Arixtra Mechanism of Action

The antithrombotic activity of fondaparinux is the result of antithrombin III (ATIII) mediated selective inhibition of Factor Xa. By binding selectively to ATIII, fondaparinux potentiates (about 300 times) the innate neutralization of Factor Xa by ATIII. Neutralisation of Factor Xa interrupts the blood coagulation cascade and inhibits both thrombin formation and thrombus development. Fondaparinux does not inactivate thrombin (activated Factor II) and has no known effect on platelet function.
Pharmacology: Pharmacodynamics: At the 2.5 mg dose, fondaparinux does not have a clinically relevant affect on routine coagulation tests, such as activated partial thromboplastin time (aPTT), activated clotting time (ACT) or prothrombin time (PT)/International Normalised Ratio (INR) tests in plasma, nor bleeding time or fibrinolytic activity. However, rare spontaneous reports of elevated aPTT have been received at the 2.5 mg dose. Fondaparinux does not cross-react with sera from patients with Heparin Induced Thrombocytopenia (HIT) type II.
Anti-Xa activity: The pharmacodynamics/pharmacokinetics of fondaparinux are derived from fondaparinux plasma concentrations quantified via anti factor Xa activity. Only fondaparinux can be used to calibrate the anti-Xa assay. The international standards of heparin or low molecular weight heparin (LMWH) are not appropriate for this use. As a result, the concentration of fondaparinux is expressed as milligrams of the fondaparinux calibrator/litre.
Pharmacokinetics: Absorption: After subcutaneous dosing, fondaparinux is completely and rapidly absorbed (absolute bioavailability 100%). Following a single subcutaneous injection of ARIXTRA 2.5 mg to young healthy subjects, peak plasma concentration, mean C_max of 0.34 mg/L, is reached in approximately 2 hours. Plasma concentrations of half the mean C_max values are reached 25 min post-dosing.
In elderly healthy subjects, pharmacokinetics of fondaparinux are linear in the range of 2 to 8 mg by subcutaneous route. Following once daily subcutaneous dosing, steady state of plasma levels is obtained after 3 to 4 days with a 1.3-fold increase in C_max and AUC. Following a single i.v. bolus administration to healthy elderly subjects, the pharmacokinetics of fondaparinux are linear over the therapeutic range.
In patients undergoing hip replacement surgery receiving ARIXTRA 2.5 mg once daily subcutaneously, the peak steady-state plasma concentration is, on average, 0.39 to 0.50 mg/L and is reached approximately 3 hours post-dose. In these patients, the minimum steady-state plasma concentration is 0.14 to 0.19 mg/L.
In patients with symptomatic deep vein thrombosis and pulmonary embolism undergoing treatment with ARIXTRA 5 mg (body weight less than 50 kg), 7.5 mg (body weight 50 to 100 kg) and 10 mg (body weight greater than 100 kg) subcutaneously once daily, the body weight adjusted doses provide similar mean steady-state peaks and minimum plasma concentrations across all body weight categories. The mean peak steady-state plasma concentration is in the range of 1.20 to 1.26 mg/L. In these patients, the mean minimum steady-state plasma concentration is in the range of 0.46 to 0.62 mg/L.
Distribution: In healthy adults, intraveneously or subcutaneously administered fondaparinux distributes mainly in blood and only to a minor extent in extravascular fluid, as demonstrated by steady state and non steady state apparent volume of distribution of 7 to 11 L. In vitro, fondaparinux is highly (at least 94%) and specifically bound to antithrombin III (ATIII) and does not bind significantly to other plasma proteins, including platelet Factor 4 (PF4) or red blood cells.
Metabolism: In vivo metabolism of fondaparinux has not been investigated since the majority of the administered dose is eliminated unchanged in urine in individuals with normal kidney function.
Elimination: Fondaparinux is eliminated in urine mainly as unchanged drug. In healthy individuals, 64 to 77% of a single subcutaneous or intravenous dose is eliminated in urine in 72 hours. The elimination half-life is about 17 hours in healthy young subjects and about 21 hours in healthy elderly subjects. In patients with normal renal function, the mean fondaparinux clearance is 7.82 mL/min.
Special Patient Populations: Renal impairment: Fondaparinux elimination is prolonged in patients with renal impairment since the major route of elimination is urinary excretion of unchanged drug. In patients undergoing prophylaxis following elective hip surgery or hip fracture surgery, the total clearance of fondaparinux is approximately 25% lower in patients with mild renal impairment (creatinine clearance 50 to 80 mL/min), approximately 40% lower in patients with moderate renal impairment (creatinine clearance 30 to 50 mL/min) and approximately 55% lower in patients with severe renal impairment (less than 30 mL/min), compared to patients with normal renal function. The associated terminal half-life values were 29 hours in moderate and 72 hours in patients with severe renal impairment. A similar relationship between fondaparinux clearance and extent of renal impairment was observed in DVT treatment patients.
Prevention of VTE: A population pharmacokinetic model was developed using data obtained from patients undergoing major orthopaedic surgery of the lower limbs (MOSLL) receiving fondaparinux and included patients with creatinine clearance as low as 23.5 mL/min. Pharmacokinetic simulations using this model showed that predicted average exposures of fondaparinux in patients with creatinine clearance between 20-30 mL/min receiving 2.5 mg on alternate days were similar to those seen in patients with mild to moderate renal impairment (creatinine clearance 30 to 80 mL/min) receiving 2.5 mg once daily (see Dosage & Administration and Precautions).
Hepatic impairment: Unbound concentrations of fondaparinux are expected to be unchanged in patients with mild to moderate hepatic impairment, and therefore, no dose adjustment is necessary based on pharmacokinetics. Following a single, subcutaneous dose of fondaparinux in subjects with moderate hepatic impairment (Child-Pugh Category B), C_max and AUC were decreased by 22% and 39%, respectively, as compared to subjects with normal liver function. The lower plasma concentrations of fondaparinux were attributed to reduced binding to ATIII secondary to the lower ATIII plasma concentrations in subjects with hepatic impairment thereby resulting in increased renal clearance of fondaparinux.
The pharmacokinetics of ARIXTRA has not been studied in patients with severe hepatic impairment (see Dosage & Administration and Precautions).
Elderly: Fondaparinux elimination is prolonged in patients over 75 years old. In studies evaluating ARIXTRA 2.5 mg prophylaxis in hip fracture surgery or elective hip surgery, the total clearance of fondaparinux was approximately 25% lower in patients over 75 years old as compared to patients less than 65 years old. A similar relationship between fondaparinux clearance and age was observed in DVT treatment patients.
Gender: No gender differences were observed after adjustment for body weight.
Race: Pharmacokinetic differences due to race have not been studied prospectively. However, studies performed in Asian (Japanese) healthy subjects did not reveal a different pharmacokinetic profile compared to Caucasian healthy subjects. Similarly, based on the results of population pharmacokinetic analysis conducted in patients undergoing orthopaedic surgery, no plasma clearance differences were observed between black and Caucasian patients.
Body weight: In patients weighing less than 50 kg the total clearance of fondaparinux sodium is decreased by approximately 30% (see Precautions).