FRAGMIN 10 Clinical Pharmacology

10.1 Mechanism of Action

Fragmin is a LMWH with antithrombotic properties. It acts by potentiating the activity of antithrombin III, inhibiting formation of both Factor Xa and thrombin by antithrombin.  However, it preferentially potentiates inhibition of Factor Xa, resulting in only slight increases of clotting time, i.e., activated partial thromboplastin time (APTT). Dalteparin sodium is composed of molecules with and without a specially characterized pentasaccharide, the antithrombin binding site, that is essential for high affinity binding to the plasma protein antithrombin (AT III).

10.2 Pharmacodynamics

Doses of Fragmin Injection of up to 10,000 anti-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.

Specific activity of Fragmin is consistent with that of unfractionated heparin regarding anti-Xa activity but has less effects on APTT. For Fragmin, only high doses lead to noticeable increases in the APTT; therefore, measurement of APTT can be used only as an indicator of overdosage. In the case of Fragmin, anti-Xa activity of plasma is used both as an estimate of clotting activity, and as a basis to determine dosage. Fragmin potency is described in international anti-Xa units (IU). 

The specific activity of Fragmin on factor Xa (by measurement of anti-factor Xa IU/mg) is 130, and its specific activity on factor IIa (by measurement of anti-factor IIa IU/mg) is 58. The ratio of anti-Xa/anti-IIa activity for Fragmin is 2.2 (for unfractionated heparin the anti-Xa/anti-IIa is equal to 1).

Dalteparin sodium has a smaller effect on platelet function and platelet adhesion than heparin, and thus has only a small effect on primary hemostasis. Heparin treatment depletes the pool of platelet factor 4, while dalteparin sodium has much less of an effect. Fragmin is also associated with smaller increases in free fatty acids and plasma lipoprotein lipase activities than heparin.

Fragmin administration appears to give rise to transient elevation of liver transaminases to the same extent as heparin. There is a single report of the levels not returning to normal after withdrawal of treatment. Levels nonetheless returned to normal after 2 weeks.

10.3 Pharmacokinetics

Absorption

The absolute bioavailability of Fragmin measured as the anti-Factor Xa activity after subcutaneous injection is 87 ± 6%. Compared with heparin, Fragmin is well absorbed following subcutaneous injection. The plasma concentration of dalteparin sodium following subcutaneous administration is easily predicted since there is a direct relationship between the administered dose and the anti-Factor Xa activity in plasma. Increasing the dose from 2500 IU to 10,000 IU resulted in an overall increase in anti-Factor Xa AUC that was proportionally greater by about one-third. For the twice daily dosing regimen (100 IU/kg/12 hours) of Fragmin, the steady state level is attained after 2-4 s.c. injections (24-48 hours).

Distribution

The volume of distribution was found to be approximately 3 litres (40 to 60 mL/kg).

Animal studies using radioactively labelled drug have shown that the distribution of Fragmin is similar, whether the dose is administered intravenously or subcutaneously (i.v. or s.c.).

Metabolism

After administration of IV doses of 40, 60 and 120 IU/kg, mean plasma half-lives were 2.1 ± 0.3 , 2.3 ± 0.4 hours, and 2.0 ± 0.3 respectively that was twice as long as for heparin. The half life after subcutaneous injection of Fragmin in the doses 2500, 5000 and 10 000 IU anti Xa, was 3.4, 3.3 and 3.9 hours respectively. Longer plasma half-lives were observed following subcutaneous injections possibly due to delayed absorption. 

Elimination

Dalteparin is primarily excreted by the kidneys; however, the biological activity of the renally eliminated fragments is not well characterized. In 72 hours, approximately 70 % of radioactive Fragmin dose has been excreted in urine, however less than 5% of anti-Xa activity is detectable in the urine. The mean plasma clearances of dalteparin anti-Factor Xa activity in normal volunteers following single IV bolus doses of 120 IU/kg was 20.5 ± 2.45 mL/min. Dalteparin sodium, in contrast to heparin, is not cleared by a saturable mechanism, thus elimination half-life is dose independent.

Special Populations and Conditions

• Pediatrics: A prospective study by Nohe et al. investigated the efficacy, safety and inverse age relation in the dose of dalteparin to achieve therapeutic plasma anti-Xa activity in 48 paediatric patients (from 31 weeks preterm to 18 years) with arterial and venous thrombosis.Anti-Xa levels were adjusted 4 hours post-dose to 0.2 to 0.4 IU/mL for prophylaxis and to 0.4 to 1.0 IU/mL for therapy. The treatment duration was 3 to 6 months. In 10 patients who received dalteparin (95 ± 52 IU/kg s.c. once daily) for thromboprophylaxis, no thromboembolic events occurred.  The dose for antithrombotic therapy was 129 ± 43 IU/kg sc once daily. In the 23 patients given dalteparin for primary antithrombotic therapy, 7/23 (30%) had complete recanalization, 7/23 (30%) had partial recanalization, and 9/23 (40%) had no recanalization. In the 8 patients administered dalteparin for secondary antithrombotic therapy following successful thrombolysis, recanalisation was maintained or improved. In the 5 patients receiving dalteparin following failed thrombolysis, no recanalization was seen. Minor bleeding, reported in 2/48 children (4%), resolved after dose reduction.

  Study FRAG-A001-201 was an open-label, multi-center, Phase 2 clinical trial to determine twice-daily dosing recommendations for dalteparin (s.c. injection 12 hours apart), as a function of age, in order to achieve therapeutic anti-Xa levels (0.5 to 1.0 IU/mL) at 4 hours (±1 h) post-dose. A total of 38 pediatric patients with (N = 26) or without (N = 12) cancer received dalteparin for up to 3 months for the treatment and secondary prophylaxis of VTE, with starting doses defined for 5 age groups (Table 16). All patients had dose adjustments in increments or decrements of 25 IU/kg in order to achieve 0.5 to 1.0 IU/mL during the 7-day dose adjustment period. A total of 26 patients completed the study and 12 prematurely discontinued (4 due to adverse events, 3 patients withdrew consent and 5 for other reasons). At study completion, 21 (61.8%) patients had achieved resolution of the qualifying VTE; 7 (20.6%) patients showed regression, 2 (5.9%) patients showed no change, no patients showed progression and 4 (11.8%) patients did not contribute data for this analysis. In addition, 1 (2.9%) patient experienced a new VTE during the study. None of the patients received concomitant treatment with vitamin K antagonists.

  Supplementary data on the dose of dalteparin required to achieve therapeutic anti-Xa levels were obtained from the Kids-DOTT and Mayo Clinic Studies with similar dosage recommendations. The median doses of dalteparin (IU/kg) to achieve required therapeutic anti- Xa levels per age group are presented in Table 16. Time to achieve therapeutic anti-Xa levels during the dose adjustment was approximately 4 days for patients aged < 8 years, and 2 days for patients aged ≥ 8 years in Study FRAG-A001-201.

• Pregnancy and Breast-feeding: In a prospective trial, the EThIG study, 810 pregnant women were assigned to one of three dosing strategies according to pre-defined risk factors related to history of VTE and thrombophilic profile. Low-risk women (group I) received 50–100 IU dalteparin/ kg body weight/ day for 14 days postpartum. Women at high (group II) or very high risk (group III) received dalteparin from enrolment until six weeks postpartum (50–100 IU and 100–200 IU/ kg/ day, respectively. Symptomatic VTE occurred in five women (0.6 %; 95% CI 0.2, 1.5%). There were no events in group I; three women in group II (2 antepartum, 1 postpartum) and two in group III (both postpartum) suffered of a VTE event.  Bleeding was classified as serious in 24 episodes (3.0% 95% CI: 1.9, 4.4 %) in 22 women (2.7% 95% CI: 1.8, 4.2 %), and no cases of fatal bleeding occurred. Thrombocytopenia occurred in 18 women (2.2%; 95% CI: 1.4, 3.6%), with no cases with clinical or laboratory features of heparin-induced thrombocytopenia (HIT).
• Renal Insufficiency : 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 (see Renal and Use in Patients with Renal Impairment).  
  In a multi-center, open-label, prospective cohort study (DIRECT study) of critically ill patients with severe acute or chronic renal insufficiency or dialysis (mean creatinine clearance of 18.9 ml/min), 138 evaluable patients received at least one dose of subcutaneous dalteparin 5,000 IU once daily as thromboprophylaxis. The median duration of dalteparin administration was 7 days. Trough anti-Xa levels were measured twice weekly, at 20 hours post dose, to assess for dalteparin bioaccumulation (defined as anti-Xa levels > 0.40 IU/mL). No patient (0%; 95% CI: 0, 3.0) had bioaccumulation, during the study. Peak anti-Xa levels were between 0.29 IU/mL and 0.34 IU/mL and trough levels were below the lower limit of detection (<0.06 IU/mL). These peak anti-Xa levels achieved with prophylactic dose of dalteparin were consistent with peak prophylactic levels of anticoagulation of 0.20–0.40 IU/ml observed in other hospitalized medical and surgical patients.
• Obesity: In a prospective, cohort study, 37 overweight patients were a priori stratified into three weight classes: (A) within 20 % of ideal body weight (IBW) (N=13), (B) 20-40% of IBW (n=14), and (C) greater than 40% of IBW (n=10). All patients, with serum creatinine levels <150µmol/L, received dalteparin sodium 200 IU/kg based on actual body weight subcutaneously once daily for the treatment of DVT or pulmonary embolism for a minimum of 5 days. All patients had peak anti-Xa levels measured 3-4 h following their Day 3 injection and trough anti-Xa levels measured immediately prior to injections on Day 3 and Day 5. Patients were stratified per weight in three different groups: A, B, C with mean daily doses of dalteparin respectively of 14,030 IU, 17,646 IU, and 23,565 IU. Mean (SD) peak anti-Xa levels on Day 3 were 1.01 (0.20) IU/ml, 0.97 (0.21) IU/ml and 1.12 (0.22) IU/ml for groups A, B and C, respectively. Mean (SD) trough anti-Xa levels on Day 3 were 0.12 (0.05) IU/ml, 0.11 (0.03) IU/ml and 0.11 (0.03) IU/ml for groups A, B and C, respectively. Similar trough anti-Xa levels were observed on Day 5. No thromboembolic or bleeding complications occurred during dalteparin therapy in any patients.
• Intensive Care Unit (ICU) Patients: In a large international randomized, controlled multicenter study³⁴, the thromboprophylactic effect of dalteparin 5,000 IU once daily was compared to unfractionated heparin (UFH) 5,000 IU twice daily in 3746 critically ill medical and surgical patients who were admitted in the intensive care unit (ICU). The primary outcome was proximal leg deep vein thrombosis (DVT) as determined by periodic compression ultrasound. The median duration of study drug in both groups was 7 days. Proximal leg DVT was reported by 5.1% patients in the dalteparin group and 5.8% patients in the UFH group. The proportion of patients with pulmonary emboli was 1.3% in the dalteparin group and 2.3% in the UFH group. The rates of major bleeding and death in the hospital were 5.5% and 22.1% in the dalteparin group, and 5.6% and 24.5% in the UFH group. Of these parameters, only the rate of pulmonary emboli showed a statistically significant difference between treatment groups.