Skip to main content
SpringerLink
Log in

Pharmacokinetics of the novel PAR-1 antagonist vorapaxar in patients with hepatic impairment

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

To determine whether hepatic impairment has an effect on the pharmacokinetics (PK) of vorapaxar or M20, its main pharmacologically active metabolite.

Methods

This was an open-label study in which a single 40-mg oral dose of vorapaxar was administered to patients with mild (n = 6), moderate (n = 6), and severe (n = 4) hepatic impairment and healthy controls (n = 16) matched for age, gender, weight, and height. Blood samples for vorapaxar and M20 assay were collected predose and at frequent intervals up to 8 weeks postdose.

Results

Plasma vorapaxar and M20 PK profiles were similar between patients with impaired liver function and healthy controls. Group mean values for vorapaxar Cmax and AUCtf were 206–279 ng/mL and 14,200–18,200 ng·h/mL, respectively, with the lowest values observed in patients with severe impairment. Vorapaxar median Tmax and mean t1/2 values were 1.00–1.75 h and 298–366 h, respectively. There was no apparent correlation between vorapaxar or M20 exposure or t1/2 values and disease severity. Vorapaxar was generally well tolerated; one serious adverse event (gastrointestinal bleeding secondary to ruptured esophageal varices) was reported in a patient with severe hepatic impairment.

Conclusions

Hepatic impairment had no clinically relevant effect on the PK of vorapaxar and M20. No dose or dosage adjustment of vorapaxar will be required in patients with mild to moderate hepatic impairment. Although systemic exposure to vorapaxar does not appear to increase in patients with severe hepatic impairment, administration of vorapaxar to such patients is not recommended given their bleeding diathesis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Antiplatelet Trialists’ Collaboration (1994) Collaborative overview of randomised trials of antiplatelet therapy—I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Br Med J 308:81–106

    Article  Google Scholar 

  2. CAPRIE Steering Committee (1996) A randomised, blinded trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 348:1329–1339

    Article  Google Scholar 

  3. Dogne JM, de Leval X, Benoit P, Delarge J, Masereel B, David JL (2002) Recent advances in antiplatelet agents. Curr Med Chem 9:577–589

    Article  PubMed  CAS  Google Scholar 

  4. Bhatt DL, Fox KA, Hacke W, Berger PB, Black HR, Boden WE, Cacoub P, Cohen EA, Creager MA, Easton JD, Flather MD, Haffner SM, Hamm CW, Hankey GJ, Johnston SC, Mak KH, Mas JL, Montalescot G, Pearson TA, Steg PG, Steinhubl SR, Weber MA, Brennan DM, Fabry-Ribaudo L, Booth J, Topol EJ, for the CHARISMA Investigators (2006) Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 354:1706–1717

    Article  PubMed  CAS  Google Scholar 

  5. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK, for the Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators (2001) Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 345:494–502

    Article  PubMed  CAS  Google Scholar 

  6. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM, for the TRITON-TIMI 38 Investigators (2007) Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 357:2001–2015

    Article  PubMed  CAS  Google Scholar 

  7. Andersen H, Greenberg DL, Fujikawa K, Xu W, Chung DW, Davie EW (1999) Protease-activated receptor 1 is the primary mediator of thrombin-stimulated platelet procoagulant activity. Proc Natl Acad Sci USA 96:11189–11193

    Article  PubMed  CAS  Google Scholar 

  8. Chackalamannil S (2003) G-protein couple receptor antagonists-1: protease activated receptor-1 (PAR-1) antagonists as novel cardiovascular therapeutic agents. Curr Top Med Chem 3:1115–1123

    Article  PubMed  CAS  Google Scholar 

  9. Goto S, Yamaguchi T, Ikeda Y, Kato K, Yamaguchi H, Jensen P (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

    Article  PubMed  CAS  Google Scholar 

  10. Shinohara Y, Goto S, Doi M, Jensen P (2010) Safety of the novel protease-activated receptor-1 antagonist vorapaxar in Japanese patients with a history of ischemic stroke. J Stroke Cerebrovasc Dis. doi:10.1016/j.jstrokecerebrovasdis.2010.09.005

  11. Becker RC, Moliterno DJ, Jennings LK, Pieper KS, Pei J, Niederman A, Ziada KM, Berman G, Strony J, Joseph D, Mahaffey KW, Van de Werf F, Veltri E, Harrington RA, for the TRA-PCI Investigators (2009) 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

    Article  PubMed  CAS  Google Scholar 

  12. Morrow DA, Scirica BM, Fox KA, Berman G, Strony J, Veltri E, Bonaca MP, Fish P, McCabe CH, Braunwald E, for the TRA 2°P-TIMI 50 Investigators (2009) Evaluation of a novel antiplatelet agent for secondary prevention in patients with a history of atherosclerotic disease: design and rationale for the Thrombin-Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2°P)-TIMI 50 trial. Am Heart J 158:335–341

    Article  PubMed  CAS  Google Scholar 

  13. TRA*CER Executive and Steering Committees (2009) The thrombin receptor antagonist for clinical event reduction in acute coronary syndrome (TRA*CER) trial: study design and rationale. Am Heart J 158:327–334

    Article  Google Scholar 

  14. Kosoglou T, Reyderman L, Tiessen RG, van Vliet AA, Fales RR, Keller R, Yang B, Cutler DL (2012) Pharmacodynamics and pharmacokinetics of the novel PAR-1 antagonist vorapaxar (formerly SCH 530348) in healthy subjects. Eur J Clin Pharmacol 68:249–258

    Article  PubMed  CAS  Google Scholar 

  15. Kosoglou T, Reyderman L, Kasserra C, Jennings LK, Young S, Xuan F, Pei J, Maxwell SE, Meehan AG, Cutler DL (2012) No differences in the pharmacodynamics and pharmacokinetics of the thrombin receptor antagonist vorapaxar between healthy Japanese and Caucasian subjects. Eur J Clin Pharmacol 68:291–300

    Article  PubMed  CAS  Google Scholar 

  16. Ghosal A, Lu X, Penner N, Gao L, Ramanathan R, Chowdhury SK, Kishnani NS, Alton KB (2011) Identification of human liver cytochrome P450 enzymes involved in the metabolism of SCH 530348 (vorapaxar), a potent oral thrombin protease-activated receptor 1 antagonist. Drug Metab Dispos 39:30–38

    Article  PubMed  CAS  Google Scholar 

  17. Statkevich P, Kosoglou T, Kumar B, Li J, Xuan F, Wang Z, Meehan AG, Cutler DL (2012) Pharmacokinetics of vorapaxar and its metabolite SCH 2046273 (M20) following oral administration in healthy Chinese and US subjects (abstract). Clin Pharmacol Ther (in press)

  18. Verbeeck RK (2008) Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction. Eur J Clin Pharmacol 64:1147–1161

    Article  PubMed  CAS  Google Scholar 

  19. Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R (1973) Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 60:646–649

    Article  PubMed  CAS  Google Scholar 

  20. McLean AJ, Morgan DJ (1991) Clinical pharmacokinetics in patients with liver disease. Clin Pharmacokinet 21:42–69

    Article  PubMed  CAS  Google Scholar 

  21. Donelli MG, Zucchetti M, Munzone E, D’Incalci M, Crosignani A (1998) Pharmacokinetics of anticancer agents in patients with impaired liver function. Eur J Cancer 34:33–46

    Article  PubMed  CAS  Google Scholar 

  22. Sulsa GM, Atkinson AJ (2007) Effect of liver disease on pharmacokinetics. In: Atkinson AJ Jr, Abernethy DR, Daniels CE, Dedrick R, Markey SP (eds) Principles of clinical pharmacology, 2nd edn. Academic Press, New York, pp 73–87

    Google Scholar 

  23. Adedoyin A, Arns PA, Richards WO, Wilkinson GR, Branch RA (1998) Selective effect of liver disease on the activities of specific metabolizing enzymes: investigation of cytochromes P450 2C19 and 2D6. Clin Pharmacol Ther 64:8–17

    Article  PubMed  CAS  Google Scholar 

  24. Horak J, White J, Harris AL, Verrill M, Carmichael J, Holt A, Cantarini M, Macpherson M, Swaisland A, Swaisland H, Twelves C (2011) The effect of different etiologies of hepatic impairment on the pharmacokinetics of gefitinib. Cancer Chemother Pharmacol 68(6):1485–1495

    Google Scholar 

  25. Weil A, Martin P, Smith R, Oliver S, Langmuir P, Read J, Molz KH (2010) Pharmacokinetics of vandetanib in subjects with renal or hepatic impairment. Clin Pharmacokinet 49:607–618

    Article  PubMed  CAS  Google Scholar 

  26. Bruderer S, Detishin V, Tsvitbaum N, Dingemanse J (2011) Influence of different degrees of liver impairment on the pharmacokinetics of clazosentan. Br J Clin Pharmacol 71:52–60

    Article  PubMed  CAS  Google Scholar 

  27. Zhang C, Thabut D, Kamath PS, Shah VH (2011) Oesophageal varices in cirrhotic patients: from variceal screening to primary prophylaxis of the first oesophageal variceal bleeding. Liver Int 31:108–119

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors wish to thank Laura Black, Jing Sun, and Kristen Lewis (currently or formerly of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ, USA) for assistance in the execution of this study and the preparation of this manuscript for publication.

Conflict of interest

P. Statkevich, T. Kosoglou, B. Kumar, F. Xuan, C. Trusley, J.E. Schiller, R.B. Langdon, and D.L. Cutler all declare that they are full-time employees of Merck Sharp & Dohme Corp. (a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ, USA) or were full-time employees of Schering-Plough Corporation (now Merck Sharp & Dohme Corp.) at the time of the study, and may own stock or hold stock options in Merck & Co., Inc. R.A. Preston received research grant support from Schering-Plough Corporation for the conduct of this study and is a full-time employee of the University of Miami School of Medicine, which received funding from Schering-Plough Corporation.

Author information

Authors and Affiliations

  1. Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA

    Paul Statkevich, Teddy Kosoglou, Bharath Kumar, Fengjuan Xuan, Craig Trusley, James E. Schiller, Ronald B. Langdon & David L. Cutler

  2. Clinical Pharmacology Research Unit, Division of Clinical Pharmacology, Department of Medicine, University of Miami School of Medicine, Miami, FL, USA

    Richard A. Preston

  3. Jackson Memorial Hospital, Miami, FL, USA

    Richard A. Preston

  4. Clinical PK/PD, Merck Sharp & Dohme Corp., 2000 Galloping Hill Road, Kenilworth, NJ, 07033, USA

    Paul Statkevich

Authors
  1. Paul Statkevich
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Teddy Kosoglou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Richard A. Preston
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bharath Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Fengjuan Xuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Craig Trusley
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. James E. Schiller
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ronald B. Langdon
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. David L. Cutler
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Paul Statkevich.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Statkevich, P., Kosoglou, T., Preston, R.A. et al. Pharmacokinetics of the novel PAR-1 antagonist vorapaxar in patients with hepatic impairment. Eur J Clin Pharmacol 68, 1501–1508 (2012). https://doi.org/10.1007/s00228-012-1269-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-012-1269-7

Keywords

Search

Navigation