Pharmacokinetic (PK) and Pharmacodynamic (PD) Studies of RUC-4 Succinate, a Novel {alpha}IIb{beta}3 Pure Antagonist for First Point of Contact Treatment of ST Segment Elevated Myocardial Infarction (STEMI)

We are developing the novel αIIbβ3 pure antagonist, RUC-4, for first point of contact treatment of ST Segment Elevated Myocardial Infarction (STEMI) in combination with aspirin. We have chosen the subcutaneous (SC) route to facilitate its delivery by ambulance and emergency room personnel, and potentially by self-administration. In preparation for initiating human studies, we have conducted preclinical studies of: 1. the pharmacokinetics (PK) and pharmacodynamics (PD) of RUC-4 succinate administered IV, IM, and SC to non-human primates (NHP); 2. the impact of in vitro aspirin on the RUC-4 IC50 in human platelet-rich plasma (PRP); and 3. the effect of different anticoagulants on the IC50 of RUC-4 in human PRP.Non-human primates (Macaca fascicularis; NHPs) received RUC-4 at 1.0, 1.96, and 3.86 mg/kg IV, IM, and SC. Blood samples for IV PK studies were collected at 0, 1, 5, 15, 30, 120, and 270 min; samples for IM and SC PK studies were collected at 0, 5, 15, 30, 45, 120, and 270 min and ~27 hrs, the latter only for animals that received 3.86 mg/kg IM. There were 2 animals per group and 2 groups per dose, so no more than 4-5 samples were collected from a single animal. Platelet aggregation was performed with 5 µM ADP on citrated PRP from the NHPs that received RUC-4 IM. All doses of RUC-4 administered IM and SC were well tolerated, but animals demonstrated variable temporary bruising. None of the animals developed thrombocytopenia despite receiving up to 4 doses...
Source: Blood - Category: Hematology Authors: Tags: 332. Antithrombotic Therapy: Poster I Source Type: research