Ex vivo inhibition of β-thromboglobulin release following administration to man of ABT-299, a novel prodrug of a potent platelet activating factor antagonist

. Objective and Design: ABT-299 is a prodrug that is converted by serum esterase to a potent platelet activating factor (PAF) antagonist (A-85783). In order to evaluate the pharmacological activity of this antagonist in man the effect of ABT-299 given to healthy volunteers on ex vivo PAF-induced β-thromboglobulin (β-TG) release in blood was assessed.¶ Subjects : 37 healthy male volunteers, age 18 to 40 (mean age of 23.6 years) and free of medication, participated in the study.¶ Treatment : Subjects were administered intravenously 0.8 mg, 2 mg, or 70 mg doses of ABT-299 (6–7 subjects per group) or placebo (9 subjects, pooled).¶ Methods : Peripheral blood taken over 12 h after dosing was used for ex vivo β-TG release and, in the case of the 70 mg dose, measurement of plasma drug concentration. Data were compared by Student's t -test.¶ Results : All three doses produced highly significant inhibition (p <0.005 compared to predose values) of PAF-induced β-TG release (units/ml plasma±SEM) 12 h after drug administration (54±14 vs. 405±51, n=8; 79±23 vs. 480±127, n=7; 21±10 vs. 327±72, n=6, respectively) whereas there was no significant difference in β-TG release in the placebo group (449±90 vs. 307±49, n=9). Inhibition was associated with the rapid appearance in plasma of A-85783 and the pyridine N -oxide metabolite of A-85783. Within 2 h, the plasma concentration of the metabolite exceeded that of the parent drug. Both the parent drug and the metabolite exhibited potent in vitro inhibition of PAF-induced β-TG release (A 2 values of 4 and 1 nM respectively).¶ Conclusions : These studies are the first to illustrate the utility of the β-TG release assay for assessing ex vivo activity of PAF antagonists. These studies also demonstrate that the administration of ABT-299 to man results in potent, long lasting inhibition of PAF-mediated platelet activation, due in part to the pyridine- N -oxide metabolite, and support the potential therapeutic utility of this prodrug in treating PAF-mediated diseases.