Pharmacokinetics of eicosapentaenoic acid in plasma and red blood cells after multiple oral dosing with icosapent ethyl in healthy subjects

Braeckman, René; Stirtan, William G.; Soni, Paresh N.

doi:10.1002/cpdd.84

Cited by 41 publications

(42 citation statements)

References 22 publications

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“…Several LC-MS/MS protocols have previously been published for FA analysis [23,[25][26][27], some of which use linear ion trap quadrupole tandem mass spectrometers, often reporting relatively high LOD (up to 1ug/ml, [26])…”

Section: Discussionmentioning

confidence: 99%

“…while others have restricted methodology to EPA only [25] or EPA, DHA and AA [27]. Of note is the method of…”

Section: Discussionmentioning

confidence: 99%

“…We are aware of one other report in which LC-MS/MS was used to distinguish between free (unesterified) and total FAs by avoidance of a hydrolysis step but the aim was to detect unesterified EPA in the plasma following oral administration of -EPA ethyl ester rather than investigating compartmentalisation in cells [25]. One other study looked at PUFA distribution in cells comparing free and esterified fluorescent PUFAs in cells overexpressing the liver-type fatty acid-binding protein [33].…”

Section: Page 13 Of 32mentioning

confidence: 99%

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A liquid chromatography–tandem mass spectrometry method to measure fatty acids in biological samples

Volpato

Spencer

Race

et al. 2017

Journal of Chromatography B

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Page 1 of 32 A c c e p t e d M a n u s c r i p t Abbreviations:1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide HCl (EDC), 4-(Dimethylamino) pyridine (DMAP), 4-[2-(N,NDimethylamino)ethylaminosulfonyl]-7-(2-aminoethylamino)-2,1,3-benzoxadiazole (DAABD-AE), alphalinolenic acid (LNA) arachidonic acid (AA), colorectal cancer (CRC), coefficient of variation (CV), deuterated alpha-linolenic acid , docosapentaenoic acid (DPA), docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), EPA for Metastasis Trial EMT fatty acid FA free fatty acid FFA gas chromatography tandem mass spectrometry GC MS liquid chromatography electrospray ionization triple quadrupole tandem mass spectrometry (LC-ESI-MS/MS) limit of detection LOD limit of quantification LOQ linoleic acid (LA), oleic acid (OA), palmitic acid (PA), stearic acid (SA).A liquid chromatography-tandem mass spectrometry method to measure fatty acids in biological samples. A c c e p t e d M a n u s c r i p t Milene HIGHLIGHTS We have developed a LC-ESI-MS/MS method to measure fatty acid content of biological samples, particularly relevant to laboratory and clinical studies of PUFAs. We compared it directly with an established GC-MS protocol. The method is reproducible and suited for clinical application. The methodology allows measurements of total and unesterified fatty acids  Distribution of free versus bound FAs vary and may impact on biological activity. INTRODUCTIONLong-chain (>14 carbon atoms) polyunsaturated fatty acids (PUFAs), such as eicosapentaenoic acid (EPA, C20:5 -3) and arachidonic acid (AA, C20:4 -6) play crucial roles in normal human physiology and the We also confirmed applicability of the LC-ESI-MS/MS method to animal and human samples in the context of EPA supplementation experiments. Finally, we highlight the use of the LC-ESI-MS/MS method to compare relative changes in free (unesterified) and total (free + esterified) cellular PUFA content after exogenous EPA exposure. METHODS Reagents.EPA free fatty acid (FFA) was provided by SLA Pharma AG (Watford, UK). Use of EPA-FFA in in vitro experiments has been described previously [17]. Acetonitrile, methanol, 2-propanol, water and chloroform usedPage 5 of 32A c c e p t e d M a n u s c r i p t for fatty acid extraction were purchased from Sigma Aldrich (St. Louis, MO, USA) and were UHPLC-MS grade.Deionised purified water was generated using an Elga Maxima and Elga Purelab Option purifying system (18.2 MΩ-cm) (Veolia Water Technologies UK, High Wycombeaminoethylamino)-2,1,3-benzoxadiazole (DAABD-AE) and fatty acid standards; eicosapentaenoic acid (EPA ...

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Section: Discussionmentioning

confidence: 99%

“…while others have restricted methodology to EPA only [25] or EPA, DHA and AA [27]. Of note is the method of…”

Section: Discussionmentioning

confidence: 99%

Section: Page 13 Of 32mentioning

confidence: 99%

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A liquid chromatography–tandem mass spectrometry method to measure fatty acids in biological samples

Volpato

Spencer

Race

et al. 2017

Journal of Chromatography B

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“…Icosapent ethyl exhibits a linear and dose-dependent relationship with plasma EPA concentrations and does not affect plasma DHA levels [21]. Peak plasma EPA concentrations (C max ) were attained approximately 5 hours after administration, and steady state was attained by day 14 [14,26]. Following the administration of icosapent ethyl 4 g/day for 28 days, the steady-state EPA C max was 347 lg/mL and the area under the EPA plasma concentration-time curve (AUC) from time zero to 24 h (AUC 24 ) was 6,519 lgÁh/mL.…”

Section: Absorption and Distributionmentioning

confidence: 99%

“…More than 99 % of the unesterified EPA is bound to plasma proteins. At steady state, the mean volume of distribution of EPA is approximately 88 L [14,26].…”

Section: Absorption and Distributionmentioning

confidence: 99%

Icosapent Ethyl: A Review of Its Use in Severe Hypertriglyceridemia

Kim

McCormack

2014

Am J Cardiovasc Drugs

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Icosapent ethyl (Vascepa®) is a high-purity ethyl ester of eicosapentaenoic acid (EPA) that is de-esterified to EPA following oral administration. Both EPA and docosahexaenoic acid (DHA) are long-chain omega-3 fatty acids that have been associated with triglyceride (TG)-lowering. However, DHA has been associated with increased low-density lipoprotein cholesterol (LDL-C) levels. Icosapent ethyl contains ≥96 % of the EPA ethyl ester, does not contain DHA, and is approved in the USA for use as an adjunct to diet to lower TG levels in adult patients with severe (≥500 mg/dL [≥5.65 mmol/L]) hypertriglyceridemia. In a pivotal phase III trial, oral icosapent ethyl 4 g/day significantly decreased the placebo-corrected median TG levels by 33.1 %. It did not increase LDL-C, had favorable effects on other lipid parameters, and had a tolerability profile similar to that of placebo. Therefore, icosapent ethyl is an effective and well-tolerated agent for the treatment of severe hypertriglyceridemia in adults.

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Pharmacokinetics of Icosapent Ethyl: An Open‐Label, Multiple Oral Dose, Parallel Design Study in Healthy Chinese Subjects

Fang

Yang

et al. 2022

Clinical Pharm in Drug Dev

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Icosapent ethyl (IPE) is a high-purity prescription form of eicosapentaenoic acid (EPA) ethyl ester that has been approved to lower triglyceride levels in adult patients with severe (≥500 mg/dL) hypertriglyceridemia. Before this study, there were no pharmacokinetics (PK) or safety data in Chinese patients after receiving IPE. The purpose of this study was to evaluate the PK of EPA in plasma and red blood cells and safety after oral administration of IPE capsules for 28 consecutive days in healthy Chinese subjects. It was a randomized, open-label, parallel-designed multiple-dose, phase I study. Twenty-four subjects were enrolled and randomly assigned to 2 groups, including 6 men and 6 women in each group. Group A received IPE 2.0 g/day (1×1 g twice daily), and group B received IPE 4.0 g/day (2×1 g twice daily) with dosing after standard meals for 28 days. During the treatment period, PK samples were collected from all subjects before the morning dose on days 1, 14, 26, and 28. Following completion of the last study drug administration in the morning on day 28, an 18-day posttreatment PK sample collection period was followed. Twenty-four eligible subjects were enrolled in this study, and 1 subject withdrew from the study. The main PK parameters (baseline-corrected maximum observed plasma concentration and area under the plasma concentration-time curve during a dosing interval) of plasma total EPA, RBC EPA, and plasma unesterified EPA increased with dose. Chinese healthy subjects who took IPE capsules orally in the dose range of 2.0 to 4.0 g/day for 28 consecutive days were safe and tolerable.

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Pharmacokinetics of eicosapentaenoic acid in plasma and red blood cells after multiple oral dosing with icosapent ethyl in healthy subjects

Cited by 41 publications

References 22 publications

A liquid chromatography–tandem mass spectrometry method to measure fatty acids in biological samples

A liquid chromatography–tandem mass spectrometry method to measure fatty acids in biological samples

Icosapent Ethyl: A Review of Its Use in Severe Hypertriglyceridemia

Pharmacokinetics of Icosapent Ethyl: An Open‐Label, Multiple Oral Dose, Parallel Design Study in Healthy Chinese Subjects

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