Omega-3 fatty acid exposure with a low-fat diet in patients with past hypertriglyceridemia-induced acute pancreatitis; an exploratory, randomized, open-label crossover study

Abstract

Background: Omega-3 fatty acids (OM3-FAs) are recommended with a low-fat diet for severe hypertriglyceridemia (SHTG), to reduce triglycerides and acute pancreatitis (AP) risk. A low-fat diet may reduce pancreatic lipase secretion, which is required to absorb OM3-ethyl esters (OM3-EEs), but not OM3-carboxylic acids (OM3-CAs).

Methods: In this exploratory, randomized, open-label, crossover study, 15 patients with SHTG and previous AP were instructed to take OM3-CA (2 g or 4 g) and OM3-EE 4 g once daily for 4 weeks, while adhering to a low-fat diet. On day 28 of each treatment phase, a single dose was administered in the clinic with a liquid low-fat meal, to assess 24-h plasma exposure. Geometric least-squares mean ratios were used for between-treatment comparisons of baseline (day 0)-adjusted area under the plasma concentration versus time curves (AUC_0-24) and maximum plasma concentrations (C_max) for eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).

Results: Before initiating OM3-FA treatment, mean baseline fasting plasma EPA + DHA concentrations (nmol/mL) were 723 for OM3-CA 2 g, 465 for OM3-CA 4 g and 522 for OM3-EE 4 g. At week 4, mean pre-dose fasting plasma EPA + DHA concentrations increased by similar amounts (+ 735 - + 768 nmol/mL) for each treatment. During the 24-h exposure assessment (day 28), mean plasma EPA + DHA increased from pre-dose to the maximum achieved concentration by + 32.7%, + 45.8% and + 3.1% with single doses of OM3-CA 2 g, OM3-CA 4 g and OM3-EE 4 g, respectively. Baseline-adjusted AUC_0-24 was 60% higher for OM3-CA 4 g than for OM3-EE 4 g and baseline-adjusted C_max was 94% higher (both non-significant).

Conclusions: Greater 24-h exposure of OM3-CA versus OM3-EE was observed for some parameters when administered with a low-fat meal at the clinic on day 28. However, increases in pre-dose fasting plasma EPA + DHA over the preceding 4-week dosing period were similar between treatments, leading overall to non-significant differences in baseline (day 0)-adjusted AUC_0-24 and C_max EPA + DHA values. It is not clear why the greater 24-h exposure of OM3-CA versus OM3-EE observed with a low-fat meal did not translate into significantly higher pre-dose fasting levels of DHA + EPA with longer-term use.

Trial registration: ClinicalTrials.gov, NCT02189252, Registered 23 June 2014.

Keywords: Clinical trials; Docosahexaenoic acid; Eicosapentaenoic acid; Fish oil; Omega-3 carboxylic acids; Omega-3 ethyl esters; Omega-3 fatty acids; Pharmacokinetics; Triglycerides; Viscosity.

Fig. 1

Crossover study design. Details of the assessments at each visit are provided in the methods. ^aTreatment sequences were: OM3-CA 4 g/day: OM3-EE 4 g/day (n = 4); OM3-EE 4 g/day: OM3-CA 4 g/day (n = 4); OM3-CA 2 g/day: OM3-EE 4 g/day (n = 3); and OM3-EE 4 g/day: OM3-CA 2 g/day (n = 4). ^bParticipants were given a 4-week supply of the study drug and took their first dose. ^cPharmacokinetics assessment visit. Study dose was administered in combination with a liquid meal providing 500 kcal (12 g fat, 18 g protein and 80 g carbohydrates). Blood samples were collected before (t = 0) the low-fat load, and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 and 24 h afterwards for postprandial assessments of omega-3 fatty acids, TGs, FFAs and apolipoproteins. Participants received breakfast, lunch, dinner and snacks (according to their calculated energy needs for weight maintenance) for consumption in the 2 days before the pharmacokinetics visit. OM3-CA, omega-3 carboxylic fatty acids; OM3-EE, omega-3 ethyl esters

Fig. 2

Mean unadjusted plasma total EPA + total DHA concentrations over the whole study. ^aMean values are for Treatment I and Treatment II (see Fig. 1)

Fig. 3

Mean (± SD) baseline-adjusted concentrations over time (24-h pharmacokinetic assessment on day 28 for Treatment I and Treatment II) for the different treatments administered with a low-fat liquid meal. (a) Plasma total EPA + total DHA, (b) total EPA and (c) total DHA for the OM3-CA 2 g/day (n = 6); OM3-CA 4 g/day (n = 6) and OM3-EE 4 g/day (n = 12) treatments. Blood samples were taken 1.5, 0.75 and 0.25 h before the first dose of study drug on day 0 (baseline). These values were then averaged and subtracted from each individual unadjusted concentration from 0 to 24 h to obtain baseline-adjusted values. DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; OM3-CA, omega-3 carboxylic acids; OM3-EE, omega-3 ethyl esters; SD, standard deviation