Disposition and Metabolism of Ticagrelor, a Novel P2Y₁₂ Receptor Antagonist, in Mice, Rats, and Marmosets

Abstract

ABSTRACT:Ticagrelor is a reversibly binding and selective oral P2Y 12 antagonist, developed for the prevention of atherothrombotic events in patients with acute coronary syndromes. The disposition and metabolism of [ 14 C]ticagrelor was investigated in mice, rats, and marmosets to demonstrate that these preclinical toxicity species showed similar metabolic profiles to human. Incubations with hepatocytes or microsomes from multiple species were also studied to compare with in vivo metabolic profiles. The routes of excretion were similar for both oral and intravenous administration in mice, rats, and marmosets with fecal excretion being the major elimination pathway accounting for 59 to 96% of the total radioactivity administered. Urinary excretion of drug-related material accounted for only 1 to 15% of the total radioactivity administered. Milk samples from lactating rats displayed significantly higher levels of total radioactivity than plasma after oral administration of ticagrelor. This demonstrated that ticagrelor and/or its metabolites were readily transferred into rat milk and that neonatal rats could be exposed to ticagrelor-related compounds via maternal milk. Ticagrelor and active metabolite AR-C124910 (loss of hydroxyethyl side chain) were the major components in plasma from all species studied and similar to human plasma profiles. The primary metabolite of ticagrelor excreted in urine across all species was an inactive metabolite, AR-C133913 (loss of difluorophenylcyclopropyl group). Ticagrelor, AR-C124910, and AR-C133913 were the major components found in feces from the three species examined. Overall, in vivo metabolite profiles were qualitatively similar across all species and consistent with in vitro results.

Signaling via P2Y12 May Be Critical for Early Stabilization of Platelet Aggregates

“…20,26 Plasma levels of both compounds in our model were similar to functionally relevant concentrations achieved in other pharmacodynamic animal studies. We chose intravenous administration of ticagrelor over enteral options to precisely control the timing and concentration of drug exposure to the freshly formed thrombus.…”

Measurement of Platelet Function in an Experimental Stroke Model With Aspirin and Clopidogrel Treatment

“…These treatment effects occurred in a comparable range to previously reported results in humans (28), although relatively high treatment dosages (of 60 mg/kg ASA and 22.5 mg/kg CPG) were used. The faster metabolism of mice and different administration protocols (crushing and diluting tablets which are designed for enteric resorption in humans) may explain these comparable effects in spite of a higher absolute dose (19,22,29,30). Ultimately, while there was some variability in the response, we did not identify any non-responders, and all ASA+CPG mice showed reduced platelet reactivity.…”

Ticagrelor: Pharmacokinetic, Pharmacodynamic and Pharmacogenetic Profile: An Update

“…In vitro studies evaluating the metabolism of ticagrelor have been conducted in hepatocyte and microsomal preparations from several animal species [ 27 ]. Multiple metabolites were identified and the major metabolites across all species were AR-C124910XX and AR-C133913XX.…”

“…The use of ticagrelor is contraindicated in patients with severe hepatic impairment [ 29 ]. As ticagrelor metabolism occurs in the liver [ 27 , 28 ], exposure to the parent drug will probably increase in severe hepatic impairment [ 29 ]. In addition, the bleeding risk is increased in severe hepatic impairment because of reduced synthesis of coagulation proteins [ 29 ].…”