Tolerability, pharmacokinetics, and pharmacodynamics of DX-9065a, a new synthetic potent anticoagulant and specific factor Xa inhibitor, in healthy male volunteers

Murayama, Nobuyuki; Tanaka, Makoto; Kunitada, Satoshi; Yamada, Hironao; Inoue, Takashi; Terada, Yasuko; Masami, Fujita; Ikeda, Yasuo

doi:10.1016/s0009-9236(99)70033-0

Cited by 51 publications

(35 citation statements)

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“…Targeted concentrations were modeled from phase I studies in young, healthy male volunteers. 17,18 Median measured plasma concentrations were higher than target, with most of the variation in pharmacokinetic response attributed to dose and weight. Furthermore, although drug levels were halved 4 hours after infusion, DX-9065a remained measurable at 7 days.…”

Section: Discussionmentioning

confidence: 99%

“…16 When given to healthy male volunteers, DX-9065a has been well tolerated, with no serious adverse events or clinically significant changes in routine laboratory assessments or bleeding time. 17,18 DX-9065a exhibits renal clearance, 17 and, in a study of single, increasing, intravenous doses of DX-9065a, peak plasma concentrations reached 1640 ng/mL in subjects receiving 30 mg over a period of 1 hour. 18 At these levels, Xa clotting time increased 3.9-fold; prothrombin time (PT), 2.9-fold; and activated partial thromboplastin time (aPTT), 2.1-fold.…”

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First Experience With Direct Factor Xa Inhibition in Patients With Stable Coronary Disease

et al. 2002

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Background-Thrombin generation is critical to the formation of an arterial thrombus after rupture of an atherosclerotic plaque. In patients with stable coronary disease receiving standard medical therapy, we evaluated the pharmacokinetics, pharmacodynamics, and safety profile of DX-9065a, a novel small-molecule anticoagulant that directly, selectively, and reversibly inhibits factor Xa. Methods and Results-In a double-blind trial, 73 patients (median age, 63 years; 29% women) were randomly assigned to receive a fixed-dose intravenous bolus, followed by a 72-hour infusion of placebo or 1 of 4 weight-adjusted regimens of DX-9065a. Plasma samples were collected during infusion and a 24-hour elimination period. Only minor bleeding occurred, predominantly ecchymoses at infusion sites, and its incidence did not differ significantly among the groups, including placebo. Median hemoglobin, platelet count, serum creatinine level, and liver function tests did not change significantly from baseline during infusion or elimination. Significant predictors of pharmacokinetic response included infusion dose and weight. At 60 hours into the DX-9065a infusion, plasma drug levels correlated strongly with anti-factor Xa activity (rϭ0.97), prothrombin time (rϭ0.77), and international normalized ratio (rϭ0.72) but less so with activated partial thromboplastin time (rϭ0.56; all PϽ0.001). Conclusions-This is the first study of a selective, reversible, and direct small-molecule factor Xa inhibitor in patients with stable coronary disease. These data lay the foundation for further investigation of factor Xa inhibitors in the treatment of patients with coronary atherothrombosis.

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First Experience With Direct Factor Xa Inhibition in Patients With Stable Coronary Disease

et al. 2002

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“…DX-9065a: A synthetic nonpeptidic direct factor Xa inhibitor, DX9065a is administered parentally, has a dose-dependent half-life that ranges from 40 min to 5 h, and is cleared by the kidneys. [109][110][111] DX9065a was evaluated in patients with non-ST-elevation ACS and in patients undergoing PCI. In the ACS trial, 402 patients were randomized to weight-adjusted heparin or to low-or high-dose DX-9065a.…”

Section: Factor Xa Inhibitorsmentioning

confidence: 99%

New Antithrombotic Drugs

Weitz

Eikelboom

Samama

2012

Chest

284

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“…This agent is a synthetic non-peptidic low-molecular weight inhibitor that binds reversibly to the active site of factor Xa (Herbert et al, 1996;Murayama et al, 1999). It has been shown to be effective in thrombosis models in laboratory animals.…”

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The status of new anticoagulants

Bates¹,

Weitz

2006

Br J Haematol

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SummaryCurrently available anticoagulants include heparin, lowmolecular weight heparin, fondaparinux and warfarin. Despite advances with low-molecular weight heparin and fondaparinux, the currently available agents have limitations that have provided the impetus for the development of new drugs for prevention and treatment of both venous and arterial thromboembolism. Novel anticoagulants targeting specific steps in coagulation are in various stages of development. This paper reviews the pharmacology of these new agents and describes the results of clinical trials with new anticoagulants in more advanced stages of clinical testing.

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Tolerability, pharmacokinetics, and pharmacodynamics of DX-9065a, a new synthetic potent anticoagulant and specific factor Xa inhibitor, in healthy male volunteers

Abstract: DX-9065a had a good correlation between linear pharmacokinetics and pharmacodynamics after intravenous administration in humans.

Cited by 51 publications

References 18 publications

First Experience With Direct Factor Xa Inhibition in Patients With Stable Coronary Disease

First Experience With Direct Factor Xa Inhibition in Patients With Stable Coronary Disease

New Antithrombotic Drugs

The status of new anticoagulants

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