title: Apixaban inhibition of factor Xa: Microscopic rate constants and inhibition mechanism in purified protein systems and in human plasma.
abstract: Apixaban is a potent, direct, selective, and orally active inhibitor of coagulation factor Xa. Rate constants for apixaban binding to free and prothrombinase-bound factor Xa were measured using multiple techniques. The inhibition mechanism was determined in purified systems and in a plasma prothrombin clotting time assay. Apixaban inhibits factor Xa with a K(i) of 0.25 nM at 37°C, an association rate constant of approximately 20 μM(-1) s(-1), and a dissociation half-life of 1-2 min. Under physiological conditions apixaban exhibits mixed-type inhibition and maintains high factor Xa affinity with a K(i) of 0.62 nM and association rate constant of 12 μM(-1) s(-1) for prothrombinase, and a K(i) of 1.7 nM and association rate constant of 4 μM(-1) s(-1) for the prothrombinase:prothrombin complex. Experiments in prothrombin depleted human plasma showed that the mechanism and kinetics of inhibition are maintained in plasma. The mechanistic detail derived from these experiments can be used to understand and interpret the pharmacodynamic action of apixaban.
authors.affiliation: Thrombosis Biology, Bristol-Myers Squibb Company, Pennington, NJ, USA. joseph.luettgen@bms.com
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Luettgen
authors.forename: Robert M
authors.initials: RM
authors.lastname: Knabb
authors.forename: Kan
authors.initials: K
authors.lastname: He
authors.forename: Donald J P
authors.initials: DJ
authors.lastname: Pinto
authors.forename: Alan R
authors.initials: AR
authors.lastname: Rendina
mesh_terms: D015951:Factor Xa / Q000378:metabolism; D065427:Factor Xa Inhibitors; D006801:Humans; D007700:Kinetics; D011720:Pyrazoles / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D011728:Pyridones / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D013925:Thromboplastin / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D065427:Factor Xa Inhibitors; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban; D013925:Thromboplastin; D015951:Factor Xa