In vitro comparison of platelet aggregation between zalunfiban and selatogrel in healthy donors
Authors: Rikken A O F , Van 'T Hof A W J , Gibson C M , Granger C B , Montalescot G , Curry B J , Jennings L K , Ten Berg J M 
Published: November 2023

Abstract

Background
Two subcutaneously injected antiplatelet drugs, zalunfiban and selatogrel, are under development for prehospital administration for STEMI and (N)STEMI, respectively. Zalunfiban is a glycoprotein IIb/IIIa inhibitor that produces high-grade inhibition of platelet aggregation induced by ADP or a thrombin receptor activating peptide (TRAP) within 15 minutes. Selatogrel is a P2Y12 inhibitor that produces high-grade inhibition of platelet aggregation initiated by ADP within 15 minutes. We have studied the relative potencies of the drugs at levels achievable in vivo in inhibiting platelet aggregation. Since trisodium citrate (TSC) has been reported to enhance the antiplatelet effect of zalunfiban and inhibit the antiplatelet effect off selatogrel, aggregation studies were performed with both blood anticoagulated with TSC and the non-chelating anticoagulant PPACK. Whereas both ADP and thrombin are present at the site of vascular injury within seconds, we tested the effects of both ADP and TRAP.

Purpose
To compare directly the effects of zalunfiban and selatogrel on ADP- and TRAP-induced platelet aggregation.

Methods
Light transmission platelet aggregometry was performed within 4 hours of blood collection (BioData PAP-8E). Whole blood from healthy donors not taking aspirin (N=10) was anticoagulated with 3.2% TSC and 100 μM PPACK. Platelet-rich plasma (PRP) was prepared and adjusted to a platelet count of 250,000/µl. Three clinically relevant incremental concentrations of zalunfiban and selatogrel were added to PRP and platelet aggregation was initiated with 20 μM ADP or 20 μM TRAP. Tracings were recorded for at least 10 minutes after agonist addition. Platelet aggregation was quantified based on the instrument’s measurement of the primary slope (PrSl) of aggregation, which is a measure of the change in light transmission per unit time sustained over at least a 15 second period.

Results
In TSC-anticoagulated PRP, zalunfiban was more effective in inhibiting the PrSl of both ADP- and TRAP-induced platelet aggregation at all drug concentrations [Figure 1, panel A and B]. In PPACK-anticoagulated PRP, selatogrel showed greater inhibition of ADP-induced platelet aggregation at the lowest concentration tested, similar inhibition at the intermediate concentration, and slightly less inhibition at the highest doses. In sharp contrast, with TRAP-induced aggregation, zalunfiban demonstrated dose-related inhibition, reaching greater than 80% inhibition at the highest dose, whereas selatogrel produced less than 20% inhibition at all three doses.

Conclusion
Selatogrel is a potent inhibitor of ADP-induced platelet aggregation, but has low impact on TRAP-induced platelet aggregation, whereas zalunfiban is a potent inhibitor of both ADP and TRAP-induced platelet aggregation. The difference between the drugs needs to be considered in light of the known generation of thrombin at the site of vascular injury within seconds.Comparison of Platelet Inhibition