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Novel antiplatelet agent shows promise in first-in-human study
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Use of PZ-128, a cell-penetrating pepducin therapy, successfully demonstrated inhibition of platelet aggregation in a first-in-human study.
According to the study background, PZ-128 targets protease-activated receptor-1 (PAR1), a platelet-activating receptor, similar to the mechanism of action of vorapaxar (Zontivity, Merck). However, vorapaxar is a slow-acting agent and is not approved for use in cardiac procedures, while PZ-128 is fast-acting and could potentially be used to prevent ischemic complications in patients undergoing PCI.
For the NHLBI-funded study, researchers administered PZ-128 to 32 patients with CAD or multiple risk factors for CAD (mean age, 57 years; 59% men; 50% white); one patient was not dosed because of an adverse event. Safety, antiplatelet efficacy and pharmacokinetics were assessed at baseline, 30 minutes, 1 hour, 2 hours, 6 hours, 24 hours, 7 days and 10 days.
Paul A. Gurbel, MD, from Inova Center for Thrombosis Research and Drug Development, Inova Heart and Vascular Institute, Falls Church, Virginia, and colleagues found that higher the dose of PZ-128 administered, the better PZ-128 blocked platelet aggregation. At 30 minutes to 6 hours, the researchers observed 20% to 40% platelet inhibition with a dose of 0.3 mg/kg, 40% to 60% platelet inhibition with a dose of 0.5 mg/kg and more than 80% to 100% platelet inhibition with a dose of 1 to 2 mg/kg.
Patients who received aspirin in addition to a 0.5-mg/kg or 1-mg/kg dose of PZ-128 had 65% to 100% platelet inhibition at 30 minutes to 2 hours and 95% to 100% platelet inhibition by 6 hours, Gurbel, a member of the Cardiology Today’s Intervention Editorial Board, and colleagues wrote.
In addition, the effects of platelet inhibition with a PZ-128 dose of 0.5 mg/kg were reversible, with 50% recovery at 24 hours, and the drug was not detectable in urine.
The researchers found that the effects were due to impact of PZ-128 on PAR1, as there were no significant effects on platelet aggregation induced by AYPGKF, ADP or collagen.
Gurbel and colleagues reported that the drug had no effects on bleeding, coagulation, clinical chemistry or ECG parameters. – by Erik Swain
Disclosure: The study was funded by the NHLBI. Gurbel reports financial ties with Accumetrics, AstraZeneca, Bayer, Boehringer Ingelheim, Coramed, CSL Behring, Daiichi Sankyo, Eli Lilly, Haemonetics, Janssen Pharmaceuticals, Merck and Sinnowa. Three other researchers report financial ties with Eli Lilly, Oasis Pharmaceuticals and Procter and Gamble.
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