysteinyl leukotrienes (LTC 4, LTD 4, LTE 4) can be measured in a number of biological fluids including bronchoalveolar lavage fluid (BALF), blood, urine and sputum from asthmatic patients.

Zileuton is an orally active inhibitor of ex vivoLTB 4formation in several species, including mice, rats, rabbits, dogs, sheep, and monkeys. Zileuton inhibits arachidonic acid-induced ear edema in mice, neutrophil migration in mice in response to polyacrylamide gel, and eosinophil migration into the lungs of antigen-challenged sheep. In a mouse model of allergic inflammation, zileuton inhibited neutrophil and eosinophil influx, reduced the levels of multiple cytokines in the BALF, and reduced serum IgE levels. Zileuton inhibits leukotriene-dependent smooth muscle contractions in vitroin guinea pig and human airways. The compound inhibits leukotriene-dependent bronchospasm in antigen and arachidonic acid-challenged guinea pigs. In antigen-challenged sheep, zileuton inhibits late-phase bronchoconstriction and airway hyperreactivity. The clinical relevance of these findings is unknown.

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 to 55) following single dose of 1200 mg (2 x 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 (C max) and the mean extent of absorption (AUC) of zileuton extended-release tablets by 18 and 34%, respectively, and prolonged T maxfrom 2.1 hours to 4.3 hours. The relative bioavailability of zileuton extended-release tablets to zileuton immediate-release tablets with respect to C maxand 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 C maxand 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 to 56) following multiple doses of 1200 mg (2 x 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 C minof zileuton extended-release tablets by 43% and 170%, respectively, but had no effect on C max. Therefore, zileuton extended-release tablets are 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 C max, C min, 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 C maxof zileuton extended-release tablets is about 35% lower than that of zileuton immediate-release tablets but the C minand 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 vitrostudies 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 mcg/mL of the inactive metabolite A-66193 with an AUC of 93 mcg·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.