Genexiban Mechanism of Action

Pharmacology: Apixaban is a potent, oral, reversible, direct and highly selective active site inhibitor of factor Xa. It does not require antithrombin III for antithrombotic activity. Apixaban inhibits free and clot-bound factor Xa, and prothrombinase activity. Apixaban has no direct effects on platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin. By inhibiting factor Xa, apixaban prevents thrombin generation and thrombus development. Preclinical studies of apixaban in animal models have demonstrated antithrombotic efficacy in the prevention of arterial and venous thrombosis at doses that preserved haemostasis.
Pharmacodynamics: The pharmacodynamic effects of apixaban are reflective of the mechanism of action (FXa inhibition). As a result of FXa inhibition, apixaban prolongs clotting tests such as prothrombin time (PT), INR and activated partial thromboplastin time (aPTT). Changes observed in these clotting tests at the expected therapeutic dose are small and subject to a high degree of variability. They are not recommended to assess the pharmacodynamic effects of apixaban. In the thrombin generation assay, apixaban reduced endogenous thrombin potential, a measure of thrombin generation in human plasma.
Pharmacokinetics: Apixaban demonstrates linear pharmacokinetics with dose-proportional increases in exposure for oral doses up to 10 mg.
Absorption: The absolute bioavailability of apixaban is approximately 50% for doses up to 10 mg. Apixaban is rapidly absorbed with maximum concentrations (Cmax) appearing 3 to 4 hours after tablets intake. Intake with food does not affect apixaban AUC or Cmax at the 10 mg dose. Apixaban can be taken with or without food. Apixaban demonstrates linear pharmacokinetics with dose proportional increases in exposure for oral doses up to 10 mg. At doses ≥25 mg, apixaban displays dissolution limited absorption with decreased bioavailability. Apixaban exposure parameters exhibit low to moderate variability reflected by a within-subject and inter-subject variability of ~20% CV and ~30% CV respectively. Following oral administration of 10 mg of apixaban as 2 crushed 5 mg tablets suspended in 30 mL of water, exposure was similar to that after oral administration of 2 intact 5 mg tablets. Following oral administration of 10 mg of apixaban as 2 crushed 5 mg tablets mixed with 30 g of applesauce, the Cmax and AUC were 20% and 16% lower, respectively, when compared to administration of 2 intact 5 mg tablets. Following administration of a crushed 5 mg apixaban tablet that was suspended in 60 mL D5W and delivered through a nasogastric tube, exposure was similar to that seen in other clinical trials involving healthy volunteers receiving a single oral 5 mg tablet dose.
Distribution: Plasma protein binding in humans is approximately 87%. The volume of distribution (Vss) is approximately 21 liters.
Metabolism: Apixaban has multiple routes of elimination. Of the administered apixaban dose in humans, approximately 25% was recovered as metabolites, with the majority recovered in feces. Apixaban is metabolized mainly via CYP3A4 with minor contributions from CYP1A2, 2C8, 2C9, 2C19, and 2J2. O-demethylation and hydroxylation at the 3-oxopiperidinyl moiety are the major sites of biotransformation. Unchanged apixaban is the major drug-related component in human plasma; there are no active circulating metabolites.
Elimination: Apixaban is eliminated in both urine and feces. Renal excretion accounts for about 27% of total clearance. Additional contributions from biliary and direct intestinal excretion were observed in clinical and nonclinical studies, respectively. Apixaban has a total clearance of approximately 3.3 L/hour and an apparent half-life of approximately 12 hours following oral administration.
Apixaban is a substrate of transport proteins, P-gp and breast cancer resistance protein.
Drug interaction studies: In in vitro apixaban studies at concentrations significantly greater than therapeutic exposures, no inhibitory effect on the activity of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6, CYP3A4/5, or CYP2C19, nor induction effect on the activity of CYP1A2, CYP2B6, or CYP3A4/5 were observed. Therefore, apixaban is not expected to alter the metabolic clearance of co-administered drugs that are metabolized by these enzymes. Apixaban is not a significant inhibitor of P-gp. The effects of co-administered drugs on the pharmacokinetics of apixaban are summarized in Figure 1. (See Figure 1.)

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In dedicated studies conducted in healthy subjects, famotidine, atenolol, prasugrel, and enoxaparin did not meaningfully alter the pharmacokinetics of apixaban.
In studies conducted in healthy subjects, apixaban did not meaningfully alter the pharmacokinetics of digoxin, naproxen, atenolol, prasugrel, or acetylsalicylic acid. (See Figure 2.)

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Gender: A study in healthy subjects comparing the pharmacokinetics in males and females showed no meaningful difference.
Race: The results across pharmacokinetic studies in normal subjects showed no differences in apixaban pharmacokinetics among White/Caucasian, Asian, and Black/African American subjects. No dose adjustment is required based on race/ethnicity.
Hemodialysis in ESRD subjects: Systemic exposure to apixaban administered as a single 5 mg dose in ESRD subjects dosed immediately after the completion of a 4-hour hemodialysis session (postdialysis) is 36% higher when compared to subjects with normal renal function (Figure 2).
The systemic exposure to apixaban administered 2 hours prior to a 4-hour hemodialysis session with a dialysate flow rate of 500 mL/min and a blood flow rate in the range of 350 to 500 mL/min is 17% higher compared to those with normal renal function. The dialysis clearance of apixaban is approximately 18 mL/min. The systemic exposure of apixaban is 14% lower on dialysis when compared to not on dialysis. Protein binding was similar (92%-94%) between healthy controls and ESRD subjects during the on-dialysis and off-dialysis periods.