Effects of ABT-761, a novel 5-lipoxygenase inhibitor, on the pharmacokinetics of a single dose of ethinyl estradiol and levonorgestrel in healthy female volunteers.
ABT-761 is a second-generation 5-lipoxygenase inhibitor in clinical development for the treatment of asthma. The effects of ABT-761 on the pharmacokinetics of an oral contraceptive were assessed in 21 female adult volunteers in a phase I, multiple-dose, open-label study. Subjects received a single dose of oral contraceptive (30 microg ethinyl estradiol and 0.15 mg of levonorgestrel) on each of days 1 and 29. Oral doses of 300 mg of ABT-761 were administered once daily beginning on day 15 continuing through day 29. Statistically significant decreases in maximum concentration (Cmax) and area under the concentration-time curve (AUC) of ethinyl estradiol were observed when oral contraceptive was administered concomitantly with ABT-761 compared with administration of oral contraceptive alone. The mean elimination rate constant of ethinyl estradiol increased by 30% (a mean decrease of 3.8 hours in half-life), and the mean apparent volume of distribution during the terminal phase (Vd(beta)/F) of ethinyl estradiol increased by 73% in the presence of ABT-761. Mean Cmax and AUC values for norgestrel decreased by 12% and 10%, respectively, when administered with ABT-761. Mean values for time to Cmax (tmax), terminal rate constant (beta), half-life (t1/2), and Vd(beta)/F of norgestrel were similar when oral contraceptive was administered alone or concomitantly with ABT-761. The mechanism responsible for the effect of ABT-761 on the clearance of ethinyl estradiol remains undefined. Because results of previous multiple-dose studies of ABT-761 do not provide any evidence of autoinduction, the effects of ABT-761 on the pharmacokinetics of ethinyl estradiol are more likely related to absorption of ethinyl estradiol.
Abbott Laboratories, Abbott Park, Illinois 60064-3500, USA.
S L
SL
Wong
R F
RF
O'Dea
L M
LM
Dube
W M
WM
Awni
D000328:Adult; D003271:Contraceptive Agents, Female / Q000493:pharmacokinetics*; D003276:Contraceptives, Oral / Q000493:pharmacokinetics; D004347:Drug Interactions; D045166:Estradiol Congeners / Q000493:pharmacokinetics*; D004997:Ethinyl Estradiol / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D006918:Hydroxyurea / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D016912:Levonorgestrel / Q000493:pharmacokinetics*; D016859:Lipoxygenase Inhibitors / Q000009:adverse effects / Q000494:pharmacology*
D003271:Contraceptive Agents, Female; D003276:Contraceptives, Oral; D045166:Estradiol Congeners; D016859:Lipoxygenase Inhibitors; D004997:Ethinyl Estradiol; D016912:Levonorgestrel; C096921:atreleuton; D006918:Hydroxyurea