Effect of Food, Antacid, and Age on the Pharmacokinetics of the Oral Thrombin Receptor Antagonist Vorapaxar (SCH 530348) in Healthy Volunteers Teddy Kosoglou 1 , Larisa Reyderman 1 , Jack Tseng 1 , Bharath Kumar 1 , Fengjuan Xuan 1 , James Schiller 1 , Alan G. Meehan 1 , Kenneth Kim 2 , and David L. Cutler 1 Abstract This randomized, open‐label, parallel group study examined the effects of food, antacid, and age on the pharmacokinetics of vorapaxar. In total, 101 subjects were enrolled including 83 young adults (18–45 years) and 18 elderly subjects (>65 years). Subjects received single‐dose vorapaxar 40 mg after a 10‐hour fast (young and elderly) or with extra‐strength antacid, food, or 1 or 2 hours after food (young only). Vorapaxar 40 mg was rapidly absorbed after a fast (median T max : 1 hour). Administration with food or 1 or 2 hours post‐meal modestly increased vorapaxar mean area under the curve (AUC) and C max and prolonged median T max by 1 hour. Concomitant food modestly increased vorapaxar AUC from time zero to infinity [AUC(I)] and C max 43% and 31%, respectively. Antacid modestly decreased vorapaxar AUC(I) by 15% and C max by 38%, and increased median T max by 1 hour. Vorapaxar AUC(I) and C max were 41% and 29% higher, respectively, in elderly versus young subjects. Concomitant food and older age were associated with modest increases, and antacid was associated with a small decrease in vorapaxar exposure, which are not expected to affect the drug’s safety or efficacy. Keywords Vorapaxar, SCH 530348, pharmacokinetics, food, antacid, age, interaction Introduction Vorapaxar (SCH 530348), a novel antiplatelet agent in advanced clinical development for the prevention and treatment of atherothrombotic disease, is a potent, orally bioavailable thrombin receptor antagonist (TRA) selective for the protease-activated receptor 1 (PAR-1). 1,2 Vorapaxar is a potent inhibitor of platelet activation and aggregation induced via PAR-1 receptor stimulation by thrombin (in vivo) or thrombin receptor agonist peptide (TRAP) (ex vivo) but does not interfere with the platelet activation and aggregation induced by other platelet agonists, such as adenosine diphosphate (ADP), collagen, thromboxane mimetic U46619, or a PAR-4 agonist peptide. Furthermore, vorapaxar does not affect the coagulation parameters (e.g., prothrombin time and activated partial thromboplastin time, ecarin time, activated clotting time), consistent with its lack of interference with the pro-coagulant activity of thrombin (cleavage of fibrinogen into fibrin). 1 Earlier Phase I studies demonstrated dose-related pharmacokinetics and pharmacodynamics (inhibition of TRAP-induced platelet aggregation) after administration of single doses of vorapaxar up to 40 mg or multiple once- daily doses of vorapaxar up to 5 mg for 28 days, 3–5 without notable differences between the Japanese and Caucasian subjects. 4 The 40-mg loading dose of vorapaxar rapidly (within 1 hour) induced complete (80%) inhibition of TRAP-induced platelet aggregation. 3–5 Food, changes in gastrointestinal pH, and age can all have significant effects on the pharmacokinetics of drugs at therapeutic doses, resulting in sub- or supra-therapeutic plasma concentrations. The present study was conducted to evaluate the effect of food, timing of meals, antacid, and age on the pharmacokinetics of vorapaxar Clinical Pharmacology in Drug Development 2(3) 223–230 © The Author(s) 2013 DOI: 10.1002/cpdd.30 1 Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA 2 WCCT Global, LLC, Cypress, CA, USA Submitted for publication 1 June 2012; accepted 6 March 2013 Corresponding Author: Teddy Kosoglou, Clinical Pharmacology, Merck Sharp & Dohme Corp., 351 N. Sumneytown Pike, UG4–D48, North Wales, PA 19454, USA. (e‐mail: teddy.kosoglou2@merck.com) Original Article