Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

12.2 Pharmacodynamics
Doses of FRAGMIN Injection of up to 10,000 anti-Factor Xa IU administered subcutaneously as a single dose or two 5,000 IU doses 12 hours apart to healthy subjects did not produce a significant change in platelet aggregation, fibrinolysis, or global clotting tests such as prothrombin time (PT), thrombin time (TT) or APTT. Subcutaneous administration of doses of 5,000 IU twice daily of FRAGMIN for seven consecutive days to patients undergoing abdominal surgery did not markedly affect APTT, Platelet Factor 4 (PF4), or lipoprotein lipase.

Pharmacokinetic Properties

12.3 Pharmacokinetics


Adults
Mean peak levels of plasma anti-Xa activity following single subcutaneous doses of 2,500, 5,000 and 10,000 IU were 0.19 ± 0.04, 0.41 ± 0.07 and 0.82 ± 0.10 IU/mL, respectively, and were attained in about 4 hours in most subjects.
Absolute bioavailability in healthy volunteers, measured as the anti-Xa activity, was 87 ± 6%. Increasing the dose from 2,500 to 10,000 IU resulted in an overall increase in anti-Xa AUC that was greater than proportional by about one-third.
Peak anti-Xa activity increased more or less linearly with dose over the same dose range. There appeared to be no appreciable accumulation of anti-Xa activity with twice-daily dosing of 100 IU/kg subcutaneously for up to 7 days.
The volume of distribution for dalteparin anti-Xa activity was 40 to 60 mL/kg. The mean plasma clearances of dalteparin anti-Xa activity in normal volunteers following single intravenous bolus doses of 30 and 120 anti-Xa IU/kg were 24.6 ± 5.4 and 15.6 ± 2.4 mL/hr/kg, respectively. The corresponding mean disposition half-lives were 1.47 ± 0.3 and 2.5 ± 0.3 hours.
Following intravenous doses of 40 and 60 IU/kg, mean terminal half-lives were 2.1 ± 0.3 and 2.3 ± 0.4 hours, respectively. Longer apparent terminal half-lives (3 to 5 hours) are observed following subcutaneous dosing, possibly due to delayed absorption. In patients with chronic renal insufficiency requiring hemodialysis, the mean terminal half- life of anti-Xa activity following a single intravenous dose of 5,000 IU FRAGMIN was 5.7 ± 2.0 hours, i.e., considerably longer than values observed in healthy volunteers, therefore, greater accumulation can be expected in these patients.