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 de velopment for the treatment of asthma. The effects of ABT-761 on the p harmacokinetics of an oral contraceptive were assessed in 21 female ad ult volunteers in a phase I, multiple-dose, open-label study. Subjects received a single dose of oral contraceptive (30 mu g ethinyl estradi ol 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 max imum 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 o f oral contraceptive alone. The mean elimination rate constant of ethi nyl estradiol increased by 30% (a mean decrease of 3.8 hours in half-l ife), and the mean apparent volume of distribution during the terminal phase (Vd(beta)/F) of ethinyl estradiol increased by 73% in the prese nce 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 (beta), half-life (t(1/2)), and Vd(beta)/F of norgestrel were similar when oral contrace ptive was administered alone or concomitantly with ABT-761. The mechan ism 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 mo re likely related to absorption of ethinyl estradiol. Journal of Clini cal Pharmacology, 1998;38:642-648 (C)1998 The American College of Clin ical Pharmacology.