Pharmacodynamics and pharmacokinetics of the novel PAR-1 antagonist vorapaxar (formerly SCH 530348) in healthy subjects

European Journal of Clinical Pharmacology

Volumn 68, Issue 3, 2012, Pages 249-258

  Kosoglou, Teddy ^a   Reyderman, Larisa ^a,c   Tiessen, Renger G ^b   Van Vliet, André A ^b   Fales, Robert R ^a   Keller, Robert ^a   Yang, Bo ^a   Cutler, David L ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

^b PRA Health Sciences   (Netherlands)

^c EISAI INC   (United States)

Author keywords

PAR 1 antagonist; Pharmacodynamics; Pharmacokinetics; Platelet aggregation; SCH 530348; Thrombin receptor antagonist; Vorapaxar

Indexed keywords

PLACEBO; THROMBIN RECEPTOR ACTIVATING PEPTIDE; VORAPAXAR;

ADULT; AREA UNDER THE CURVE; ARTICLE; BLEEDING TIME; BRAIN CONTUSION; CONTROLLED STUDY; DIZZINESS; DOUBLE BLIND PROCEDURE; DRUG ABSORPTION; DRUG ACCUMULATION; DRUG ACTIVITY; DRUG DISTRIBUTION; DRUG DOSE ESCALATION; DRUG EFFECT; DRUG ELIMINATION; DRUG HALF LIFE; DRUG INDUCED HEADACHE; DRUG METABOLISM; DRUG POTENCY; DRUG SAFETY; DRUG TOLERABILITY; EPISTAXIS; FATIGUE; FEMALE; FLATULENCE; HEMATOMA; HUMAN; HUMAN EXPERIMENT; INJECTION SITE EXTRAVASATION; LOADING DRUG DOSE; LOOSE FECES; LOW DRUG DOSE; MAINTENANCE THERAPY; MALE; MAXIMUM PLASMA CONCENTRATION; MULTIPLE CYCLE TREATMENT; NAUSEA; NORMAL HUMAN; PELVIS FRACTURE; PHARMACODYNAMICS; PHASE 1 CLINICAL TRIAL; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL; SINGLE DRUG DOSE; SKIN BRUISING; THROMBOCYTE AGGREGATION; TIME TO MAXIMUM PLASMA CONCENTRATION;

ADOLESCENT; ADULT; BLEEDING TIME; FEMALE; HUMANS; LACTONES; MALE; MIDDLE AGED; PLATELET AGGREGATION; PLATELET AGGREGATION INHIBITORS; PYRIDINES; RECEPTOR, PAR-1; YOUNG ADULT;

EID: 84857041061     PISSN: 00316970     EISSN: 14321041     Source Type: Journal    
DOI: 10.1007/s00228-011-1120-6     Document Type: Article

References (23)

1. G Davi C Patrono 2007 Platelet activation and atherothrombosis N Engl J Med 357 2482 2494 18077812 10.1056/NEJMra071014 1:CAS:528:DC%2BD2sXhsVemurrL (Pubitemid 350272787)
2. DJ Angiolillo D Capodanno S Goto 2010 Platelet thrombin receptor antagonism and atherothrombosis Eur Heart J 31 17 28 19948715 10.1093/eurheartj/ehp504 1:CAS:528:DC%2BC3cXhtFOmsQ%3D%3D
3. DL Bhatt KA Fox W Hacke PB Berger HR Black WE Boden P Cacoub EA Cohen MA Creager JD Easton MD Flather SM Haffner CW Hamm GJ Hankey SC Johnston KH Mak JL Mas G Montalescot TA Pearson PG Steg SR Steinhubl MA Weber DM Brennan L Fabry-Ribaudo J Booth EJ Topol 2006 CHARISMA Investigators. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events N Engl J Med 354 1706 1717 16531616 10.1056/NEJMoa060989 1:CAS:528: DC%2BD28Xjs12gsLk%3D
4. SD Wiviott E Braunwald CH McCabe G Montalescot W Ruzyllo S Gottlieb FJ Neumann D Ardissino S De Servi SA Murphy J Riesmeyer G Weerakkody CM Gibson EM Antman 2007 TRITON-TIMI 38 investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes N Engl J Med 357 2001 2015 17982182 10.1056/NEJMoa0706482 1:CAS:528:DC%2BD2sXhtlWis7rN (Pubitemid 350106708)
5. S Yusuf F Zhao SR Mehta S Chrolavicius G Tognoni KK Fox 2001 Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation N Engl J Med 345 494 502 11519503 10.1056/NEJMoa010746 1:CAS:528:DC%2BD3MXms1arsrY%3D (Pubitemid 32758501)
6. LA García Rodríguez S Hernández-Díaz FJ de Abajo 2001 Association between aspirin and upper gastrointestinal complications: systematic review of epidemiologic studies Br J Clin Pharmacol 52 563 571 11736865 10.1046/j.0306-5251.2001.01476.x
7. SV Rao K O'Grady KS Pieper CB Granger LK Newby F Van de Werf KW Mahaffey RM Califf RA Harrington 2005 Impact of bleeding severity on clinical outcomes among patients with acute coronary syndromes Am J Cardiol 96 1200 1206 16253582 10.1016/j.amjcard.2005.06.056 (Pubitemid 41505393)
8. KE Brummel SG Paradis S Butenas KG Mann 2002 Thrombin functions during tissue factor-induced blood coagulation Blood 100 148 152 12070020 10.1182/blood.V100.1.148 1:CAS:528:DC%2BD38XltF2rsLk%3D (Pubitemid 35177440)
9. KG Mann 2003 Thrombin formation Chest 124 Suppl 3 4S 10S 12970118 10.1378/chest.124.3-suppl.4S 1:CAS:528:DC%2BD3sXotVensL0%3D (Pubitemid 37128430)
10. M Chintala K Shimizu M Ogawa H Yamaguchi M Doi P Jensen 2008 Basic and translational research on proteinase-activated receptors: antagonism of the proteinase-activated receptor 1 for thrombin, a novel approach to antiplatelet therapy for atherothrombotic disease J Pharmacol Sci 108 433 438 19098390 10.1254/jphs.08R06FM 1:CAS:528:DC%2BD1MXhvFWksQ%3D%3D
11. CK Derian BP Damiano MF Addo AL Darrow MR D'Andrea M Nedelman HC Zhang BE Maryanoff P Andrade-Gordon 2003 Blockade of the thrombin receptor protease-activated receptor-1 with a small-molecule antagonist prevents thrombus formation and vascular occlusion in nonhuman primates J Pharmacol Exp Ther 304 855 861 12538843 10.1124/jpet.102.042663 1:CAS:528:DC%2BD3sXpvVCluw%3D%3D (Pubitemid 36152366)
12. Y Kato Y Kita Y Hirasawa-Taniyama M Nishio K Mihara K Ito T Yamanaka J Seki S Miyata S Mutoh 2003 Inhibition of arterial thrombosis by a protease-activated receptor 1 antagonist, FR171113, in the guinea pig Eur J Pharmacol 473 163 169 12892834 10.1016/S0014-2999(03)01973-3 1:CAS:528:DC%2BD3sXlvVWgurg%3D (Pubitemid 36929880)
13. S Chackalamannil Y Wang WJ Greenlee Z Hu Y Xia HS Ahn G Boykow Y Hsieh J Palamanda J Agans-Fantuzzi S Kurowski M Graziano M Chintala 2008 Discovery of a novel, orally active himbacine-based thrombin receptor antagonist (SCH 530348) with potent antiplatelet activity J Med Chem 51 3061 3064 18447380 10.1021/jm800180e 1:CAS:528:DC%2BD1cXlt1Ghu70%3D (Pubitemid 351821864)
14. SK Hildemann C Bode 2009 Improving antiplatelet therapy for atherothrombotic disease: preclinical results with SCH 530348, the first oral thrombin receptor antagonist selective for PAR-1 Hämostaseologie 29 349 355 19882073 1:CAS:528:DC%2BD1MXhs1SlsbjJ
15. RC Becker DJ Moliterno LK Jennings KS Pieper J Pei A Niederman KM Ziada G Berman J Strony D Joseph KW Mahaffey F Van de Werf E Veltri RA Harrington 2009 TRA-PCI Investigators. Safety and tolerability of SCH 530348 in patients undergoing non-urgent percutaneous coronary intervention: a randomised, double-blind, placebo-controlled phase II study Lancet 373 919 928 19286091 10.1016/S0140-6736(09)60230-0 1:CAS:528:DC%2BD1MXjtFKqtrs%3D
16. Y Ozaki K Satoh Y Yatomi T Yamamoto Y Shirasawa S Kume 1994 Detection of platelet aggregates with a particle counting method using light scattering Anal Biochem 218 284 294 8074282 10.1006/abio.1994.1180 1:CAS:528:DyaK2cXivFehsLw%3D (Pubitemid 24141625)
17. CH Mielke Jr MM Kaneshiro IA Maher JM Weiner SI Rapaport 1969 The standardized normal Ivy bleeding time and its prolongation by aspirin Blood 34 204 215 5794116
18. T Kosoglou L Reyderman R Tiessen RR Fales DL Cutler R Keller B Yang JJ Van Lier A Wadham AA Van Vliet 2009 TRAP-induced platelet aggregation following single and multiple rising oral doses of SCH 530348, a novel thrombin receptor antagonist, in healthy volunteers Clin Pharmacol Ther 85 S1 S21 Abstract PI-40
19. T Kosoglou L Reyderman C Kasserra S Young J Pei SE Maxwell J Schiller DL Cutler 2008 Optimizing dose of the novel thrombin receptor antagonist SCH 530348 based on pharmacodynamics and pharmacokinetics in healthy subjects Clin Pharmacol Ther 83 S1 S55 Abstract PII-42
20. LK Jennings A Earhart RC Becker L Reyderman E Veltri J Strony RA Harrington 2007 Thrombin receptor antagonist (TRA;SCH 530348) is a selective, potent inhibitor of PAR1 activity with predictable pharmacokinetics (abstract) Circulation 116 suppl II-674 Abstract 3010
21. M Chintala S Vemulapalli S Kurowski C Sabin D Reynolds K Prevete G Friedrichs 2008 SCH 530348, a novel oral antiplatelet agent, demonstrated no bleeding risk alone or in combination with aspirin and clopidogrel in cynomolgus monkeys (abstract) Arterioscl Thromb Vasc Biol 28 e138 e139 Abstract P579
22. S Goto T Yamaguchi Y Ikeda K Kato H Yamaguchi P Jensen 2010 Safety and exploratory efficacy of the novel thrombin receptor (PAR-1) antagonist SCH530348 for non-ST-segment elevation acute coronary syndrome J Atheroscler Thromb 17 156 164 20124733 10.5551/jat.3038 1:CAS:528:DC%2BC3MXhvVeru7w%3D
23. ER Vandendries JR Hamilton SR Coughlin B Furie BC Furie 2007 Par4 is required for platelet thrombus propagation but not fibrin generation in a mouse model of thrombosis Proc Natl Acad Sci USA 104 288 292 17190826 10.1073/pnas.0610188104 1:CAS:528:DC%2BD2sXjt12ksQ%3D%3D (Pubitemid 46068024)