PHARMACOKINETIC PROFILES AND PHARMACOKINETIC AND PHARMACODYNAMIC RELATIONSHIP OF A VWF INHIBITORY APTAMER IN THE CYNOMOLGUS MONKEY
Abstract number: P-T-209
Hutabarat1 R.M., McCauley1 T., Makim1 A., Lewis1 S., Merlino1 P., Gilbert1 M., Bouchard1 P.
1Research and Development, Archemix Corp, Cambridge, United States
How-to-cite Hutabarat RM, McCauley T, Makim A, Lewis S, Merlino P, Gilbert M, Bouchard P. PHARMACOKINETIC PROFILES AND PHARMACOKINETIC AND PHARMACODYNAMIC RELATIONSHIP OF A VWF INHIBITORY APTAMER IN THE CYNOMOLGUS MONKEY. J Thromb Haemost 2007; 5 Supplement 2: P-T-209
Introduction: We have developed a 5'-20KDa-PEGylated aptamer(ARC1779)directed against the A1 domain of human von Willebrand Factor(vWF). ARC1779 is being evaluated as a novel anti-platelet agent for inhibition of vWF-mediated thrombus formation. The objective of this study was to determine the pharmacokinetic(PK) profiles and the pharmacokinetic and pharmacodynamic(PK/PD) relationship of ARC1779 in cynomolgus monkeys.
Methods: Monkeys(3M/3F)were assigned to 3 groups and received a 5, 10, or 20 mg/kg IV doses, followed by a 2-week washout, then an IV bolus + 4-hr infusion for a total dose of 0.6, 1.2 and 2.4 mg/kg. ARC1779 and vWF plasma levels were determined by HPLC and IMUBIND® vWF ELISA, respectively. Inhibition of vWF activity was measured by PFA-100® and READDS® vWF activity ELISA. Noncompartmental PK parameters were determined using WinNonlin.
Results: ARC1779 Cmax, and AUC0-last values increased linearly and proportionally with dose. Following a bolus dose at 5, 10, and 20 mg/kg, the mean Cmax values were 118, 282 and 495 ug/mL, the mean AUC0-last values were 375, 1084 and 2487 ugxhr/mL, with mean elimination t1/2 values of 4.33, 5.58, and 4.35 hrs, respectively. Following IV bolus + 4-hr infusion, the mean plasma levels during infusion were 4.54, 9.35 and 17.39 ug/mL with mean AUC0-last values of 23, 50 and 90 ugxhr/mL for the total dose of 0.6, 1.2 ad 2.4 mg/kg, respectively. Following a single IV bolus or a single IV bolus + 4-hr infusion, the PK/PD relationship of ARC1779 plasma concentrations to inhibit platelet function were an EC90 of 5.81 and 3.28 ug/mL, and to inhibit vWF activity were an EC90 5.95 and 4.25 ug/mL, respectively. VWF plasma concentration was not effected by ARC1779.
Conclusions: The study showed ARC1779 PK profiles were linear and proportional with increase in dose following a single IV bolus or IV bolus + 4 hrs infusion, and ARC1779 blocked vWF dependent platelet function in predictable concentration dependent manner characterized by Emax model.