Effect of Food, Antacid, and Age on the Pharmacokinetics of the Oral Thrombin Receptor Antagonist Vorapaxar (SCH 530348) in Healthy Volunteers

Kosoglou, Teddy; Reyderman, Larisa; Tseng, Jack; Kumar, Bharath; Xuan, Fengjuan; Schiller, James E.; Meehan, Alan G.; Kim, Kenneth; Cutler, David L.

doi:10.1002/cpdd.30

Cited by 12 publications

(7 citation statements)

References 6 publications

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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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“…Therefore, it can be given without concern of antacids and meals. 10,12,20 The liver extensively metabolizes vorapaxar by the cytochrome P450 (CYP) enzyme pathway, CYP3A4 and CYP2J2, with a half-life of 126-311 hours. 12,21 The long half-life makes the action of the drug effectively irreversible although it is a reversible PAR-1 antagonist.…”

Section: Pharmacokinetics and Pharmacodynamicsmentioning

confidence: 99%

Protease-Activated Receptor 1 Inhibitors: Novel Antiplatelet Drugs in Prevention of Atherothrombosis

Al-Khafaji

Mutyala

Al-Khafaji

et al. 2017

American Journal of Therapeutics

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Protease-activated receptor (PAR)-1 inhibitors have recently become popular in the use of atherosclerosis among clinicians. Atherosclerosis can cause cardiovascular and cerebrovascular events leading to one of the major causes of mortality worldwide. Thrombin-mediated platelets can cause atherosclerotic plaques, and these platelets are activated by thrombin through the PAR-1. Vorapaxar and atopaxar are novel antiplatelet drugs that inhibit the thrombin-induced platelet activation by antagonizing the PAR-1. The objective of this article is to review the mechanism of action of vorapaxar and atopaxar and explain the rationale for using them in atherothrombosis patients including myocardial infarction, peripheral arterial disease, and stroke.

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“…The recommended dose is one tablet daily. 16 , 38 Vorapaxar can be used with aspirin and/or clopidogrel based on standards of care. 16 There is a lack of clinical data in use of vorapaxar with other antiplatelet drugs or as monotherapy.…”

Section: Dosage and Administrationmentioning

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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Effect of Food, Antacid, and Age on the Pharmacokinetics of the Oral Thrombin Receptor Antagonist Vorapaxar (SCH 530348) in Healthy Volunteers

Cited by 12 publications

References 6 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

Protease-Activated Receptor 1 Inhibitors: Novel Antiplatelet Drugs in Prevention of Atherothrombosis

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

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