Apixaban Metabolism and Pharmacokinetics after Oral Administration to Humans

Abstract

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...

Spontaneous rectus sheath hematoma in a patient treated with apixaban

“…The situation is further complicated by the absence of specific antidotes to these oral anticoagulants; this makes management of above mentioned bleeding complications extremely difficult because only follow up supportive treatment can be offered to the patient (3). The half life of apixaban is 12 hours and about 25% of the drug is renally excreted (4). For this reason supportive treatment and follow up of apixaban treated patients is very crucial.…”

Nuevos anticoagulantes orales: actualización

“…La excreción es mayoritariamente fecal, siendo sólo 25% por vía renal. 21 -Edoxabán: Su máximo plasmático es en 1-2 horas, y acción máxima anti-FXa en 1.5hs. Su T½ y biodisponibilidad son de 10-14 horas y 62%, respectivamente.…”

Pharmacological profile of non-vitamin K antagonist oral anticoagulants

“…The majority of the recovered dose is in feces and biliary clearance is a minor apixaban elimination pathway (<5% of dose). Intestinal secretion of this NOAC also occurs (Wong et al, 2011;Raghavan et al, 2009). …”

“…For factor Xa inhibition, apixaban decreases thrombin production and the development of thrombi (Figure 1). It has no direct effect on platelet aggregation, nonetheless indirectly inhibits aggregation of platelet induced by thrombin (FDA, 2016;Raghavan et al, 2009). …”