PHARMACOKINETICS AND PHARMACODYNAMICS OF SINGLE AND MULTIPLE ORAL DOSES OF A NOVEL 5-LIPOXYGENASE INHIBITOR (ABT-761) IN HEALTHY-VOLUNTEERS

Objectives: This study evaluated the safety, pharmacokinetics and phar macodynamics of ABT-761 [R(+)-N-[3- rophenylmethyl)-2-thienyl]-1-methy l-2-propynyl]-N- hydroxyurea], a new N-hydroxyurea analog. Methods: Th is was a randomized, double-blind, placebo-controlled, single-and mult iple-dose (Ig-day) study of ABT-761 (50 to 200 mg/day) in healthy, non smoking adult male volunteers. The pharmacokinetics were evaluated by investigation of the time-and dose-dependent effects of ABT-761, and t he pharmacologic selectivity of ABT-761 was evaluated based on calcium ionophore-stimulated leukotriene B-4 (LTB4) and thromboxane B-2 (TXB2 ) biosynthesis ex vivo in whole blood. Results: After single and multi ple doses, mean observed time to reach maximum concentration values of ABT-761 ranged from 4.0 to 7.5 hours. Mean values for maximum concent ration and area under the plasma concentration-time curve from 0 to 24 hours increased approximately linearly with dose. Mean terminal half- life and apparent volume of distribution during the terminal eliminati on phase of ABT-761 ranged from 15.4 to 17.8 hours and 69.5 to 78.9 L, respectively, and was dose independent. Steady state was reached on d ay 11 after multiple dosing. Less than 0.05% of unchanged ABT-761 was recovered in urine within the 24-hour period after day 15 dosing. Popu lation ABT-761 plasma concentration at which 50% of the maximum possib le inhibition was observed for LTB4 inhibition was 0.24 mu g/ml. No di fferences in mean TXB4 inhibition were observed between the subjects r eceiving ABT-761 and placebo. Conclusions: These results indicate that ABT-761 is a potent and selective inhibitor of 5-lipoxygenase and the pharmacokinetics of ABT-761 are time and dose independent between 50 and 200 mg/day after single and multiple dosing.