Introduction
PM102 is a novel synthetic peptide that effectively reverses the anticoagulant effect of heparin. It can be used as a bolus and infusion, and its rapid efficacy and rapid clearance make it an ideal candidate for clinical development.
Pharmacologic action
PM102, administered as an intravenous bolus, produced dose-dependent reversal of heparin-induced anticoagulation. Heparin reversal by PM102 was rapid, complete, and dose-dependent. The rapid, safe, and effective reversal of heparin-induced anticoagulation in the setting of cardiovascular surgery is necessary to avoid excessive bleeding.
Function
Doses of 1 mg/kg, 3 mg/kg and, 30 mg/kg of PM102 produced complete reversal of heparin-induced increases in activated partial thromboplastin time (aPTT). The onset of aPTT reversal was evident at 1 min after dosing and was near maximal between 1 to 5 min after dosing. There was no apparent rebound during the 60 min observation period, even with the highest dose used. The dose of PM102 that produced complete reversal in the rat was less than that previously reported for the guinea pig (7.5 mg/kg) and Yorkshire pig (10 mg/kg). The higher sensitivity of the rat model may be due to differences in heparin dose, differential binding of PM102 to plasma proteins, or differences in hemostasis in the rat. Besides, infusion of PM102 over 10 min reversed heparin anticoagulation with similar potency to that observed for bolus administration. The onset of action was delayed relative to the same total dose given as a bolus; however, the maximum effect was similar.
Pharmacokinetics and metabolism
The appearance of PM102 in plasma was rapid following bolus and infusion dosing with peak appearance within 1 to 3 min after bolus dosing and 11 min after the 10 min infusion dose. Following single 0.1, 0.3, 1, 3, and 30 mg/kg PM102 bolus administration the mean plasma time to maximum concentration
(Tmax) for PM102 was 1 to 2.6 min. Concentrations of PM102 generally declined in a rapid fashion after reaching Tmax with a mean T1/2 of 4.30 to 31.5 min. Mean maximum concentration in plasma
(Cmax) and AUC0−t values for PM102 increased proportionally with the increase in dose for bolus administration from 0.1 to 0.3 mg/kg, but then generally increased in a less than proportional fashion for the higher doses. Increases in AUC above approximately 75 min-μg/ml appeared to align with the inhibition of aPTT, although no specific PK/PD modeling was performed.
References:
1. D. J. Cushing, W. D. Cooper, M. L. Cohen, J. R. McVoy, M. Sobel and R. B. Harris. Reversal of heparin-induced increases in aPTT in the rat by PM102, a novel heparin antagonist. Eur. J. Pharmacol., 2010, 635(1-3), 165-170.
2. S. Shenoy, M. Sobel and R. B. Harris. Development of heparin antagonists with focused biological activity. Curr. Pharm. Design, 1999, 5(12), 965-986.
3. B. P. Schick, D. Maslow, A. Moshinski and J. D. San Antonio. Novel concatameric heparin-binding peptides reverse heparin and low-molecular-weight heparin anticoagulant activities in patient plasma in vitro and in rats in vivo. Blood, 2004, 103(4), 1356-1363.
