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 μg 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 (C max ) 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 β /F) of ethinyl estradiol increased by 73% in the presence of ABT‐761. Mean C max and AUC values for norgestrel decreased by 12% and 10%, respectively, when administered with ABT‐761. Mean values for time to C max (t max ), terminal rate constant (β), half‐life (t 1/2 ), and Vd β /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.