Evaluation of ticagrelor pharmacodynamic interactions with reversibly binding or non-reversibly binding P2Y(12) antagonists in an ex-vivo canine model.
BACKGROUND
As ticagrelor, clopidogrel and cangrelor therapies may be used in the same clinical setting, their potential pharmacodynamic interactions are of interest. Hence, we investigated possible interactions between these agents in dogs using a variety of switching protocols.


METHODS
Six male dogs all received 7 different dosing regimens separated by 1-5week washout periods: cangrelor (1μg/kg/min, intravenous infusion); ticagrelor (0.8mg/kg, oral); clopidogrel (3mg/kg, intravenous injection); cangrelor together with ticagrelor initiated 10minutes after cangrelor infusion start or clopidogrel given 30minutes after cangrelor infusion start; ticagrelor followed by clopidogrel given 3 or 7hours after ticagrelor dosing. ADP-induced whole blood platelet aggregation was measured by impedance aggregometry.


RESULTS
Mean maximum inhibition of platelet aggregation (IPA) was 81-87% at 6minutes (cangrelor), 3hours (ticagrelor) and 4hours (clopidogrel) postdosing and platelet function recovered after 1.5hours, 12hours, and 9days, respectively. IPA at 2hours post clopidogrel was reduced to 39% when clopidogrel was given during cangrelor infusion versus 69% for clopidogrel alone. With clopidogrel dosed 3hours after ticagrelor, IPA was reduced after washout of ticagrelor to 38% at 24hrs vs. 68% for clopidogrel alone, but an interaction was not seen when clopidogrel was dosed 7hours after ticagrelor. No pharmacodynamic interaction occurred between ticagrelor and cangrelor.


CONCLUSIONS
The extent of the pharmacodynamic drug-drug interactions observed between clopidogrel and cangrelor or ticagrelor apparently depends on the level of receptor occupancy when clopidogrel is administered. Importantly, no significant pharmacodynamic interaction occurred between ticagrelor/clopidogrel when clopidogrel was given at clinical trough IPA levels with ticagrelor. No significant pharmacodynamic interaction occurred with cangrelor and ticagrelor.
Department of Bioscience, AstraZeneca R&D Mölndal, Sweden. Anna.Ravnefjord@astrazeneca.com
Anna
A
Ravnefjord
Jessika
J
Weilitz
Britt-Marie
BM
Emanuelsson
J J J
JJ
van Giezen
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000249:Adenosine Monophosphate / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects; D000077144:Clopidogrel; D004285:Dogs; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D058925:Receptors, Purinergic P2Y12 / Q000378:metabolism*; D000077486:Ticagrelor; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D000249:Adenosine Monophosphate; C117446:cangrelor; D000077144:Clopidogrel; D000077486:Ticagrelor; D000241:Adenosine; D013988:Ticlopidine