Impact of ticagrelor administration strategy on its pharmacokinetics and pharmacodynamics in patients with unstable angina pectoris: a protocol of a randomized study

Abstract

Introduction. Dual antiplatelet therapy with aspirin and a P2Y12 receptor inhibitor constitutes an essential part of the management of patients with acute coronary syndromes (ACS). Based on the favorable results of the PLATO trial, ticagrelor is currently recommended as the first line P2Y12 receptor inhibitor in a broad spectrum of ACS patients. According to the recently published data, several conditions, including concurrent analgesia with morphine and clinical presentation as an ACS, may alter ticagrelor absorption and its antiplatelet effect. Therefore, the goal of the present study was to investigate pharmacokinetics and pharmacodynamics of new ticagrelor administration strategies aimed to overcome limitations of the standard ticagrelor loading regimen. Methods/design. The study is designed as a phase IV, single center, randomized, investigator-initiated, parallel-group, open-label, interventional study comparing the influence of various ticagrelor administration strategies on its pharmacokinetics and pharmacodynamics. Patients with unstable angina pectoris will be randomized in a 1:1:1 ratio into one of three arms, each receiving a 180 mg ticagrelor loading dose (LD). Ticagrelor administration strategies comprise: 1) pulverized ticagrelor administered sublingually, 2) pulverized ticagrelor in 10 mL suspension in tap water administered orally and 3) integral ticagrelor tablets administered orally. An internal pilot study including 30 (10 in each of the arms) is planned in order to determine the final sample size. The primary endpoint of the trial is time (tmax) required for ticagrelor and its active metabolite AR-C124900XX to reach maximum plasma concentration within time frame of six hours after administration of ticagrelor LD. The secondary endpoints include ticagrelor and AR-C124900XX maximum plasma concentration, area under the plasma concentration-time curve for ticagrelor and AR-C124900XX (AUC 0–6h) and platelet reactivity assessed with Multiple Electrode Aggregometry using the Multiplate™ Analyzer prior to and within time frame of six hours following ticagrelor LD. Discussion. This study is expected to provide essential evidence-based data on the impact of ticagrelor administration strategy on its pharmacokinetics and pharmacodynamics in patients with unstable angina pectoris. Hopefully, based on its results, further clinical outcome-powered trials on new ticagrelor administration strategies will be designed and conducted.