Evaluation of ticagrelor pharmacodynamic interactions with reversibly binding or non-reversibly binding P2Y12 antagonists in an ex-vivo canine model

IntroductionAs 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.MethodsSix male dogs all received 7 different dosing regimens separated by 1–5 week washout periods: cangrelor (1 μg/kg/min, intravenous infusion); ticagrelor (0.8 mg/kg, oral); clopidogrel (3 mg/kg, intravenous injection); cangrelor together with ticagrelor initiated 10 minutes after cangrelor infusion start or clopidogrel given 30 minutes after cangrelor infusion start; ticagrelor followed by clopidogrel given 3 or 7 hours after ticagrelor dosing. ADP-induced whole blood platelet aggregation was measured by impedance aggregometry.ResultsMean maximum inhibition of platelet aggregation (IPA) was 81–87% at 6 minutes (cangrelor), 3 hours (ticagrelor) and 4 hours (clopidogrel) postdosing and platelet function recovered after 1.5 hours, 12 hours, and 9 days, respectively. IPA at 2 hours post clopidogrel was reduced to 39% when clopidogrel was given during cangrelor infusion versus 69% for clopidogrel alone. With clopidogrel dosed 3 hours after ticagrelor, IPA was reduced after washout of ticagrelor to 38% at 24 hrs vs. 68% for clopidogrel alone, but an interaction was not seen when clopidogrel was dosed 7 hours after ticagrelor. No pharmacodynamic interaction occurred between ticagrelor and cangrelor.ConclusionsThe 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.