Pharmacokinetics of vorapaxar and its metabolite following oral administration in healthy Chinese and American subjects

Chen, Xia; Kosoglou, Teddy; Statkevich, Paul; Kumar, Bharath; Li, Jing; Dockendorf, Marissa; Wang, Guoqin; Lowe, Robert S.; Jiang, Ji; Li, Hongzhong; Wang, Zaiqi; Cutler, David L.; Hu, Pei

doi:10.5414/cp202121

Cited by 8 publications

(6 citation statements)

References 22 publications

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“…The plasma concentrations of vorapaxar on days 6 and 7 measured in each period of the present study (C max = 54–67 ng/mL; C trough day 6 and 7 = 47–51 ng/mL in this study) confirmed attainment of appropriate steady‐state conditions. Results from previous phase I clinical trials of vorapaxar in healthy volunteers also support that day 6 and 7 vorapaxar concentrations in this study are consistent with steady‐state concentrations for 2.5 mg once‐daily dose …”

Section: Discussionsupporting

confidence: 90%

Effect of Vorapaxar Alone and in Combination with Aspirin on Bleeding Time and Platelet Aggregation in Healthy Adult Subjects

Kraft

Gilmartin

Chappell

et al. 2016

Clinical Translational Sci

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The effect of the protease‐activated receptor‐1 (PAR‐1) antagonist vorapaxar on human bleeding time is not known. This was a randomized, two‐period, open‐label trial in healthy men (n = 31) and women (n = 5). In period 1, subjects received 81 mg aspirin q.d. or a vorapaxar regimen achieving steady‐state plasma concentrations equivalent to chronic 2.5 mg q.d. doses, for 7 days. In period 2, each group added 7 days of the therapy alternate to that of period 1 without washout. Bleeding time and platelet aggregation using arachidonic acid, ADP, and TRAP agonists were assessed. Bleeding time geometric mean ratio (90% CI) for vorapaxar/baseline was 1.01 (0.88–1.15), aspirin/baseline was 1.32 (1.15–1.51), vorapaxar + aspirin/vorapaxar was 1.47 (1.26–1.70), and vorapaxar + aspirin/aspirin was 1.12 (0.96–1.30). Unlike aspirin, vorapaxar did not prolong bleeding time compared with baseline. Bleeding time following administration of vorapaxar with aspirin was similar to that following aspirin alone.

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Section: Discussionsupporting

confidence: 90%

Effect of Vorapaxar Alone and in Combination with Aspirin on Bleeding Time and Platelet Aggregation in Healthy Adult Subjects

Kraft

Gilmartin

Chappell

et al. 2016

Clinical Translational Sci

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“…As of now, to our knowledge, a few research studies on Vorapaxar estimation and pharmacokinetics have been reported [5][6][7][8][9] like pharmacokinetics and pharmacodynamics 5 , Pharmacokinetics of vorapaxar and its metabolite following oral administration in healthy Chinese and American subjects 6 , Determination of a novel thrombin receptor antagonist (SCH 530348) in human plasma by LC-MS/MS 7 with concentration range of 0.1-1000 ng/mL in human plasma samples, Pharmacokinetic Drug-Drug Interaction Between Prasugrel and Vorapaxar 8 , Estimation of Vorapaxar with different drugs BY UV-VIS 9 .…”

Section: Review Of Literaturementioning

confidence: 99%

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2020

IJPSR

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The validated analytical method was applied for estimation of vorapaxar in aqueous and human plasma with vorapaxar-D5 as an internal standard by using UPLC-ESI-MS/MS. The chromatographic separation was achieved with 5mM Ammonium Formate Buffer (pH: 4.0): Methanol: Acetontrile, (40:30:30, % v/v) using the Pursuit XRs-100Å, C18, 4.6 × 50 mm, 10 µm. The total analysis time was 3.5 min and flow rate was set to 0.2 ml/min. The mass transitions of vorapaxar and vorapaxar-D5 obtained were m/z 591.4447.2 and 498.6447.2. The standard curve shows correlation coefficient (r 2) greater than 0.999 with a range of 0.01-200.0 ng/ml using the linear regression model. The developed method was applied successfully for studying the pharmacokinetics of vorapaxar in rabbits. INTRODUCTION: Vorapaxar is a reversible antagonist of the protease-activated receptor-1 (PAR-1) expressed on platelets, but its long halflife makes it effectively irreversible. Vorapaxar inhibits thrombin-induced and thrombin receptor agonist peptide (TRAP)-induced platelet aggregation in-vitro studies. Vorapaxar does not inhibit platelet aggregation induced by adenosine diphosphate (ADP), collagen or a thromboxane mimetic and does not affect coagulation parameters ex-vivo. PAR-1 receptors are also expressed in a wide variety of cell types, including endothelial cells, neurons, and smooth muscle cells, but the pharmacodynamic effects of vorapaxar in these cell types have not been assessed 1-2 .

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“…There have not been any ethnic differences observed in pharmacokinetics and pharmacodynamics of the drug. 22 CYP3A4 is the main enzyme involved in the production of the inactive M19 metabolite, which is then pursued by a lower substrate conversion of CYP1A1 and CYP2C19. 22 M20 is the major active hydroxyl metabolite of vorapaxar (accounts for ;20% of exposure to vorapaxar), which is formed by CYP2J2 and CYP3A4.…”

Section: Pharmacokinetics and Pharmacodynamicsmentioning

confidence: 99%

“…22 M20 is the major active hydroxyl metabolite of vorapaxar (accounts for ;20% of exposure to vorapaxar), which is formed by CYP2J2 and CYP3A4. 22 CYP3A4 is expected to play the main role in formation of M20 because of the large amount of CYP3A4 found in human intestine (;82%) and liver (;40%) when compared with CYP2J2 (,2%). 23 The agent is also known to have high bioavailability (;85%) and $99% protein binding to albumin.…”

Section: Pharmacokinetics and Pharmacodynamicsmentioning

confidence: 99%

“…4,24 The drug is predominately removed by the body through the feces (58%) and urine (25%) as M19, inactive amine metabolite. 22 Atopaxar is metabolized mainly by CYP3A4 system and has estimated shorter plasma half-life (22-26 hours) when compared with vorapaxar, and good bioavailability. 25,26 The shorter half-life of atopaxar can be a possible advantage in patients actively bleeding or in need for urgent surgery.…”

Section: Pharmacokinetics and Pharmacodynamicsmentioning

confidence: 99%

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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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Pharmacokinetics of vorapaxar and its metabolite following oral administration in healthy Chinese and American subjects

Abstract: The pharmacokinetic profiles of vorapaxar and M20 and the metabolite/parent ratios in healthy Chinese were generally comparable to those in a healthy Western population.

Cited by 8 publications

References 22 publications

Effect of Vorapaxar Alone and in Combination with Aspirin on Bleeding Time and Platelet Aggregation in Healthy Adult Subjects

Effect of Vorapaxar Alone and in Combination with Aspirin on Bleeding Time and Platelet Aggregation in Healthy Adult Subjects

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

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