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Vascepa

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Vascepa

CLINICAL PHARMACOLOGY

Mechanism of Action

Studies suggest that EPA reduces hepatic very low-density lipoprotein triglycerides (VLDL-TG) synthesis and/or secretion and enhances TG clearance from circulating VLDL particles. Potential mechanisms of action include increased β-oxidation; inhibition of acyl-CoA:1,2-diacylglycerol acyltransferase (DGAT); decreased lipogenesis in the liver; and increased plasma lipoprotein lipase activity.

Pharmacokinetics

Absorption

After oral administration, VASCEPA is de-esterified during the absorption process and the active metabolite EPA is absorbed in the small intestine and enters the systemic circulation mainly via the thoracic duct lymphatic system. Peak plasma concentrations of EPA were reached approximately 5 hours following oral doses of VASCEPA.

VASCEPA was administered with or following a meal in all clinical studies; no food effect studies were performed. Take VASCEPA with or following a meal.

Distribution

The mean volume of distribution at steady-state of EPA is approximately 88 liters. The majority of EPA circulating in plasma is incorporated in phospholipids, triglycerides and cholesteryl esters, and < 1% is present as the unesterified fatty acid. Greater than 99% of unesterified EPA is bound to plasma proteins.

Metabolism and Excretion

EPA is mainly metabolized by the liver via beta-oxidation similar to dietary fatty acids. Beta oxidation splits the long carbon chain of EPA into acetyl Coenzyme A, which is converted into energy via the Krebs cycle. Cytochrome P450-mediated metabolism is a minor pathway of elimination of EPA. The total plasma clearance of EPA at steady state is 684 mL/hr. The plasma elimination half-life (t1/2) of EPA is approximately 89 hours. VASCEPA does not undergo renal excretion.

Drug-Drug Interactions

VASCEPA was studied at the 4 g/day dose level with the following medications which are typical substrates of cytochrome P450 enzymes, and no drug-drug interactions were observed:

Omeprazole: In a drug-drug interaction study with 28 healthy adult subjects, VASCEPA 4 g/day at steady-state did not significantly change the steady-state AUCτ or Cmax of omeprazole when co-administered at 40 mg/day to steady-state.

Rosiglitazone: In a drug-drug interaction study with 28 healthy adult subjects, VASCEPA 4 g/day at steady-state did not significantly change the single dose AUC or Cmax of rosiglitazone at 8 mg.

Warfarin: In a drug-drug interaction study with 25 healthy adult subjects, VASCEPA 4 g/day at steady-state did not significantly change the single dose AUC or Cmax of R-and S-warfarin or the anti-coagulation pharmacodynamics of warfarin when co-administered as racemic warfarin at 25 mg.

Atorvastatin: In a drug-drug interaction study of 26 healthy adult subjects, VASCEPA 4 g/day at steady-state did not significantly change the steady-state AUCτ or Cmax of atorvastatin, 2-hydroxyatorvastatin, or 4-hydroxyatorvastatin when co-administered with atorvastatin 80 mg/day to steady-state.

Specific Populations

Gender: When administered VASCEPA in clinical trials, plasma total EPA concentrations did not differ significantly between men and women.

Pediatric: The pharmacokinetics of VASCEPA has not been studied in pediatric patients.

Hepatic or Renal Impairment: VASCEPA has not been studied in patients with renal or hepatic impairment.

Clinical Studies

Severe Hypertriglyceridemia

The effects of VASCEPA 4 grams per day were assessed in a randomized, placebo-controlled, double-blind, parallel-group study of adult patients (76 on VASCEPA, 75 on placebo) with severe hypertriglyceridemia. Patients whose baseline TG levels were between 500 and 2,000 mg/dL were enrolled in this study for 12 weeks. The median baseline TG and LDL-C levels in these patients were 684 mg/dL and 86 mg/dL, respectively. Median baseline HDL-C level was 27 mg/dL. The randomized population in this study was mostly Caucasian (88%) and male (76%). The mean age was 53 years and the mean body mass index was 31 kg/m² . Twenty-five percent of patients were on concomitant statin therapy, 28% were diabetics, and 39% of the patients had TG levels > 750 mg/dL.

The changes in the major lipoprotein lipid parameters for the groups receiving VASCEPA or placebo are shown in Table 2.

Table 2: Median Baseline and Percent Change from Baseline in Lipid Parameters in Patients with Severe Hypertriglyceridemia ( ≥ 500 mg/dL)

Parameter VASCEPA 4 g/day
N=76
Placebo
N=75
Difference (95% Confidence Interval)
Baseline % Change Baseline % Change
TG (mg/dL) 680 -27 703 10 -33* (-47, -22)
LDL-C (mg/dL) 91 -5 86 -3 -2 (-13, +8)
Non-HDL-C (mg/dL) 225 -8 229 8 -18 (-25, -11)
TC (mg/dL) 254 -7 256 8 -16 (-22, -11)
HDL-C (mg/dL) 27 -4 27 0 -4 (-9, +2)
VLDL-C (mg/dL) 123 -20 124 14 -29** (-43, -14)
Apo B (mg/dL) 121 -4 118 4 -9**(-14, -3)
% Change= Median Percent Change from Baseline
Difference= Median of [VASCEPA % Change – Placebo % Change] (Hodges-Lehmann Estimate) p-values from Wilcoxon rank-sum test
*p-value < 0.001 (primary efficacy endpoint)
**p-value < 0.05 (key secondary efficacy endpoints determined to be statistically significant according to the pre-specified multiple comparison procedure)

VASCEPA 4 grams per day reduced median TG, VLDL-C, and Apo B levels from baseline relative to placebo. The reduction in TG observed with VASCEPA was not associated with elevations in LDL-C levels relative to placebo.

The effect of VASCEPA on the risk of pancreatitis in patients with severe hypertriglyceridemia has not been determined.

The effect of VASCEPA on cardiovascular mortality and morbidity in patients with severe hypertriglyceridemia has not been determined.

Last reviewed on RxList: 12/6/2013
This monograph has been modified to include the generic and brand name in many instances.

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