Choice of Dose and Composition of the Meal

A study investigating the potential influence of concomitant food intake should be performed under conditions that really stresses the system, that is a "worst case" approach should be used. Therefore, the highest dose in the expected therapeutic range should be chosen. A sound justification for the use of a lower dose strength is recommended, e.g., tolerability problems that precludes dosing at the highest dose level without previous dose titration starting at a lower level. If a modified release (MR) formulation has been developed, in vitro dissolution testing can be substituted for an in vivo study for other, usually the lower, strengths of the MR tablets. If the in vitro release profiles between the MR formulations differ, or the excipients differ qualitatively between the dosage strengths, additional in vivo food studies may be required for the other dosage strengths.

The composition of the meal should be of high caloric content (approximately 800-1000 calories) where 50% of the content consists of fat. The FDA gives an example of test meal, which fulfills these criteria, which is composed of two eggs fried in butter, two strips of bacon, two buttered slices of toast, four ounces (about 110g) of hash brown potatoes, and eight ounces (240 mL) of whole milk [20]. This meal gives about 150 calories from protein, 250 calories from carbohydrates, and 500-600 calories from fat. Alternate meal compositions can be used, but it is important that the proportions of fat, protein, and carbohydrates are kept to give a similar caloric content to the proposed test meal. The description of the meal should be included in both the protocol and the final report.

One may argue that the described breakfast is not an appropriate test meal for the vast majority of patients, since only a fraction of any population eats this type of breakfast. However, the purpose of the test meal is to study the effects of maximal perturbations created by concomitant food intake, both with respect to interaction between the drug, the pharmaceu-tical formulation, and the nutritional content of the meal. The high caloric content, in part originating from the high fat content, will also amplify the physiological effects of the test meal, e.g., the delay in gastric emptying and the increase in splanchnic blood flow.

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