Population pharmacokinetics of zileution, a selective 5-lipoxygenase inhibitor, in patients with rheumatoid arthritis.
The pharmacokinetics of zileuton, a novel selective 5-lipoxygenase inhibitor, were studied in 37 patients with rheumatoid arthritis after administration of 200 mg, 400 mg, and 600 mg, zileuton for 4 weeks. Patients had 6-h pharmacokinetic evaluation of zileuton on day 14. Plasma zileuton concentrations were quantitated using HPLC. Zileuton pharmacokinetic parameters were estimated using standard noncompartmental methods. A population analysis of zileuton pharmacokinetics was also performed with the NONMEM computer program. The pharmacokinetics of zileuton in patients with rheumatoid arthritis were similar to those previously estimated in normal healthy humans. The peak concentrations and the areas under the curves during the dosing interval were dose proportional. 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 noncompartmental estimates. Differences in body weight, but not age or gender, helped explain some of the variability in the pharmacokinetics of zileuton in patients. Therefore, there is no pharmacokinetic basis for alteration of the zileuton dose size or the dosing schedule in patients with rheumatoid arthritis.
Awni
W M
WM
Department of Pharmacokinetics and Biopharmaceutics, Abbott Laboratories, Abbott Park, Illinois 60064-3500, USA.
Granneman
G R
GR
Locke
C S
CS
Brandwein
S R
SR
Dube
L M
LM
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D005260:Female; D006801:Humans; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D007700:Kinetics; D016859:Lipoxygenase Inhibitors / Q000493:pharmacokinetics*; D008297:Male; D008433:Mathematics; D008875:Middle Aged; D013997:Time Factors
D016859:Lipoxygenase Inhibitors; C063449:zileuton; D006918:Hydroxyurea