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The SARfaris: GPCR, Kinase, ADME

Saturday, 12 January 2013

New Drug Approvals 2012 - Pt. XXXIII - Apixaban (ELIQUIS®)

ATC code : B01AF02
Wikipedia : Apixaban

On December 28, FDA approved Apixaban (Trade Name: ELIQUIS®; ChEMBLCHEMBL231779KEGGD03213; ChemSpider8358471; DrugBankDB07828; PubChemCID 10182969) as an anticoagulant for prevention of venous thromboembolism and related events, indicated to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation. 

Atrial fibrillation (AF) is most common cardiac arrhythmia (irregular heart beat). There are many classes of AF according to American College of Cardiology (ACC), American Heart Association (AHA) and the European Society of Cardiology (ESC) one of which is non-valvular AF - absence of rheumatic mitral valve disease, a prosthetic heart valve, or mitral valve repair (AF which not caused by a heart valve problem). Usually AF increases the degree of stroke risk, can be up to seven times that of the average population. AF is one of the major cardiogenic risk factors for stroke. For instance, patients with inappropriate or abnormal blood clotting (coagulation disorder) will result in clot formation in heart which can easily find their way into the brain, resulting in stroke.

Coagulation (thrombogenesis) is the process by which blood forms clots. Coagulation cascade has two pathways which lead to fibrin formation, they are intrinsic pathway and extrinsic pathway. The pathways are a series of reactions, in which a zymogen of a serine protease and its glycoprotein co-factor are activated to become active components that then catalyze the next reaction in the cascade, ultimately resulting in cross-linked fibrin. Apixaban belongs to Direct factor Xa inhibitors ('xabans') class of anticoagulant drugs, which directly acts on Factor X (FX) in the coagulation cascade without antithrombin as mediator. 

Apixaban is reversible and selective active site inhibitor of Factor Xa (FXa) . It does not require antithrombin III for antithrombotic activity. Apixaban inhibits free and clot-bound FXa, and prothrombinase activity. Apixaban has no direct effect on platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin. By inhibiting FXa, apixaban decreases thrombin generation and thrombus development.

The PDBe entry (PDBe : 2p16) for the crystal structure for human Factor X (chain A & chain L) in complex with Apixaban (blue-green - molecule shaped) is shown above.

IUPAC Name : 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide
Canonical SMILES : COc1ccc(cc1)n2nc(C(=O)N)c3CCN(C(=O)c23)c4ccc(cc4)N5CCCCC5=O
Standard InChI : 1S/C25H25N5O4/c1-34-19-11-9-18(10-12-19)30-23-20(22(27-30)24(26)32)13-15-29(25(23)33)17-7-5-16(6-8-17)28-14-3-2-4-21(28)31/h5-12H,2-4,13-15H2,1H3,(H2,26,32)

Apixaban is available for oral administration at doses of 2.5 mg and 5 mg. It displays prolonged absorption with bioavailability of ~50% for doses up to 10 mg. Plasma protein binding was estimated to be ~87% and Vss is ~21 liters. Apixaban is metabolized by mainly via CYP3A4 with minor contributions from CYP1A2, CYP2C8, CYP2C9, CYP2C19 and CYP2J2. Approximately 25% of Apixaban is recovered in urine and faeces. Despite a short clearance half-life about 6 hrs, apparent half-life is 12 hrs, due to prolonged absorption phase; renal excretion accounts to 27% of the clearance.

Apixaban comes with a boxed warning for risks and remedies while discontinuing drug. There is one other direct factor Xa inhibitor approved by FDA in 2011, Rivaroxaban (ChEMBL : CHEMBL198362, ATC code  : B01AX06, PubChem : CID6433119), was "first in class" FXa inhibitor (can be accessed by one of our old blog posts, here) which had similar boxed warning along with spinal/epidural hematoma in surgical settings.

The license holder is Bristol-Myers Squibb, and the product website is

Full prescribing information can be found here.


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