Pharmacokinetics and pharmacodynamics of the novel PAR-1 antagonist vorapaxar in patients with end-stage renal disease

Kosoglou, Teddy; Kraft, Walter K.; Kumar, Bharath; Statkevich, Paul; Xuan, Fengjuan; Ma, Lei; Jennings, Lisa K.; Schiller, James E.; Langdon, Ronald B.; Cutler, David L.

doi:10.1007/s00228-012-1217-6

Cited by 28 publications

(20 citation statements)

References 22 publications

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“…9,10 The vorapaxar loading dose of 40 mg was selected, as it was likely to be the highest clinically relevant dose, and is the loading dose evaluated in a large Phase 3 clinical trial. 9 Moreover, this dosing regimen was selected to simulate extreme vorapaxar exposure situations, such as during coadministration with potent CYP3A4 inhibitors like ketoconazole, which has been shown to approximately = were not calculated for all the subjects enrolled in the study, as the terminal phase could not be adequately characterized. double the exposure to vorapaxar.…”

Section: Discussionmentioning

confidence: 99%

“…5,6 Vorapaxar (formerly SCH 530348) is a PAR-1 antagonist approved for the treatment of patients with a previous myocardial infarction or peripheral artery disease. [7][8][9][10][11] It is metabolized to M20, primarily by cytochrome P450 (CYP3A4) in human liver enzymes. 12,13 However, in vitro incubations of 14 C-vorapaxar with cDNA-expressed recombinant human cytochrome P450 (CYP) enzymes and human liver microsomes indicate that vorapaxar is a potential direct inhibitor of CYP2C8 with an IC50 of 1.5 mM (739 ng/mL), twice the C max concentration usually achieved following a 40 mg loading dose.…”

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confidence: 99%

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Vorapaxar, an oral PAR‐1 receptor antagonist, does not affect the pharmacokinetics of rosiglitazone

Kosoglou

Kumar

Statkevich

et al. 2014

Clinical Pharm in Drug Dev

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Vorapaxar, an oral PAR‐1 receptor antagonist, does not affect the pharmacokinetics of rosiglitazone

Kosoglou

Kumar

Statkevich

et al. 2014

Clinical Pharm in Drug Dev

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“…The drug undergoes oxidative metabolism through the CYP3A4 enzymes, is 90% excreted in bile, and has a half-life ranging from ~5 to 11 days. In phase I clinical trials, as a single high dose (20–40 mg) vorapaxar was potent, fast acting, and resulted in prolonged inhibition of Thrombin Receptor Activating Peptide (TRAP)- induced platelet aggregation (>80% inhibition at 1 h that was sustained for >72 h) [20]. A daily dose of vorapaxar 2.5 mg sustained the inhibitory effect for 28 days.…”

Section: Discussionmentioning

confidence: 99%

Targeting Platelet Thrombin Receptor Signaling to Prevent Thrombosis

Wallace

Smyth

2013

Pharmaceuticals

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Platelets contribute fundamentally to ischemic heart disease, and antiplatelet therapy has been critical to reducing acute thrombotic complications of atherosclerotic disease. Thrombin, by acting on protease activated receptors (PAR), is one of the most potent platelet activators. PAR-1 antagonists may therefore provide more comprehensive antithrombotic effects. We review the pathophysiology of atherothrombosis, platelet activation by thrombin, the role of platelet protease activated receptors (PAR), and the clinical data supporting their use.

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“…29 Furthermore, end-stage renal disease had no clinically significant effects on the pharmacokinetics or pharmacodynamics of a single oral dose of vorapaxar 10 mg in an open-label study in 8 patients on hemodialysis and 7 matched healthy volunteers. 30 In a large randomized clinical trial, 33% of patients were 65 years or older and 9% were 75 years or older. There were no overall age-related differences in safety or efficacy.…”

Section: Drug Interactionsmentioning

confidence: 99%

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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Pharmacokinetics and pharmacodynamics of the novel PAR-1 antagonist vorapaxar in patients with end-stage renal disease

Abstract: ESRD had no clinically relevant effect on the PK profile of vorapaxar or its ability to inhibit TRAP-induced platelet aggregation.

Cited by 28 publications

References 22 publications

Vorapaxar, an oral PAR‐1 receptor antagonist, does not affect the pharmacokinetics of rosiglitazone

Vorapaxar, an oral PAR‐1 receptor antagonist, does not affect the pharmacokinetics of rosiglitazone

Targeting Platelet Thrombin Receptor Signaling to Prevent Thrombosis

Vorapaxar

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