Selective Factor Xa Inhibition Improves Efficacy of Venous Thromboembolism Prophylaxis in Orthopedic Surgery

Comp, Philip C.

doi:10.1592/phco.23.6.772.32190

Cited by 6 publications

(2 citation statements)

References 150 publications

(127 reference statements)

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“…Factor Xa forms the prothrombinase complex with phospholipids, calcium ions, and a cofactor, factor Va, which is responsible for the generation of thrombin from prothrombin. Although factor Xa inhibition attenuates the generation of thrombin, it does not affect thrombin activity, thereby preserving hemostasis, which, in clinical terms, may translate to efficacy with lower bleeding risk (Comp, 2003;Kubitza and Haas, 2006). Clinical proof of principle for the efficacy and potential of factor Xa inhibitors is available from fondaparinux, an indirect factor Xa inhibitor (Walenga et al, 1988;Samama and Gerotziafas, 2003;Simoons et al, 2004;Wong et al, 2006; Yusuf et al, 2006a,b;Schumacher et al, 2007) [prescribing information for Arixtra (fondaparinux sodium) injection, http://us.gsk.com/products/assets/ us_arixtra.pdf].…”

Section: Introductionmentioning

confidence: 99%

Apixaban Metabolism and Pharmacokinetics after Oral Administration to Humans

Raghavan¹,

Frost²,

Zhang³

et al. 2009

Drug Metabolism and Disposition

556

421

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ABSTRACT:The metabolism and disposition of [ 14 C]apixaban, an orally bioavailable, highly selective, and direct acting/reversible factor Xa inhibitor, was investigated in 10 healthy male subjects without (group 1, n ‫؍‬ 6) and with bile collection (group 2, n ‫؍‬ 4) after a single 20-mg oral dose. Urine, blood, and feces samples were collected from all subjects. Bile samples were also collected for 3 to 8 h after dosing from group 2 subjects. There were no serious adverse events or discontinuations due to adverse effects. In plasma, apixaban was the major circulating component and O-demethyl apixaban sulfate, a stable and water-soluble metabolite, was the significant metabolite. The exposure of apixaban (C max and area under the plasma concentration versus time curve) in subjects with bile collection was generally similar to that in subjects without bile collection. The administered dose was recovered in feces (group 1, 56.0%; group 2, 46.7%) and urine (group 1, 24.5%; group 2, 28.8%), with the parent drug representing approximately half of the recovered dose. Biliary excretion represented a minor elimination pathway (2.44% of the administered dose) from group 2 subjects within the limited collection period. Metabolic pathways identified for apixaban included O-demethylation, hydroxylation, and sulfation of hydroxylated O-demethyl apixaban. Thus, apixaban is an orally bioavailable inhibitor of factor Xa with elimination pathways that include metabolism and renal excretion.Thromboembolic events, including acute myocardial infarction, unstable angina, deep vein thrombosis, pulmonary embolism, and ischemic stroke continue to be the leading cause of morbidity and mortality in the United States and other Western countries (Heit et al., 2005;Rosamond et al., 2007). Current therapies for the treatment and prevention of thromboembolic events, such as vitamin K antagonists (e.g., warfarin), heparin, and low-molecular-weight heparin (e.g., enoxaparin), are suboptimal (O'Donnell and Weitz, 2004;Wittkowsky, 2004;Campbell, 2006). However, the requirement for intravenous or subcutaneous injection and/or the need for careful monitoring because of the risk of excessive bleeding or unpredictable/inconsistent pharmacokinetics (PK) can complicate administration and present barriers to the use of these agents (O'Brien and Caro, 2002;Wittkowsky, 2004;Campbell, 2006). Therefore, new, orally active anticoagulants with predictable pharmacokinetic profiles that can be administered with a reduced need for monitoring are needed.Factor Xa is a key serine protease in the coagulation cascade and is a promising target enzyme for new therapeutic agents for the treatment and prevention of arterial and venous thrombosis (Kaiser, 2002;Samama, 2002;Walenga et al., 2003). In particular, factor Xa plays a critical role in blood coagulation, serving as the juncture between the extrinsic (tissue factor initiated) and intrinsic (surface activation and amplification) systems (Mann et al., 2003). Factor Xa forms the prothrombinase complex with phospholi...

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Section: Introductionmentioning

confidence: 99%

Apixaban Metabolism and Pharmacokinetics after Oral Administration to Humans

Raghavan¹,

Frost²,

Zhang³

et al. 2009

Drug Metabolism and Disposition

556

421

View full text Add to dashboard Cite

show abstract

“…Factor Xa forms the prothrombinase complex with phospholipids, calcium ions, and a cofactor, factor Va, which is responsible for the generation of thrombin from prothrombin. Although factor Xa inhibition attenuates the generation of thrombin, it does not affect thrombin activity, thereby preserving hemostasis, which, in clinical terms, may translate to efficacy with lower bleeding risk (Comp, 2003;Kubitza and Haas, 2006). Indeed, studies have shown that factor Xa inhibitors interrupt thrombus growth in large blood vessels under low shear (venous thrombosis) and high shear (arterial thrombosis) conditions, with minimal disruption of normal hemostasis, suggesting the suitability of such agents in the management of both venous and arterial thromboembolic disorders (Orvim et al, 1995;Shimbo et al, 2002).…”

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confidence: 99%