Pharmacokinetics and Pharmacodynamics of Ticagrelor and Prasugrel in Healthy Male Korean Volunteers

• Published in: Clinical therapeutics Vol. 37; no. 3; pp. 563 - 573
• Main Authors: Jeon, Hae-Sun, MD, Kim, Mi-Jo, MD, PhD, Choi, Hee-Youn, MD, Kim, Yo-Han, MD, Kim, Eun-Hwa, BS, Kim, A-Reum, MS, Park, Hyun-Jung, BS, Bae, Kyun-Seop, MD, PhD, Lim, Hyeong-Seok, MD, PhD
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-03-2015; Elsevier Limited
• Subjects: Acute coronary syndromes; Adenosine - administration & dosage; Adenosine - analogs & derivatives; Adenosine - pharmacokinetics; Adenosine - pharmacology; Adult; antiplatelet agents; Asian Continental Ancestry Group; Binding sites; Bioavailability; Blood platelets; Blood Platelets - drug effects; Body mass index; Cardiovascular disease; Coronary vessels; Cross-Over Studies; Drug dosages; Drug therapy; Family medical history; healthy volunteers; Humans; Internal Medicine; Male; Medical Education; Metabolism; Metabolites; Middle Aged; Mortality; pharmacodynamics; pharmacokinetics; Piperazines - pharmacokinetics; Platelet Aggregation - drug effects; Platelet Aggregation Inhibitors - administration & dosage; Platelet Aggregation Inhibitors - pharmacokinetics; Platelet Aggregation Inhibitors - pharmacology; Platelet Function Tests; prasugrel; Prasugrel Hydrochloride - administration & dosage; Prasugrel Hydrochloride - pharmacokinetics; Prasugrel Hydrochloride - pharmacology; Tandem Mass Spectrometry; ticagrelor; Young Adult; United States > US; pharmacokinetics; antiplatelet agents; prasugrel; ticagrelor; pharmacodynamics; healthy volunteers
• ISSN: 0149-2918; 1879-114X
• DOI: 10.1016/j.clinthera.2015.01.010

Abstract Purpose A combination of clopidogrel and aspirin is the standard treatment for patients with acute coronary syndrome and those undergoing percutaneous coronary intervention. Two novel antiplatelet agents, ticagrelor and prasugrel, have been shown to rapidly and more effectively inhibit the P2Y12 receptor compared with clopidogrel. The aim of this study was to evaluate and compare the pharmacokinetics (PK) and pharmacodynamics (PD) of ticagrelor and prasugrel in healthy male Korean volunteers. Methods Two separate studies were conducted. One study was performed by using a single-sequence, open-label, crossover design in 12 volunteers who received a single oral dose of ticagrelor (180 mg) and then a single oral dose of prasugrel (60 mg for 4 volunteers and 30 mg for 8 volunteers) with a 7-day washout period. The other study was a randomized, open-label, parallel-group investigation in which 8 volunteers received a single oral dose of prasugrel (10 mg for 4 volunteers and 30 mg for 4 volunteers). In each study, blood samples for PK and platelet aggregation inhibition analysis were serially collected after the administration of each dose. Plasma concentrations of ticagrelor, AR-C124910XX (the active metabolite of ticagrelor), R-95913 (the inactive metabolite of prasugrel), and R-138727 (the active metabolite of prasugrel) were measured by using a validated LC-MS/MS method. PK was analyzed by using a noncompartmental method. Maximal platelet aggregations were assessed with light transmission aggregometry after induction with 20 μmol/L of adenosine diphosphate. Findings Twenty healthy male Korean volunteers participated in the 2 studies. Plasma concentrations of ticagrelor and AR-C124910XX were obtained from 12 subjects, R-95913 from 20 subjects, and R-138727 from 8 subjects. Both ticagrelor and prasugrel were rapidly absorbed, with the shortest median Tmax of 2.0 and 2.25 hours for ticagrelor and AR-C124910XX, respectively, and a Tmax of 0.5 hour for both R-95913 and R-138727. Strong inhibition of platelet aggregation was shown after administration of both ticagrelor and prasugrel, with slightly stronger and more rapid inhibition with prasugrel in the tested doses. Inhibitory activities of prasugrel lasted longer than those of ticagrelor, reflecting the difference in binding kinetics between the 2 drugs. Implications Prasugrel 30 and 60 mg exhibited slightly stronger, more rapid, and sustainable platelet inhibitory effects compared with ticagrelor 180 mg. These differing effects should be considered when determining the efficacy and adverse effects of ticagrelor and prasugrel. ClinicalTrials.gov identifier: NCT01876797 and NCT02075268.