Metabolism of ticagrelor in patients with acute coronary syndromes

Abstract

Ticagrelor is a state-of-the-art antiplatelet agent used for the treatment of patients with acute coronary syndromes (ACS). Unlike remaining oral P2Y12 receptor inhibitors ticagrelor does not require metabolic activation to exert its antiplatelet action. Still, ticagrelor is extensively metabolized by hepatic CYP3A enzymes, and AR-C124910XX is its only active metabolite. A post hoc analysis of patient-level (n = 117) pharmacokinetic data pooled from two prospective studies was performed to identify clinical characteristics affecting the degree of AR-C124910XX formation during the first six hours after 180 mg ticagrelor loading dose in the setting of ACS. Both linear and multiple regression analyses indicated that ACS patients presenting with ST-elevation myocardial infarction or suffering from diabetes mellitus are more likely to have decreased rate of ticagrelor metabolism during the acute phase of ACS. Administration of morphine during ACS was found to negatively influence transformation of ticagrelor into AR-C124910XX when assessed with linear regression analysis, but not with multiple regression analysis. On the other hand, smoking appears to increase the degree of ticagrelor transformation in ACS patients. Mechanisms underlying our findings and their clinical significance warrant further research.

Ticagrelor Pharmacokinetics and Pharmacodynamics in Chinese Patients with STEMI and NSTEMI Without Opioid Administration

“…As compared with swallowing ticagrelor, crushed ticagrelor tablets in the semi-upright sitting position [16,17] or [18,19] also accelerate platelet inhibition. Except for drug interactions, a previous study revealed that smoking appears to increase the degree of ticagrelor transformation in patients with ACS [20]. On the contrary, our results pointed out no differences in AUC 0-12 ratio between AR-C124910XX and ticagrelor for smokers and non-smokers.…”

Impact of mild therapeutic hypothermia on bioavailability of ticagrelor in patients with acute myocardial infarction after out-of-hospital cardiac arrest

“…Moreover, presence of different AR-C124910XX formation rates between compared groups suggests potential diversity in drug metabolism and/or elimination. Recently, it has been reported that the presence of STEMI and diabetes are connected with impaired metabolism of ticagrelor during the first 6 h after ticagrelor LD for acute coronary syndrome [26]. In the current trial clear differences were observed in ticagrelor's active metabolite formation between patients with and without OHCA treated with MTH, however small the size of cardiac arrest, the survivor group did not allow formal conclusions to be drawn.…”

Stratified Approaches to Antiplatelet Therapies Based on Platelet Reactivity Testing

“…In a subsequent analysis, it has been reported that the main determinants of HTPR at 1 and 2 h after ticagrelor loading dose are presence of STEMI and morphine co-administration (66). Furthermore, the presence of STEMI and diabetes mellitus were found to be associated with impaired metabolism of ticagrelor within first 6 h post ticagrelor loading dose in ACS patients (67). It has been recently published, that bioavailability of ticagrelor in MI patients managed with mild therapeutic hypothermia after out-of-hospital cardiac arrest is significantly decreased, thus increasing the risk of stent thrombosis, a possibly lethal complication, which is not uncommon in this specific subset of patients (68, 69).…”