EVALUATION OF THE EFFECT OF FOOD ON THE PHARMACOKINETICS OF AVITRIPTAN

Bioavailability of avitriptan was found to decrease significantly when administered 5 min after a standard high fat meal. The studies descri bed herein were carried out to gain insight into the mechanism of this food effect. A series of studies were conducted in humans to assess t he effect of timing of meal, type of meal, gastric pH, change in the f ormulation and dose on the bioavailability of avitriptan. Avitriptan w as administered as a 50 mg capsule under fasted condition and at 30 mi n, 1, 2 and 4 h after a standard high fat meal. The reduction in avitr iptan bioavailability persisted even at 4 h post high fat meal, althou gh as the time interval between the meal and dose increased, the effec t of meal tended to decrease. Bioavailability of avitriptan also decre ased significantly when the drug was administered after a high protein and a high carbohydrate meal. Elevation in gastric pH caused by food was not found to be responsible for the food-related decrease in bioav ailability of avitriptan since ranitidine pretreatment did not lead to a decrease in bioavailability. When administered as a 50 mg C-14-labe led solution after a standard high fat meal, bioavailability of avitri ptan decreased although the decrease was less compared with that obser ved for a capsule dosage form. Plasma concentrations and cumulative ur inary excretion of total radioactivity also decreased in the fed condi tion, indicating the absorption of avitriptan was affected. The decrea se in avitriptan AUC was somewhat more pronounced than the decrease in the exposure to the total radioactivity suggesting a food-related inc rease in the first-pass metabolism of avitriptan. Effect of the standa rd high fat meal on avitriptan administered as a 150 mg capsule was si milar to that observed at the 50 mg dose. Overall, the results indicat e that bioavailability of avitriptan is significantly reduced irrespec tive of the type of meal, dose and dosage form and the effect persists for as long as 4 h post meal. Thus, it appears that avitriptan absorp tion and bioavailability are highly sensitive to presence of food in t he stomach and any food-related changes in gastric emptying time and g astrointestinal motility. (C) 1998 John Wiley & Sons, Ltd.