From the Guidelines
Dalteparin is primarily metabolized in the liver through desulfation and depolymerization, resulting in smaller fragments with reduced anticoagulant activity. After subcutaneous administration, dalteparin is absorbed into the bloodstream where it binds to antithromatin, enhancing its inhibitory effect on coagulation factors, particularly factor Xa 1. The drug undergoes first-order kinetics with a half-life of approximately 3-5 hours, though this can be prolonged in patients with renal impairment since some metabolites are eliminated through the kidneys.
Metabolic Pathway
The metabolism of dalteparin involves several key steps:
- Desulfation: removal of sulfate groups from the molecule
- Depolymerization: breakdown of the molecule into smaller fragments These processes result in the formation of smaller fragments with reduced anticoagulant activity. Unlike warfarin, dalteparin does not require the cytochrome P450 enzyme system for metabolism 1.
Clearance
The molecular weight of dalteparin fragments influences their clearance pathway, with higher molecular weight components being cleared primarily by the reticuloendothelial system and lower weight fragments by renal excretion. This metabolic profile explains why dalteparin requires less frequent dosing than unfractionated heparin and why dose adjustments are necessary in patients with severe renal dysfunction (creatinine clearance <30 mL/min) 1.
Dosing Considerations
In patients with severe renal impairment, monitoring of peak anti-Xa levels is recommended to ensure safe and effective dosing of dalteparin 1. The NCCN panel suggests that each institution prepare a LMWH dosing algorithm tailored for these subsets of patients, including those with renal insufficiency, body mass index >30 kg/m2, and patients ≥70 years of age 1. The dosing regimen for dalteparin should be individualized based on the patient's renal function and other clinical factors.
From the FDA Drug Label
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.
The metabolism of dalteparin is characterized by plasma clearance and disposition half-lives.
- The mean plasma clearances of dalteparin anti-Xa activity are 24.6 ± 5.4 mL/hr/kg and 15.6 ± 2.4 mL/hr/kg for single intravenous bolus doses of 30 and 120 anti-Xa units/kg, respectively.
- The mean disposition half-lives are 1.47 ± 0.3 hours and 2.5 ± 0.3 hours for the same doses.
- Terminal half-lives are 2.1 ± 0.3 hours and 2.3 ± 0.4 hours for intravenous doses of 40 units/kg and 60 units/kg, respectively.
- Subcutaneous dosing results in longer apparent terminal half-lives (3 hours to 5 hours) due to delayed absorption 2.
From the Research
Metabolism of Dalteparin
- Dalteparin is a low molecular weight heparin (LMWH) with a mean molecular weight of 5000 3.
- It has improved bioavailability and increased plasma elimination half-life compared to unfractionated heparin (UFH) 3, 4.
- Dalteparin exerts a greater inhibitory effect on plasma activity of coagulation factor Xa relative to its effects on other coagulation parameters 3, 4.
- It has less lipolytic activity than UFH 3, 4.
Pharmacokinetics
- Dalteparin can be administered subcutaneously as a single daily dose due to its improved pharmacokinetic characteristics 4.
- The drug does not alter coagulation tests and therefore does not require routine laboratory monitoring, in contrast with adjusted-dose UFH 5.
- Dalteparin has a predictable dose response and can be administered as a standard single daily subcutaneous dose for all patients 5.
Clinical Use
- Dalteparin is effective in the prophylaxis and treatment of thromboembolic disease, including deep vein thrombosis (DVT) and pulmonary embolism (PE) 3, 4, 5.
- It is also effective in the management of unstable coronary artery disease (CAD) and has shown clinical benefit in the management of patients with unstable angina or non-Q-wave myocardial infarction 3, 4.
- Dalteparin has been shown to be cost-effective when used for surgical thromboprophylaxis and has potential cost advantages over UFH 3, 4.