DrugLib.com — Drug Information Portal

Rx drug information, pharmaceutical research, clinical trials, news, and more

Vascepa (Icosapent Ethyl) - Description and Clinical Pharmacology

 
 



DESCRIPTION

VASCEPA, a lipid-regulating agent, is supplied as a 1-gram amber-colored, liquid-filled soft gelatin capsule for oral administration.

Each VASCEPA capsule contains 1 gram of icosapent ethyl. Icosapent ethyl is an ethyl ester of the omega-3 fatty acid eicosapentaenoic acid (EPA). The empirical formula of icosapent ethyl is C22H34O2 and the molecular weight is 330.51. The chemical name for icosapent ethyl is ethyl all-cis-5,8,11,14,17-icosapentaenoate with the following chemical structure:

VASCEPA 1-gram capsules also contain the following inactive ingredients: tocopherol, gelatin, glycerin, maltitol, sorbitol, and purified water.

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 beta-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 4 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.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 2-year rat carcinogenicity study with oral gavage doses of 0.09, 0.27, and 0.91 g/kg/day icosapent ethyl, respectively, males did not exhibit drug-related neoplasms. Hemangiomas and hemangiosarcomas of the mesenteric lymph node, the site of drug absorption, were observed in females at clinically relevant exposures based on body surface area comparisons across species relative to the maximum clinical dose of 4 g/day. Overall incidence of hemangiomas and hemangiosarcomas in all vascular tissues did not increase with treatment.

In a 6-month carcinogenicity study in Tg.rasH2 transgenic mice with oral gavage doses of 0.5, 1, 2, and 4.6 g/kg/day icosapent ethyl, drug-related incidences of benign squamous cell papilloma in the skin and subcutis of the tail was observed in high dose male mice. The papillomas were considered to develop secondary to chronic irritation of the proximal tail associated with fecal excretion of oil and therefore not clinically relevant. Drug-related neoplasms were not observed in female mice.

Icosapent ethyl was not mutagenic with or without metabolic activation in the bacterial mutagenesis (Ames) assay or in the in vivo mouse micronucleus assay. A chromosomal aberration assay in Chinese Hamster Ovary (CHO) cells was positive for clastogenicity with and without metabolic activation.

In an oral gavage rat fertility study, ethyl-EPA, administered at doses of 0.3, 1, and 3 g/kg/day to male rats for 9 weeks before mating and to female rats for 14 days before mating through day 7 of gestation, increased anogenital distance in female pups and increased cervical ribs were observed at 3 g/kg/day (7 times human systemic exposure with 4 g/day clinical dose based on a body surface area comparison).

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
% Change= Median Percent Change from Baseline
Difference= Median of [VASCEPA % Change — Placebo % Change] (Hodges-Lehmann Estimate)
p-values from Wilcoxon rank-sum test
TG (mg/dL) 680 -27 703 +10 -33p-value < 0.001 (primary efficacy endpoint) (-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 1 (-43, -14)
Apo B (mg/dL) 121 -4 118 +4 -9(-14, -3)

1 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 levels has not been determined.

-- advertisement -- The American Red Cross
 
Home | About Us | Contact Us | Site usage policy | Privacy policy

All Rights reserved - Copyright DrugLib.com, 2006-2017