Abstract 19606: PZ-128: First in Human Pepducin Inhibitor of PAR-1 Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability
Background: PZ-128 is a first-in-class cell penetrating lipopeptide pepducin that inhibits PAR-1-G protein signaling by forming a structure highly similar to the corresponding off-state juxtamembrane region of the GPCR. PZ-128 inhibited PAR-1 and thrombosis in non-human primates. Its effects in humans are unknown.
Methods and Results: PZ-128 was administered by continuous intravenous infusion (0.01 mg/kg to 2 mg/kg) to patients with multiple cardiovascular risk factors (n=31). Safety, tolerability, and pharmacokinetic (PK) effects were assessed. Platelet receptor function was assessed by conventional aggregation at baseline and 0.5, 1, 2, 6, 24 h and 8-11 d post-dosing. There were no effects on ECG, hematologic or clinical chemistry parameters. At 0.5 mg/kg given over 2 h there was 40 % and 50 % inhibition (8 μM SFLLRN) at 0.5 and 2 h, respectively. At 1-2 mg/kg, there was 25% and 75% inhibition at 0.5 h and 95-100% inhibition at 1-2 h (p<0.05 for 1 mg dose). Maximal platelet aggregation (8 μM SFLLRN) was 66-100% recovered by 24 h at 0.5-2 mg/kg. There was no significant inhibition of PAR-4, ADP, or collagen receptors at any time point. PZ-128 plasma levels were linear with dose (R=0.99) and reached Cmax levels of 2 μM, 2.5 μM, 5 μM, and 12 μM at 0.3, 0.5, 1 and 2 mg/kg doses, respectively. The terminal elimination plasma half-life was 49 ± 6 min.
Conclusion: PZ-128 is a promising parenteral antiplatelet agent that provided rapid, specific, dose-dependent, and reversible inhibition of platelet PAR-1 through a novel mechanism.
Author Disclosures: P.A. Gurbel: Research Grant; Significant; New Haven Pharmaceuticals, Bayer, Daiichi Sankyo, AstraZeneca, Haemonetics, DCRI, HCRI, NIH, Coramed. Other Research Support; Modest; Sinnowa. Speakers Bureau; Modest; ASTRAZENECA, DAIICHI SANKYO, MERCK. Honoraria; Modest; ASTRAZENECA, DAIICHI SANKYO, MERCK, Jensen. Consultant/Advisory Board; Modest; ASTRAZENECA, DAIICHI SANKYO, MERCK, Jensen. K.P. Bliden: None. U.S. Tantry: None. S.E. Turner: Employment; Significant; Tufts Medical Center. M. Gesheff: None. L. Covic: Employment; Significant; Tufts Medical Center. A. Kuliopulos: Employment; Significant; Tufts Medical Center.
- © 2015 by American Heart Association, Inc.