Pharmacokinetics and pharmacodynamics of single and multiple oral doses of a novel 5-lipoxygenase inhibitor (ABT-761) in healthy volunteers

• Published in: Clinical pharmacology and therapeutics 1998-03, Vol.63 (3), p.324-331
• Main Authors: Wong, Shekman L., Drajesk, Jeffrey, Chang, Min, Lanni, Carmine, Witt, Galen, Hansen, Robert, Awni, Walid M.
• Format: Article
• Language: English
• Subjects: Administration, Oral; Adult; Biological and medical sciences; Double-Blind Method; Drug Administration Schedule; Female; Humans; Hydroxyurea - administration & dosage; Hydroxyurea - adverse effects; Hydroxyurea - analogs & derivatives; Hydroxyurea - pharmacokinetics; Hydroxyurea - pharmacology; Lipoxygenase Inhibitors; Male; Medical sciences; Pharmacology. Drug treatments; Reference Values; Respiratory system
• ISSN: 0009-9236; 1532-6535
• DOI: 10.1016/S0009-9236(98)90164-3

Objectives This study evaluated the safety, pharmacokinetics and pharmacodynamics of ABT‐761 [R(+)‐N‐[3‐[5‐(4‐fluorophenylmethyl)‐2‐thienyl]‐1‐methyl‐2‐propynyl]‐N‐hydroxyurea], a new N‐hydroxyurea analog. Methods This was a randomized, double‐blind, placebo‐controlled, single‐ and multiple‐dose (15‐day) study of ABT‐761 (50 to 200 mg/day) in healthy, nonsmoking adult male volunteers. The pharmacokinetics were evaluated by investigation of the time‐ and dose‐dependent effects of ABT‐761, and the pharmacologic selectivity of ABT‐761 was evaluated based on calcium ionophore‐stimulated leukotriene B4 (LTB4) and thromboxane B2 (TXB2) biosynthesis ex vivo in whole blood. Results After single and multiple doses, mean observed time to reach maximum concentration values of ABT‐761 ranged from 4.0 to 7.5 hours. Mean values for maximum concentration 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 elimination 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 day 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. Population ABT‐761 plasma concentration at which 50% of the maximum possible inhibition was observed for LTB4 inhibition was 0.24 μg/ml. No differences in mean TXB2 inhibition were observed between the subjects receiving 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. Clinical Pharmacology & Therapeutics (1998) 63, 324–331; doi: