Fraxiparine Mechanism of Action

Pharmacotherapeutic group: Antithrombotic agents - Heparin group. ATC Code: B01AB06.
Pharmacology: Pharmacodynamics: Mechanism of Action: Nadroparin is a low molecular weight heparin made by depolymerisation of standard heparin. It is a glycosaminoglycan with a mean molecular weight of approximately 4300 daltons.
Nadroparin exhibits a high-affinity binding to the plasma protein anti-thrombin III (ATIII). This binding leads to an accelerated inhibition of factor Xa, which contributes to the high antithrombotic potential of nadroparin.
Other mechanisms that contribute to the antithrombotic activity of nadroparin include stimulation of tissue factor pathway inhibitor (TFP1), activation of fibrinolysis via direct release of tissue plasminogen activator from endothelial cells, and the modification of haemorrheological parameters (decreased blood viscosity and increased platelet and granulocyte membrane fluidity).
Pharmacodynamic Effects: Nadroparin has a high ratio of anti-Xa to anti-IIa activity. It has both immediate and prolonged antithrombotic action.
Compared with unfractionated heparin, nadroparin has less effect on thrombocyte function and aggregation and only a slight effect on primary haemostasis.
Pharmacokinetics: The pharmacokinetic properties of nadroparin have been assessed on the basis of biological activity, i.e. measurement of anti-factor Xa activity.
Absorption: Following subcutaneous administration, the peak anti-Xa activity (C_max) is reached after approximately 3 to 5 hours (T_max). Bioavailability is almost complete (around 88%). After i.v. injection, the peak plasma anti-Xa level is reached within less than 10 minutes, and the half-life is around 2 hours.
Elimination: The elimination half-life after subcutaneous injection is approximately 3.5 hours. However, anti-Xa activity is detectable for at least 18 hours following an injection of 19000 anti-Xa IU.
Special Patient Populations: Elderly: Renal function generally decreases with age so elimination is slower in the elderly (see Renal Impairment as follows). The possibility of renal impairment in this age group must be considered and the dosage adjusted accordingly (see Dosage & Administration and Precautions).
Renal Impairment: In a clinical study investigating the pharmacokinetics of nadroparin administered intravenously in patients with varying degrees of renal impairment, a correlation was found between nadroparin clearance and the creatinine clearance. In patients with moderate renal impairment (creatinine clearance 36-43 ml/min), both mean AUC and half-life were increased by 52 and 39% respectively compared with healthy volunteers. In these patients, mean plasma clearance of nadroparin was decreased to 63% of normal. Wide inter-individual variability was observed in the study. In subjects with severe renal impairment (creatinine clearance 10-20 ml/min) both mean AUC and half-life were increased by 95 and 112% respectively compared with healthy volunteers. Plasma clearance in patients with severe renal impairment was decreased to 50% of that observed in patients with normal renal function. In subjects with severe renal impairment (creatinine clearance 3-6 ml/min) on haemodialysis, both mean AUC and half-life were increased by 62 and 65% respectively compared with healthy volunteers. Plasma clearance in haemodialysis patients with severe renal impairment was decreased to 67% of that observed in patients with normal renal function (see Dosage & Administration and Precautions).
Toxicology: Preclinical Safety Data: Preclinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeat dose toxicity, genotoxicity, mutagenic potential and reproductive toxicology.