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

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

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24 Scopus citations

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 C max 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.

Original languageEnglish (US)
Pages (from-to)1501-1508
Number of pages8
JournalEuropean Journal of Clinical Pharmacology
Volume68
Issue number11
DOIs
StatePublished - Nov 1 2012

Keywords

  • Hepatic impairment
  • PAR-1 antagonist
  • Pharmacokinetics
  • SCH 530348
  • Thrombin receptor antagonist
  • Vorapaxar

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology

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    Statkevich, P., Kosoglou, T., Preston, R. A., Kumar, B., Xuan, F., Trusley, C., Schiller, J. E., Langdon, R. B., & Cutler, D. L. (2012). Pharmacokinetics of the novel PAR-1 antagonist vorapaxar in patients with hepatic impairment. European Journal of Clinical Pharmacology, 68(11), 1501-1508. https://doi.org/10.1007/s00228-012-1269-7