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| Primary information |
|---|
| ID | 15509 |
| Therapeutic ID | Th1604 |
| Protein Name | Andexanet alfa |
| Sequence | >Th1604_Andexanet_alfa
ANSFLFWNKYKDGDQCETSPCQNQGKCKDGLGEYTCTCLEGFEGKNCELFTRKLCSLDNGDCDQFCHEEQNSVVCSCARGYTLADNGKACIPTGPYPCGKQTLERRKRRKRIVGGQECKDGECPWQALLINEENEGFCGGTILSEFYILTAAHCLYQAKRFKVRVGDRNTEQEEGGEAVHEVEVVIKHNRFTKETYDFDIAVLRLKTPITFRMNVAPACLPERDWAESTLMTQKTGIVSGFGRTHEKGRQSTRLKMLEVPYVDRNSCKLSSSFIITQNMFCAGYDTKQEDACQGDAGGPHVTRFKDTYFVTGIVSWGEGCARKGKYGIYTKVTAFLKWIDRSMKTRGLPKAKSHAPEVITSSPLK
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| Molecular Weight | NA |
| Chemical Formula | NA |
| Isoelectric Point | NA |
| Hydrophobicity | NA |
| Melting point | NA |
| Half-life | The elimination half-life ranges from 5 to 7 hours [L3725]. |
| Description | Andexanet alfa is a recombinant human coagulation Factor Xa that promotes blood coagulation. It was developed by Portola Pharmaceuticals and was approved in in May 2018. It is marketed as Andexxa for intravenous injection or infusion and is indicated for the reversal of anticoagulation in combination with [rivaroxaban] and [apixaban] in cases of life-threatening or uncontrolled bleeding. Rivaroxaban and apixaban are Factor Xa inhibitors that promote anticoagulation in situations where blood clotting is unfavourable, such as in deep vein thrombosis and pulmonary embolism. However, the use of these agents is associated with a risk for uncontrollable bleeding episodes that can lead to can cause serious or fatal bleeding. Andexanet alfa is currently under regulatory review by the European Union and is undergoing clinical development in Japan [A35518]. Andexanet alfa works by binding to Factor Xa inhibitors and prevent them from interacting with endogenous Factor Xa. It displayed high affinity (0.53–1.53 nmol/L) to apixaban, betrixaban, edoxaban and rivaroxaban [A35518]. However, the effectiveness of andexanet alfa on treating bleeding related to any FXa inhibitors other than apixaban and rivaroxaban was not demonstrated, thus such use is limited [L3725]. Its pharmacokinetic properties are not reported to be affected by factor Xa inhibitors [A35518]. Andexanet alfa retains the structural similarity to that of endogenous human factor Xa, but exists in its mature functional form without the need for activation via the intrinsic or extrinsic coagulation pathways [A35558] and remains catalytically inactive due to structural modification [A35518]. The procoagulation potential of andexanet alfa is eliminated through the removal of a 34-residue fragment containing Gla: via this truncation, andexanet alfa is unable to bind to membrane surfaces and assemble the prothrombinase complex [A35558]. It also prevents andexanet alfa from taking up space on phospholipid surface membranes, so that native FXa may bind and assemble the prothrominase complex [A35558]. The amino acid residue modification from serine to alanine in the binding site of the catalytic domain allows more effective binding to FXa inhibitors and deters the andexanet alfa from converting prothrombin to thrombin [A35558]. |
| Indication/Disease | Andexanet alfa is indicated for patients treated with [rivaroxaban] and [apixaban], when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding [L3725]. Andexxa has not been shown to be effective for, and is not indicated for, the treatment of bleeding related to any Factor Xa inhibitors other than apixaban and rivaroxaban [L3725]. |
| Pharmacodynamics | _In vitro_, andexanet alfa was shown to dose-dependently reverse the activity of apixaban, betrixaban, edoxaban, rivaroxaban, enoxaparin and fondaparinux on Factor Xa in human and rat plasma [A35518]. In a randomized placebo-controlled study of healthy elderly volunteers, co-administration of andexanet alfa bolus with 5 mg of apixaban twice daily resulted in a reduction of anti-factor Xa activity by 94% compared to 21% among those who received placebo, and thrombin generation was fully restored in 100% [A35519]. The anti-factor Xa activity was reduced by 92% and thrombin generation was fully restored in 96% of the subjects upon andexanet alfa bolus administration in subjects receiving 20 mg of rivaroxaban daily [A35519]. A multicenter, prospective, open-label, single-group study involving elderly patients with acute major bleeding within 18 hours after the administration of a factor Xa inhibitor was performed. In this study, the median anti-factor Xa activity in patients receiving rivaroxaban and apixaban was reduced by 89% and 93%, respectively, upon administration of andexanet alfa infusion [A35520]. In dose-ranging studies of healthy volunteers, the anti-FXa activity activity was observed within two minutes after the completion of the bolus administration. Elevation of Tissue Factor (TF)-initiated thrombin generation above the baseline range (prior to anticoagulation) occurred within two minutes following a bolus administration of andexanet alfa and was maintained throughout the duration of the continuous infusion [L3725]. The anti-FXa activity returned to the placebo levels approximately 2 hours after completion of a bolus or continuous infusion [L3725]. In contrast, TFPI activity in plasma was sustained for at least 22 hours following andexanet alfa administration [L3725]. |
| Mechanism of Action | Factor Xa inhibitors promote anticoagulation by binding to both free Factor Xa in plasma and Factor Xa attached to the prothrombinase complex. This ultimately leads to the blockade of thrombin generation or clot formation [A27288]. Andexanet alfa is a factor Xa decoy that binds to factor Xa inhibitors such as apixaban and rivaroxaban with high affinity and prevents them from binding to endogenous factor Xa. It was also shown to sequester factor Xa inhibitors, leading to reversing their anticoagulant effects and restoring the activity of endogenous factor Xa [A35518]. Andexanet alfa may also achieve procoagulation via binding and inhibiting the activity of Tissue Factor Pathway Inhibitor (TFPI), which is an endogenous inhibitor of Factor Xa [A35518]. Inhibition of TFPI by andexanet alfa resulted in a transient increase in the level of prothrombin fragments 1 and 2, thrombin-antithrombin complex and D-dimer [A35518]. Subsequently, this may result in increased tissue factor-initiated thrombin generation [L3725]. Since it is a genetically modified variant of human factor Xa, andexanet alfa is not able to cleave and activate prothrombin nor assemble into the prothrombinase complex [A35518]. |
| Toxicity | NA |
| Metabolism | There is limited information regarding the metabolism of andexanet alfa [A35558]. |
| Absorption | Following intravenous administration of bolus doses > 30 mg in healthy subjects, the exposure of andexanet alfa increased in a dose-dependent manner. |
| The volume of distribution (Vd) for andexanet alfa is approximately equivalent to the blood volume of 5 L [L3725]. |
| Clearance | Clearance for andexanet alfa is approximately 4.3 L/hr [L3725]. |
| Categories | Blood Coagulation Factors |
| Patents Number | NA |
| Date of Issue | NA |
| Date of Expiry | NA |
| Drug Interaction | NA |
| Target | Tissue factor pathway inhibitor |
| Brand Name | NA |
| Company | NA |
| Brand Description | NA |
| Prescribed For | NA |
| Chemical Name | NA |
| Formulation | NA |
| Physical Appearance | NA |
| Route of Administration | NA |
| Recommended Dosage | NA |
| Contraindication | NA |
| Side Effects | NA |
| Useful Link 1 | Link |
| Useful Link 2 | NA |
| Remarks | NA |