POPULATION PHARMACOKINETICS OF ZILEUTION, A SELECTIVE 5-LIPOXYGENASE INHIBITOR, IN PATIENTS WITH RHEUMATOID-ARTHRITIS

The pharmacokinetics of zileuton, a novel selective 5-lipoxygenase inh ibitor, were studied in 37 patients with rheumatoid arthritis after ad ministration of 200 mg, 400 mg, and 600 mg zileuton for 4 weeks. Patie nts had 6-h pharmacokinetic evaluation of zileuton on day 14. Plasma z ileuton concentrations were quantitated using HPLC. Zileuton pharmacok inetic parameters were estimated using standard noncompartmental metho ds. A population analysis of zileuton pharmacokinetics was also perfor med with the NONMEM computer program. The pharmacokinetics of zileuton in patients with rheumatoid arthritis were similar to those previousl y estimated in normal healthy humans. The peak concentrations and the areas under the curves during the dosing interval were dose proportion al. The noncompartmental means of the CL/f, terminal-phase half-life, and V/f of zileuton were approximately 545 ml min(-1), 1.4 h, and 64.3 1, respectively. The estimate of population typical values of the CL/ f for a 70-kg person (540 ml min(-1)) and V/f for a 70-kg person (64.8 1) from the NONMEM analysis were in agreement with the noncompartmenta l estimates. Differences in body weight, but not age or gender, helped explain some of the variability in the pharmacokinetics of zileuton i n patients. Therefore, there is no pharmacokinetic basis for alteratio n of the zileuton dose size or the dosing schedule in patients with rh eumatoid arthritis.