Pharmacokinetics, pharmacodynamics, and safety of a platelet GPIIb/IIIa antagonist, RGD891, following intravenous administration in healthy male volunteers

The pharmacokinetics (PK), pharmacodynamics (PD), and safety of a platelet GPIIb/IIIa receptor antagonist, RGD891, and ifs active metabolite, RGD039, were evaluated after administration of various intravenous regimens of RGD8 91 to healthy male volunteers in two Phase I studies. Plasma and urine conc entrations of RGD891 and RGD039 were measured by validated LC/MS/MS methods with minimum quantifiable limit (MQL) of 1 ng/mL and 10 ng/mL, respectivel y. PD activity was assessed by percent inhibition of ADP (20 mu M)-induced platelet aggregation. Following intravenous dosing, the RGD891 was the pred ominant compound in plasma. The PK of RGD891 was dose independent associate d with modest between-subject variability. RGD891 was rapidly cleared (Cl, 11.2-15.5 L/h), exhibited a restricted distribution (V-ss, 23.0-25.9 L) and a short terminal t(1/2 lambda z) (1.2-2.1 h). Plasma concentrations of the metabolite (RGD039) increased with dose but were variable. RGD039 had long er t(1/2 lambda z) of 4.5 to 6.6 hours. Renal excretion of unchanged drug p layed an important role in the elimination of the parent compound. Both RGD 891 and RGD039 exhibited renal clearance values that were comparable to the glomerular filtration rate. Intravenous administration of RGD891 effective ly inhibited platelet aggregation in a dose-dependent and reversible manner . At the highest dose (60 mu g/kg bolus dose + 336 mu g/kg 8-h infusion) > 90% inhibition of platelet aggregation was achieved. PD activity was primar ily attributed to the parent compound. Inhibition of platelet aggregation w as dependent on the anticoagulant present, with samples containing PPACK sh owing 20% to 30% lower activity as compared to citrate. RGD891 was safe and well tolerated across the various regimens studied. (C)2000 the American C ollege of Clinical Pharmacology.