For Optimal Bioavailability, Administer Dronedarone With a Complete Meal

This article was sponsored by Sanofi

A link to the full Prescribing Information, including Boxed WARNING, for dronedarone is available here.

Food may influence the bioavailability of orally administered therapies as it can affect tablet disintegration, drug dissolution, and/or drug transit in the gastrointestinal tract.¹ As such, administration of oral therapies with food can have an influence on treatment outcomes because a change in the bioavailability of a therapy may alter its efficacy and/or safety profile. To optimize drug plasma concentrations, maximize drug effectiveness, and minimize potential risks that may occur from either increased or decreased drug exposure, it is crucial to understand food-drug interactions.

This article aims to provide pharmacists with the necessary information to be able to advise patients on how food may affect antiarrhythmic drugs (AADs). The article focuses on a recent publication that summarizes the clinical data supporting the need for dronedarone (Multaq; Sanofi-Aventis U.S. LLC) to be taken with a substantial meal to maximize absorption.²

Effects of Food on Oral AADs

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia.³ Although the management of AF is multifaceted, AAD therapy is frequently used to control arrhythmia.^4,5 The bioavailability of several AADs has been shown to be affected by food. For instance, when administered with food, absorption of sotalol (Vaughan-Williams class III) is decreased by approximately 20%,⁶ whereas absorption of amiodarone (Vaughan-Williams class I-IV) is markedly increased.⁷ Therefore, to advise patients on how best to take their medication, an awareness of the effect of food on individual AADs is needed (Table).

Dronedarone (Vaughan-Williams class I-IV) is indicated to reduce the risk of hospitalization for AF in people in sinus rhythm with a history of paroxysmal or persistent AF.⁸ Dronedarone has low solubility in water and, as such, its absorption in the gut is limited, resulting in an absolute bioavailability of 4%.⁸ The bioavailability of drugs with low water solubility can be increased by coadministration with food, which delays gastric emptying. A recent publication (discussed below) summarizes clinical data demonstrating that the bioavailability of dronedarone is increased to approximately 15% when administered with a fat-rich meal.^2,8 Consistent with this, the package insert of dronedarone instructs that one 400-mg tablet is to be administered twice daily, the first with a morning meal and the second with an evening meal.⁸ Adherence to this instruction is important, as administration of dronedarone without a substantial meal may result in subtherapeutic drug levels, potentially reducing its clinical effectiveness.

Some health care professionals who prescribe, and pharmacists who dispense, dronedarone are unaware of the effect of food on the bioavailability of the drug. A questionnaire-based study revealed that approximately one-fifth of respondents (physicians, pharmacists, and laypersons) classed package inserts as a source of confusion.⁹ In a survey of individuals from the New York City metropolitan area, 29.7% of the 307 respondents indicated that they seldom or never read the information supplied with their medication.¹⁰ Many health care professionals and pharmacists believe that the recommendation for administration of dronedarone with food is intended only to mitigate gastrointestinal side effects (unpublished observations). Two phase 1 studies conducted to determine the effect of food on the bioavailability of dronedarone were recently published in American Heart Journal Plus: Cardiology Research and Practice.² Here, we provide a brief overview of these studies to increase awareness of the need to administer dronedarone with food.

Studies Assessing Effect of Food on Dronedarone Pharmacokinetics

The most recent study to evaluate the effect of food on the bioavailability of dronedarone was conducted in 2009 at the request of Health Canada. Twenty-six healthy male and female adults received a single oral 400-mg dose of dronedarone under two conditions: fasting and immediately after a high-fat meal (2 eggs fried in butter, 2 slices toasted white bread, 2 strips bacon, 10 g butter, 113 g hash browns, 250 mL whole milk, and 1 tablespoon jelly, providing a total of 47.4 g fat). Participants were randomized to 1 of 2 treatment sequences (fasted followed by high-fat meal or high-fat meal followed by fasted). Compared with dronedarone in the fasted state, administration with a high-fat meal resulted in a 2.8-fold increase in the maximum observed plasma concentration (C_max) and a 2.0-fold increase in the area under the plasma concentration vs time curve calculated using the trapezoidal method from time zero to the time of the last observed concentration above the lower limit of quantification (AUC_last; Figure).

Figure. Overview of the Effect of Food on Dronedarone Bioavailability

An older study, conducted in 1997, was the basis of the US Food and Drug Administration–approved labeling for dronedarone. Nine healthy male adults received a single oral 800-mg dose of dronedarone (2 x 400-mg tablets) under three conditions: fasting, immediately after a low-fat meal (120 g yogurt, 2 rolls, 40 g honey, 25 g jam, 5 g margarine, and 2 cups decaffeinated coffee, providing a total of 5.3 g fat), and after a fat-rich meal (2 eggs [scrambled], 2 slices toasted white bread, 2 strips bacon, 1 teaspoon butter, 113 g hash browns, 226 mL whole milk, and 1 tablespoon jelly, providing a total of 37.3 g fat). Participants were randomized to 1 of 3 treatment sequences (fasted, low-fat, fat-rich; low-fat, fat-rich, fasted; or fat-rich, fasted, low-fat). Administration of dronedarone with a fat-rich meal resulted in a 4.6-fold increase in C_max and a 3.1-fold increase in AUC_last compared with administration in the fasted state. Administration with a low-fat meal resulted in a 3.2-fold increase in C_max and 2.3-fold increase in AUC_last compared with administration in the fasted state (Figure).

The results from both studies support the recommendation to administer dronedarone with a substantial meal to increase its absorption and therefore its bioavailability. Although administration of dronedarone with a fat-rich meal resulted in a greater increase in bioavailability compared with a low-fat meal (Figure), the difference was small. This indicates that the fat content of the meal is not critical to maximize absorption of dronedarone. The salient point is that, to maximize its absorption, dronedarone must be administered with a substantial meal.

An important point to note is the difference in dosing between the two studies. This is because the 800-mg dose study was conducted before determination of the final approved dose for dronedarone. The 800-mg dose was later determined to be less well tolerated than the 400-mg twice-daily regimen due to gastrointestinal symptoms. The difference in dosing between the two studies resulted in a difference in magnitude of the food effect, with a greater increase in the bioavailability of dronedarone observed with the 800-mg dose vs the 400-mg dose, which is likely due to differences in tablet load and volume of drug dissolution in the stomach.

The safety of dronedarone was assessed in both studies. Of the 26 participants who received the 400-mg dose, 5 experienced treatment-emergent adverse events: 2 in the fed (high-fat meal) state (one report each for orthostatic hypotension and increased eosinophil count) and 3 in the fasted state (one participant reported hypoglycemia; another reported malaise and postural dizziness; and a third participant reported anxiety, headache, abdominal pain, vomiting, and asthenia). In the 800-mg dose study, 3 of the 9 participants experienced treatment-emergent adverse events: one reported diarrhea while another reported two episodes of non-sustained asymptomatic ventricular tachycardia. The third participant experienced the only serious adverse event, which was an accident unrelated to the study. One participant discontinued the 400-mg dose study (due to increased eosinophil count). The relationship of dronedarone to the reported adverse events in these studies is unknown partly due to the small sample sizes.

With Which Foods Should Dronedarone Be Administered?

The results discussed in this article underscore the importance of taking dronedarone with a substantial meal to maximize its absorption. Although a meal with higher fat content resulted in a higher magnitude of increased exposure, the difference in drug absorption between fat-rich and low-fat meals was minimal.

As dronedarone is taken twice daily, it is recommended to be taken with breakfast and an evening meal.⁸ Using the 800-mg study as a guide (based on the calorie content of the low-fat meal), a meal size of approximately 500 calories is suitable, with a fat content of 50 calories or less. Breakfast could be a meal of yogurt, 2 bread rolls, honey, jam, and coffee. If the main meal is typically eaten at lunchtime, switching the main meal to the evening is recommended, as taking dronedarone with a light snack may be insufficient for optimal drug absorption.

Summary

Awareness of the food effects associated with AADs is important, and health care professionals prescribing or dispensing dronedarone should counsel patients accordingly. All AADs exhibit different food effects, and individual label guidance should be followed. In the case of dronedarone, administration without a substantial meal may result in subtherapeutic drug levels, potentially reducing its clinical effectiveness. It is therefore important for health care professionals to advise their patients that dronedarone must be taken with a substantial meal to achieve maximum efficacy; a light snack is insufficient.

Acknowledgements

Coordination of the development of this manuscript, facilitation of author discussion, and critical review were provided by Karen Finnegan, PhD, CMPP at Sanofi. The authors acknowledge medical writing and editorial assistance provided by Barrie Anthony, PhD, CMPP, of Envision Pharma Group, funded by Sanofi. The authors were responsible for all content and editorial decisions and received no honoraria related to the development of this publication.

Funding

The dronedarone phase 1 studies were funded by Sanofi.

Conflict of Interest

SAS is co-founder and CEO of VeganMed, Inc. KBC serves as a consultant for Wolters Kluwer and is on the Board of Trustees for the Heart Rhythm Society.

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