Safety, pharmacokinetics, and pharmacodynamics of PD 0348292, an oral, direct factor Xa inhibitor, after single and multiple dosings in healthy subjects

Xuan, Dawei; McBride, Scott; Wastall, Philip; Porcari, Anthony R.; DiCarlo, Lorenzo A.; Boyd, Rebecca A.

doi:10.1002/cpdd.232

Cited by 4 publications

(3 citation statements)

References 24 publications

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“…26 In a subsequent publication, Xuan et al published the results of three phase I trials on healthy subjects, the first two single ascending-dose studies with randomization to oral eribaxaban (dosage between 2.5-150 mg and 0.1-2.5 mg, respectively) or placebo, while the remaining was a multiple ascending-dose study based on young subjects receiving different dosage of eribaxaban (between 5 and 30 mg) or placebo, along with a cohort of elderly people who instead received 5 mg eribaxaban or placebo. 36 In all studies, a consistent and dose-dependent inhibition (from 4-to 11fold) of thrombin generation was noted, while a modest effect was noted on routine coagulation tests. A single dose was well tolerated in both young and elderly subjects.…”

Section: Eribaxabanmentioning

confidence: 67%

“…35 The peak concentration is usually reached between 3 and 4 hours after administration, while the half-life is approximately 10 hours and nearly 16 to 35% of the drug is excreted with urine. 36 Earlier studies showed that this drug was effective to inhibit arterial thrombosis, with effect comparable to that of aspirin plus clopidogrel. 37,38 Later on, Cohen et al performed a phase II, adaptive dose-ranging study, encompassing the assessment of 100-fold dose range eribaxaban administration in 1,411 patients undergoing total knee replacement.…”

Section: Eribaxabanmentioning

confidence: 99%

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Current and Emerging Direct Oral Anticoagulants: State-of-the-Art

Lippi

Gosselin

Favaloro

2019

Semin Thromb Hemost

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Anticoagulant drugs comprise a specific subcategory of antithrombotic agents that act to inhibit blood coagulation at various stages, reducing clot development and ultimately lowering the risk of developing new-onset or recurrent thrombosis. Although the long history of anticoagulant drugs has been characteristically shaped by coumarin and heparin derivatives, a new generation of direct oral anticoagulants (DOACs), which specifically inhibit thrombin or activated factor X, combine many advantages of their progenitor drugs, and hence are prepotently revolutionizing the landscape of antithrombotic therapy. Several drugs (apixaban [BMS-562247], dabigatran [BIBR953], edoxaban [DU-1766], rivaroxaban [BAY 59–7939]) have already received widespread approval by national or supranational medicinal agencies. This narrative article provides a state-of-the-art for these and for several other DOACs at different stages of clinical evaluation (betrixaban, darexaban, eribaxaban, letaxaban, nokxaban), and certain others whose development has been discontinued (AZD-0837, fidexaban, LY517717, odiparcil, otamixaban, TTP889, and ximelagatran). What clearly emerges from our analysis is that DOACs sharing very similar mechanisms of action are still characterized by different efficacy and safety profiles. This not only depends on biochemical, biological, and pharmacokinetic characteristics, but also on lack of standardization between different clinical trials in terms of targeted disease, patient recruitment, sample size, duration and endpoints, as well as lack of harmonization around procedures used for drug licensing. These factors contribute to challenging the minds of physicians, who may find difficulty navigating their way through multiple indications, different pharmacological profiles, various side effects, and specific drug-to-drug interactions. Such considerations also burden laboratory professionals, who may face organizational and economic challenges in developing and/or implementing multiple assays to assess the pharmacodynamics (effect on coagulation) or pharmacokinetics (drug levels) of DOACs.

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Section: Eribaxabanmentioning

confidence: 67%

Section: Eribaxabanmentioning

confidence: 99%

Current and Emerging Direct Oral Anticoagulants: State-of-the-Art

Lippi

Gosselin

Favaloro

2019

Semin Thromb Hemost

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“…PD 0348292 is an oral, selective, direct and reversible FXa inhibitor that was safe and well tolerated at a wide range of doses studied in early clinical single‐ and multiple‐dose trials . The pharmacokinetics of PD 0348292 are linear and time‐independent over a dose range of 0.l mg to 10 mg and the terminal half‐life is approximately 10 h. The objectives of this dose‐ranging study were to characterize the dose‐response relationship of PD 0348292 with respect to VTE prevention and bleeding endpoints in subjects undergoing an elective, unilateral TKR and to estimate the dose equivalent to enoxaparin 30 mg bid for efficacy.…”

Section: Introductionmentioning

confidence: 99%

An adaptive‐design dose‐ranging study of PD 0348292, an oral factor Xa inhibitor, for thromboprophylaxis after total knee replacement surgery

Cohen

Boyd

Mandema³

et al. 2013

Journal of Thrombosis and Haemostasis

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study of PD 0348292, an oral factor Xa inhibitor, for thromboprophylaxis after total knee replacement surgery. J Thromb Haemost 2013; 11:1503-10.Summary. Background: PD 0348292 is an oral, selective, direct and reversible factor Xa inhibitor. This was an adaptive dose-ranging study evaluating a 100-fold PD 0348292 dose range in subjects undergoing total knee replacement (TKR). Objective: To assess the efficacy and safety of a dose range of PD 0348292 relative to enoxaparin for the prevention of venous thromboembolism (VTE). Methods: Extensive dose-response modeling and trial simulations were used to select the PD 0348292 dose range for the Phase 2 study. Subjects were randomized to a blinded PD 0348292 dose (0.1 mg qd to 10 mg qd) or open-label enoxaparin (30 mg bid) for 6-14 days after TKR surgery. Efficacy was assessed by mandatory bilateral venography. Results were analyzed using a dose-response modeling approach. Results: Observed VTE frequency ranged from 1.4-37.1% across PD 0348292 doses and was 18.1% for enoxaparin. The PD 0348292 dose-response relationship for VTE was statistically significant (P < 0.0001). The dose of PD 0348292 equivalent to enoxaparin 30 mg bid for VTE prevention was estimated to be 1.16 mg (95% CI = 0.56 mg, 2.41 mg) qd. Total bleeding ranged from 4.9% to 13.8% across PD 0348292 doses and was 6.3% with enoxaparin. The dose-response relationship for total bleeding was not statistically significant (P = 0.2464). Overall, PD 0348292 and enoxaparin were well tolerated. Conclusion: Characterization of the dose-response relationship for VTE and bleeding using an adaptive Phase 2 study design provided a strong quantitative basis for Phase 3 dose selection.

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New anticoagulants for venous thromboembolism and atrial fibrillation: what the future holds

Dimitropoulos

Rahim

Moss

et al. 2017

Expert Opinion on Investigational Drugs

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The field of anticoagulation has seen impressive progress over the last decade. The introduction of the Non Vitamin K Oral Anticoagulants (NOACs) has revolutionized practice surrounding thromboprophylaxis, treatment of thromboembolic disease and stroke prevention in atrial fibrillation (AF). However, the search for the 'holy grail' of anticoagulation, an agent that combines optimal efficacy with minimal bleeding diathesis, continues. Areas covered: In this paper we aim to summarize the current evidence from pre-clinical studies and early phase clinical trials, presenting the pharmacodynamic and pharmacokinetic properties as well as the safety and efficacy profiles of the most important antithrombotic agents in development. Expert opinion: Research focused on the development of new anticoagulation agents is rapidly expanding. Although the exploration of antithrombotic agents that act on well-established targets such factor Xa and thrombin remains the mainstay, attention has also shifted to other factors in the coagulation cascade. The evidence emerging from clinical research is growing, generating exciting possibilities in the field of anticoagulation.

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Safety, pharmacokinetics, and pharmacodynamics of PD 0348292, an oral, direct factor Xa inhibitor, after single and multiple dosings in healthy subjects

Abstract: The safety, pharmacokinetics, and pharmacodynamics of PD 0348292 were acceptable for future clinical development.

Cited by 4 publications

References 24 publications

Current and Emerging Direct Oral Anticoagulants: State-of-the-Art

Current and Emerging Direct Oral Anticoagulants: State-of-the-Art

An adaptive‐design dose‐ranging study of PD 0348292, an oral factor Xa inhibitor, for thromboprophylaxis after total knee replacement surgery

New anticoagulants for venous thromboembolism and atrial fibrillation: what the future holds

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