Clexane Mechanism of Action

Pharmacotherapeutic Group: Antithrombotic Agents; Hepatic Group: ATC code: B01A B05.
Pharmacology: Pharmacodynamics: Mechanism of action: Enoxaparin sodium is a Low Molecular Weight Heparin with a mean molecular weight of approximately 4,500 daltons. The drug substance is the sodium salt. The molecular weight distribution is:
<2000 daltons ≤20%
2000 to 8000 daltons ≥68%
>8000 daltons ≤18%.
Enoxaparin sodium is obtained by alkaline depolymerization of heparin benzyl ester derived from porcine intestinal mucosa. Its structure is characterized by a 2-O-sulfo-4-enepyranosuronic acid group at the non-reducing end and a 2-N,6-O-disulfo-D-glucosamine at the reducing end of the chain. About 20% (ranging between 15% and 25%) of the enoxaparin structure contains an 1,6 anhydro derivative on the reducing end of the polysaccharide chain.
In the in vitro purified system, enoxaparin sodium has a high anti-Xa activity (approximately 100 IU/mg) and low anti-IIa or anti thrombin activity (approximately 28 IU/mg). These anticoagulant activities are mediated through anti-thrombin III (ATIII) resulting in anti-thrombotic activities in humans.
Beyond its anti-Xa/IIa activity, further anti-thrombotic and anti-inflammatory properties of enoxaparin have been identified in healthy subjects and patients as well as in non-clinical models.
These include ATIII-dependent inhibition of other coagulation factors like factor VIIa, induction of endogenous Tissue Factor Pathway Inhibitor (TFPI) release as well as a reduced release of von Willebrand factor (vWF) from the vascular endothelium into the blood circulation. These factors are known to contribute to the overall anti-thrombotic effect of enoxaparin.
Clinical Efficacy/Clinical Studies: Treatment of unstable angina and non-Q-wave myocardial infarction: In a large multicenter study, 3,171 patients enrolled at the acute phase of unstable angina or non-Q-wave myocardial infarction were randomized to receive in association with aspirin (100 to 325 mg once daily), either subcutaneous enoxaparin sodium 1 mg/kg every 12 hours or intravenous unfractionated heparin adjusted based on activated partial thromboplastin time (aPTT). Patients had to be treated in hospital for a minimum of 2 days and a maximum of 8 days, until clinical stabilization, revascularization procedures or hospital discharge. The patients had to be followed up to 30 days. Enoxaparin sodium compared to heparin significantly decreased the incidence of recurrent angina, myocardial infarction and death, with a relative risk reduction of 16.2% at Day 14, sustained over the 30 day period. Furthermore, fewer patients in the enoxaparin sodium group underwent revascularization with either percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass grafting (CABG) (15.8% relative risk reduction at Day 30).
Treatment of acute ST-segment Elevation Myocardial Infarction (STEMI): In a large multicenter study, 20,479 patients with STEMI eligible to receive fibrinolytic therapy were randomized to receive either enoxaparin sodium in a single 30-mg intravenous bolus plus a 1 mg/kg SC dose followed by an SC injection of 1.0 mg/kg every 12 hours or intravenous unfractionated heparin adjusted based on activated partial thromboplastin time (aPTT) for 48 hours. All patients were also treated with aspirin for a minimum of 30 days. The enoxaparin dosing strategy was adjusted for severe renally impaired patients and for the elderly of at least 75 years of age. The SC injections of enoxaparin were given until hospital discharge or for a maximum of eight days (whichever came first).
4,716 patients underwent percutaneous coronary intervention receiving antithrombotic support with blinded study drug. Therefore, for patients on enoxaparin, the PCI was to be performed on enoxaparin (no switch) using the regimen established in previous studies i.e. no additional dosing, if last SC administration given less than 8 hours before balloon inflation, IV bolus of 0.3 mg/kg enoxaparin, if the last SC administration given more than 8 hours before balloon inflation.
Enoxaparin sodium compared to unfractionated heparin significantly decreased the incidence of the primary end point, a composite of death from any cause or myocardial re-infarction in the first 30 days after randomization [9.9 percent in the enoxaparin group, as compared with 12.0 percent in the unfractionated heparin group] with a 17 percent relative risk reduction (P<0.001).
The treatment benefits of enoxaparin, evident for a number of efficacy outcomes, emerged at 48 hours, at which time there was a 35 percent reduction in the relative risk of myocardial re-infarction, as compared with treatment with unfractionated heparin (P<0.001).
The beneficial effect of enoxaparin on the primary end point was consistent across key subgroups including age, gender, infarct location, history of diabetes, history of prior myocardial infarction, type of fibrinolytic administered, and time to treatment with study drug.
There was a significant treatment benefit of enoxaparin, as compared with unfractionated heparin, in patients who underwent percutaneous coronary intervention within 30 days after randomization (23 percent reduction in relative risk) or who were treated medically (15 percent reduction in relative risk, P=0.27 for interaction).
The rate of the 30 day composite endpoint of death, myocardial re-infarction or ICH (a measure of net clinical benefit) was significantly lower (p<0.0001) in the enoxaparin group (10.1%) as compared to the heparin group (12.2%), representing a 17% relative risk reduction in favor of treatment with Enoxaparin sodium (Clexane).
The beneficial effect of enoxaparin on the primary end point observed during the first 30 days was maintained over a 12 month follow-up period.
Pharmacokinetics: General characteristics: The pharmacokinetic parameters of enoxaparin sodium have been studied primarily in terms of the time course of plasma anti-Xa activity and also by anti-IIa activity, at the recommended dosage ranges after single and repeated subcutaneous administration and after single intravenous administration. The quantitative determination of anti-Xa and anti-IIa pharmacokinetic activities was conducted by validated amidolytic methods with specific substrates and an enoxaparin standard calibrated against the international standard for LMWHs (NIBSC).
Absorption: Bioavailability and Absorption: The absolute bioavailability of enoxaparin sodium after subcutaneous injection, based on anti-Xa activity, is close to 100%. Injection volume and dose concentration over the range 100-200 mg/ml does not affect pharmacokinetic parameters in healthy volunteers.
The mean maximum plasma anti-Xa activity is observed 3 to 5 hours after subcutaneous injection and achieves approximately 0.2, 0.4, 1.0 and 1.3 anti-Xa IU/ml following single-subcutaneous administration of 20 mg, 40 mg, 1 mg/kg and 1.5 mg/kg doses, respectively.
A 30 mg IV bolus immediately followed by a 1 mg/kg SC every 12 hours provided initial peak anti-Factor Xa levels of 1.16 IU/ml (n=16) and average exposure corresponding to 88% of steady-state levels. Steady-state is achieved on the second day of treatment.
Enoxaparin pharmacokinetics appear to be linear over the recommended dosage ranges. Intra-patient and inter-patient variability is low. After repeated subcutaneous administration of 40 mg once daily and 1.5 mg/kg once daily regimens in healthy volunteers, the steady-state is reached on day 2 with an average exposure ratio about 15% higher than after a single dose. Steady-state enoxaparin activity levels are well predicted by single dose pharmacokinetics. After repeated subcutaneous administration of the 1 mg/kg twice daily regimen, the steady-state is reached from day 3 to 4 with mean exposure about 65% higher than after a single dose and mean peak and trough levels of about 1.2 and 0.52 IU/ml, respectively. Based on enoxaparin sodium pharmacokinetics, this difference in steady state is expected and within the therapeutic range.
Plasma anti-IIa activity after subcutaneous administration is approximately ten-fold lower than anti-Xa activity. The mean maximum anti-IIa activity is observed approximately 3 to 4 hours following subcutaneous injection and reaches 0.13 IU/ml and 0.19 IU/ml following repeated administration of 1 mg/kg twice daily and 1.5 mg/kg once daily, respectively.
Distribution: The volume of distribution of enoxaparin sodium anti-Xa activity is about 5 liters and is close to the blood volume.
Metabolism: Enoxaparin sodium is primarily metabolized in the liver by desulfation and/or depolymerization to lower molecular weight species with much reduced biological potency.
Elimination: Enoxaparin sodium is a low clearance drug with a mean anti-Xa plasma clearance of 0.74 L/h after a 1.5 mg/kg 6-hour intravenous infusion.
Elimination appears monophasic with a half-life of about 4 hours after a single subcutaneous dose to about 7 hours after repeated dosing. Renal clearance of active fragments represents about 10% of the administered dose and total renal excretion of active and non-active fragments 40% of the dose.
Special Populations: Elderly: Based on the results of a population pharmacokinetic analysis, the enoxaparin sodium kinetic profile is not different in elderly subjects compared to younger subjects when renal function is normal. However, since renal function is known to decline with age, elderly patients may show reduced elimination of enoxaparin sodium (see Pharmacology: Pharmacokinetics under Actions, Dosage & Administration and Precautions).
Renal impairment: A linear relationship between anti-Xa plasma clearance and creatinine clearance at steady-state has been observed, which indicates decreased clearance of enoxaparin sodium in patients with reduced renal function. Anti-Xa exposure represented by AUC, at steady-state, is marginally increased in mild (creatinine clearance 50-80 ml/min) and moderate (creatinine clearance 30-50 ml/min) renal impairment after repeated subcutaneous 40 mg once daily doses. In patients with severe renal impairment (creatinine clearance <30 ml/min), the AUC at steady state is significantly increased on average by 65% after repeated subcutaneous 40 mg once daily doses (see Dosage & Administration and Precautions).
Weight: After repeated subcutaneous 1.5 mg/kg once daily dosing, mean AUC of anti-Xa activity is marginally higher at steady state in obese healthy volunteers (BMI 30-48 kg/m²) compared to non-obese control subjects, while Amax is not increased. There is a lower weight-adjusted clearance in obese subjects with subcutaneous dosing.
When non-weight adjusted dosing was administered, it was found after a single-subcutaneous 40 mg dose, that anti-Xa exposure is 52% higher in low-weight women (<45 kg) and 27% higher in low-weight men (<57 kg) when compared to normal weight control subjects (see Precautions).
Hemodialysis: In a single study, elimination rate appeared similar but AUC was two-fold higher than control population, after a single 0.25 or 0.50 mg/kg intravenous dose.
Pharmacokinetic Interactions: No pharmacokinetic interactions were observed between enoxaparin and thrombolytics when administered concomitantly.
Toxicology: Non-Clinical Safety Data: No long-term studies in animals have been performed to evaluate the carcinogenic potential of enoxaparin.
Enoxaparin was not mutagenic in in vitro tests, including the Ames test, mouse lymphoma cell forward mutation test, and human lymphocyte chromosomal aberration test, and the in vivo rat bone marrow chromosomal aberration test.
Enoxaparin was found to have no effect on fertility or reproductive performance of male and female rats at SC doses up to 20 mg/kg/day. Teratology studies have been conducted in pregnant rats and rabbits at SC doses of enoxaparin up to 30 mg/kg/day. There was no evidence of teratogenic effects or fetotoxicity due to enoxaparin.
Besides the anticoagulant effects of enoxaparin, there was no evidence of adverse effects at 15 mg/kg/day in the 13-week subcutaneous toxicity studies both in rats and dogs and at 10 mg/kg/day in the 26-week subcutaneous and intravenous toxicity studies both in rats and monkeys.