The Absence of a Clinically Significant Effect of Food on the Single Dose Pharmacokinetics of Vorapaxar, a PAR‐1 Antagonist, in Healthy Adult Subjects

Behm, Martin O.; Kosoglou, Teddy; Miltenburg, A. M. M.; Li, Jing; Statkevich, Paul; Johnson‐Levonas, Amy O.; Martinho, Monika; Fackler, Paul

doi:10.1002/cpdd.38

Cited by 10 publications

(5 citation statements)

References 4 publications

(13 reference statements)

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“…Vorapaxar pharmacokinetic parameters are unaffected by food consumption [ 14 , 15 ]. No dosage adjustment is needed for patients with end-stage renal failure [ 16 ].…”

Section: Pharmacokineticsmentioning

confidence: 99%

Vorapaxar: The Current Role and Future Directions of a Novel Protease-Activated Receptor Antagonist for Risk Reduction in Atherosclerotic Disease

2017

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IntroductionDespite the current standard of care, patients with cardiovascular disease remain at a high risk for recurrent events. Inhibition of thrombin-mediated platelet activation through protease-activated receptor-1 antagonism may provide reductions in atherosclerotic disease beyond those achievable with the current standard of care.ObjectiveOur primary objective is to evaluate the clinical literature regarding the role of vorapaxar (Zontivity™) in the reduction of cardiovascular events in patients with a history of myocardial infarction and peripheral artery disease. In particular, we focus on the potential future directions for protease-activating receptor antagonists in the treatment of a broad range of atherosclerotic diseases.Data SourcesA literature search of PubMed and EBSCO was conducted to identify randomized clinical trials from August 2005 to June 2016 using the search terms: ‘vorapaxar’, ‘SCH 530348’, ‘protease-activated receptor-1 antagonist’, and ‘Zontivity™’. Bibliographies were searched and additional resources were obtained.ResultsVorapaxar is a first-in-class, protease-activated receptor-1 antagonist. The Thrombin Receptor Antagonist for Clinical Event Reduction (TRACER) trial did not demonstrate a significant reduction in a broad primary composite endpoint. However, the Thrombin-Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2°P-TIMI 50) trial examined a more traditional composite endpoint and found a significant benefit with vorapaxar. Vorapaxar significantly increased bleeding compared with standard care. Ongoing trials will help define the role of vorapaxar in patients with peripheral arterial disease, patients with diabetes mellitus, and other important subgroups. The use of multivariate modeling may enable the identification of subgroups with maximal benefit and minimal harm from vorapaxar.ConclusionVorapaxar provides clinicians with a novel mechanism of action to further reduce the burden of ischemic heart disease. Identification of patients with a high ischemic risk and low bleeding risk would enable clinicians to maximize the utility of this unique agent.Electronic supplementary materialThe online version of this article (doi:10.1007/s40268-016-0158-4) contains supplementary material, which is available to authorized users.

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“…Vorapaxar pharmacokinetic parameters are unaffected by food consumption [ 14 , 15 ]. No dosage adjustment is needed for patients with end-stage renal failure [ 16 ].…”

Section: Pharmacokineticsmentioning

confidence: 99%

Vorapaxar: The Current Role and Future Directions of a Novel Protease-Activated Receptor Antagonist for Risk Reduction in Atherosclerotic Disease

2017

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“…However, the differences were not considered clinically significant. 14 An open-label crossover study in 16 healthy volunteers showed that food did not significantly affect the pharmacokinetics of a single oral dose of vorapaxar 2.5 mg. 15 Ethnicity does not seem to affect the pharmacokinetics and pharmacodynamics of vorapaxar. No differences were observed between age-, sex-, height-, and bodyweight-matched Japanese and white volunteers.…”

Section: Pharmacokinetics and Pharmacodynamicsmentioning

confidence: 97%

Vorapaxar

Lam

Tran

2015

Cardiology in Review

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Antiplatelet therapy reduces the risks for cardiovascular morbidity and mortality in patients with atherosclerotic disease, and it is also beneficial in managing peripheral arterial disease (PAD). These agents work through various therapeutic pathways to achieve antithrombotic effects. Although single- or two-drug regimens have been deployed to prevent vascular events, approximately 10% of the patients with acute coronary syndrome remain at risk for recurrent thrombotic events and may need a more aggressive preventative strategy. Vorapaxar offers a unique mechanism for platelet inhibition via the antagonism of protease-activated receptor-1. It is approved for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction (MI) or PAD. This new drug approval was mainly based on the results from subgroup analyses from a large landmark trial (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events-Thrombolysis in Myocardial Infarction 50), which found that vorapaxar reduces the rate of the combined end point of cardiovascular death, MI, stroke, and urgent coronary revascularization when used in addition to aspirin and/or clopidogrel in patients without a history of stroke. In this study, vorapaxar was discontinued in patients with a history of stroke due to excessive risk for intracranial hemorrhage after 2 years of therapy. As an adjunctive therapy to standard regimens, vorapaxar provides a greater net clinical benefit in MI patients who are at a lower risk for bleeding. In patients with PAD, it reduces the rates of recurrent acute limb ischemia with rehospitalization or peripheral revascularization. The most concerning adverse effect is bleeding. Vorapaxar should not be used in patients with a history of stroke, transient ischemic attack, intracranial hemorrhage, or active pathological bleeding. The risks and benefits of adding vorapaxar to intensify antiplatelet regimens should be assessed in individual patients to aim for additional therapeutic outcomes with minimal bleeding risks.

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“…The peak plasma concentration occurs within 1–2 hours. 17 , 18 Food has no effect on its oral bioavailability. The mean volume of distribution of vorapaxar is ~424 L. 16 Vorapaxar is primarily metabolized by CYP3A4 and CYP2J2 to an inactive metabolite (M19) and an equally potent active metabolite M20.…”

Section: Pharmacologymentioning

confidence: 99%

Impact of selective platelet inhibition in reducing cardiovascular risk - role of vorapaxar

Cheng

2016

VHRM

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This article reviews the pharmacology, clinical efficacy, and safety of vorapaxar in reducing cardiovascular risk. Vorapaxar is a tricyclic himbacine-derived reversible inhibitor of platelet surface protease activator receptor-1, which prevents thrombin from activating platelets. Two Phase III clinical trials and multiple subanalyses from the two trials with vorapaxar have been published. In patients with recent acute coronary syndrome, vorapaxar, when added to standard therapy, did not reduce the composite cardiovascular end point. In contrary, in a study of secondary prevention for patients with cardiovascular diseases, vorapaxar reduced the risk of cardiovascular death or ischemic events (myocardial infarction, stroke) in patients with stable atherosclerosis who were receiving standard therapy. Vorapaxar is approved in the US for use with aspirin and/or clopidogrel in the secondary prevention of thrombogenic cardiovascular events in stable patients with peripheral arterial disease or a history of myocardial infarction. Vorapaxar increases risk of bleeding and is contraindicated in patients with previous cerebrovascular events. It is essential to balance individual patient’s bleeding risk to any further cardiovascular benefits that they may get. Future investigation is also needed to evaluate use of vorapaxar with newer antiplatelet agents such as ticagrelor and cangrelor, as well as its role as monotherapy.

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The Absence of a Clinically Significant Effect of Food on the Single Dose Pharmacokinetics of Vorapaxar, a PAR‐1 Antagonist, in Healthy Adult Subjects

Cited by 10 publications

References 4 publications

Vorapaxar: The Current Role and Future Directions of a Novel Protease-Activated Receptor Antagonist for Risk Reduction in Atherosclerotic Disease

Vorapaxar: The Current Role and Future Directions of a Novel Protease-Activated Receptor Antagonist for Risk Reduction in Atherosclerotic Disease

Vorapaxar

Impact of selective platelet inhibition in reducing cardiovascular risk - role of vorapaxar

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