Hemostatic effects of the ticagrelor antidote MEDI2452 in pigs treated with ticagrelor on a background of aspirin.
Essentials MEDI2452 is a specific antidote of the platelet P2Y12receptor antagonist ticagrelor. Hemostatic effects of MEDI2452 were evaluated in pigs treated with ticagrelor and aspirin. MEDI2452 eliminated free ticagrelor within 5 min and gradually normalized platelet aggregation. Improvements in blood pressure (significant) and in blood-loss and survival (non-significant) were observed.



Background Ticagrelor, a P2Y12antagonist, is approved for the prevention of thromboembolic events. However, antiplatelet therapies carry a risk of bleeding. Objective To explore the hemostatic effects of MEDI2452, an antidote for ticagrelor. Methods Pigs, pre-treated with aspirin, were given an intravenous infusion of ticagrelor or vehicle. At the end of the infusion, a piece of a liver lobe was cut off and a bolus of MEDI2452 or vehicle was administered intravenously. Blood was collected to monitor blood loss, mean arterial blood pressure (MAP) was recorded and survival time was observed over 4 h. Blood samples for drug plasma exposures and platelet aggregation were collected. Results MEDI2452 eliminated the free concentrations of ticagrelor and its active metabolite AR-C124910XX within 5 min. ADP-induced platelet aggregation was close to normal at 60 min, which was not significantly different from aspirin alone. MEDI2452 numerically reduced ticagrelor-mediated effects: body-weight-adjusted blood loss in the 15- to 90-min interval, 12 (confidence interval [CI] 95% 7-28] vs. 17 (CI 95% 5-31) (ticagrelor and aspirin) vs. 5 (CI 95% 3-9) mL kg-1(aspirin alone), survival 70% (CI 95% 47-100) vs. 45% (CI 95% 21-92) (ticagrelor and aspirin) vs. 100% (CI 95% 100-100) (aspirin alone), and median survival time, 240 (CI 95% 180-240) vs. 169 (CI 95% 64-240) (ticagrelor and aspirin) vs. 240 (CI 95% 240-240) min (aspirin alone). Finally, MEDI2452 significantly attenuated the decline in MAP, 0.08 (CI 95% 0.07-0.09) vs. 0.141 (CI 95% 0.135-0.148) (ticagrelor and aspirin) vs. 0.04 (CI 95% 0.03-0.05) mmHg per min (aspirin alone) and maintained MAP at a significantly higher level, 73 (CI 95% 51-95) vs. 48 (CI 95% 25-70) (ticagrelor and aspirin) vs. 115 (CI 95% 94-136) mmHg (aspirin alone). Conclusion MEDI2452 eliminated free ticagrelor and AR-C124910XX within 5 min. This translated into a gradual normalization of ADP-induced platelet aggregation and significant improvement in blood pressure and numerical but non-significant improvements in blood-loss and survival.
Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development, AstraZeneca, Mölndal, Sweden.
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Pehrsson
Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development, AstraZeneca, Mölndal, Sweden.
K J
KJ
Johansson
Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development, AstraZeneca, Mölndal, Sweden.
A
A
Janefeldt
Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development, AstraZeneca, Mölndal, Sweden.
A-S
AS
Sandinge
Clinical Pharmacology and DMPK, MedImmune, Cambridge, UK.
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S
Maqbool
Clinical Pharmacology and DMPK, MedImmune, Cambridge, UK.
J
J
Goodman
Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development, AstraZeneca, Mölndal, Sweden.
J
J
Sanchez
Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development, AstraZeneca, Mölndal, Sweden.|Fraunhofer-Chalmers Center, Chalmers Science Park, Gothenburg, Sweden.|Systems and Synthetic Biology, Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.
J
J
Almquist
Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development, AstraZeneca, Mölndal, Sweden.
P
P
Gennemark
Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development, AstraZeneca, Mölndal, Sweden.
S
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Nylander
D000241:Adenosine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000737:chemistry; D000244:Adenosine Diphosphate / Q000737:chemistry; D000818:Animals; D057134:Antibodies, Neutralizing / Q000008:administration & dosage*; D000931:Antidotes / Q000008:administration & dosage*; D001241:Aspirin / Q000008:administration & dosage*; D019921:Biotinylation; D001794:Blood Pressure / Q000187:drug effects; D000080908:Broadly Neutralizing Antibodies; D006470:Hemorrhage / Q000139:chemically induced; D006487:Hemostasis; D006801:Humans; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use; D010979:Platelet Function Tests; D013552:Swine; D000077486:Ticagrelor / Q000037:antagonists & inhibitors; D013997:Time Factors
C561701:AR C124910XX; D057134:Antibodies, Neutralizing; D000931:Antidotes; D000080908:Broadly Neutralizing Antibodies; D010975:Platelet Aggregation Inhibitors; C000622443:PB-2452; D000244:Adenosine Diphosphate; D000077486:Ticagrelor; D000241:Adenosine; D001241:Aspirin
antidote; blood platelets; hemorrhage; swine; ticagrelor