(dalteparin sodium)
Dalteparin is a low molecular weight heparin with antithrombotic properties. It acts by enhancing the inhibition of Factor Xa and thrombin by antithrombin. In humans, dalteparin potentiates preferentially the inhibition of coagulation Factor Xa, while only slightly affecting the activated partial thromboplastin time (APTT).
Doses of FRAGMIN Injection of up to 10,000 anti-Xa units administered subcutaneously as a single dose or two 5,000 units 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 units 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.
Adults
Mean peak levels of plasma anti-Xa activity following single subcutaneous doses of 2,500 units, 5,000 units and 10,000 units were 0.19 ± 0.04 units/mL, 0.41 ± 0.07 units/mL and 0.82 ± 0.10 units/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 units to 10,000 units 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 units/kg subcutaneously for up to 7 days.
The volume of distribution for dalteparin anti-Xa activity was 40 mL/kg 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 units/kg were 24.6 ± 5.4 mL/hr/kg and 15.6 ± 2.4 mL/hr/kg, respectively. The corresponding mean disposition half-lives were 1.47 ± 0.3 hours and 2.5 ± 0.3 hours.
Following intravenous doses of 40 units/kg and 60 units/kg, mean terminal half-lives were 2.1 ± 0.3 hours and 2.3 ± 0.4 hours, respectively. Longer apparent terminal half-lives (3 hours 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 units 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.
Pediatric Patients
The pharmacokinetics of twice-daily subcutaneous dalteparin, measured as anti-Xa activity, was characterized in 89 pediatric patients with or without cancer from two clinical studies and 1 observational study. Dalteparin pharmacokinetics (PK) were described by a 1-compartment model with linear absorption and elimination and PK parameters are shown in Table 12. After correcting for the body weight, clearance (CL/F) decreased with increasing age, while volume of distribution at steady-state (Vd/F) remained similar. The mean elimination half-life increased with age.
| Table 12 | |||||
|---|---|---|---|---|---|
| Pharmacokinetic Parameters of Dalteparin in Pediatric Population | |||||
| Abbreviations: CL=clearance; F=absolute bioavailability; SD=standard deviation; t½β=elimination half-life; Vd=volume of distribution. | |||||
Parameter | 3 Weeks to <8 Weeks | ≥8 Weeks to <2 Years | ≥2 Years to <8 Years | ≥8 Years to <12 Years | ≥12 Years to <20 Years |
Median Age (range) (years) | 0.06 (0.04 – 0.14) | 0.5 (0.2 – 1.91) | 4.47 (2.01 – 7.6) | 9.62 (8.01 – 10.5) | 15.9 (12.0 – 19.5) |
Derived Mean (SD) CL/F (mL/h/kg) | 55.8 (3.91) | 40.4 (8.49) | 26.7 (4.75) | 22.4 (3.40) | 18.8 (3.01) |
Derived Mean (SD) Vd/F (mL/kg) | 181 (15.3) | 175 (55.3) | 160 (25.6) | 165 (27.3) | 171 (38.9) |
Derived Mean (SD) t½β (h) | 2.25 (0.173) | 3.02 (0.688) | 4.27 (1.05) | 5.11 (0.509) | 6.28 (0.937) |
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