title: Effect of food on the oral bioavailability of didanosine from encapsulated enteric-coated beads.
abstract: The objective of this study was to assess the effect of food and timing of meals on the bioavailability of didanosine from encapsulated enteric-coated beads. Four different independent, open-label, single-dose, randomized, crossover studies were conducted in healthy subjects (n = 20-30). Didanosine (400 mg) was given concomitantly with a high-fat meal, light meal, yogurt, and applesauce. In addition, didanosine was given 1, 1.5, 2, and 3 hours before and 2 hours after a light meal. Statistical comparison with fasting conditions was made using the equivalence approach for Cmax (70%-143%) and AUC (80%-125%). The high-fat meal, light meal, yogurt, and applesauce decreased the Cmax by 46%, 22%, 30%, and 24%, respectively, and lowered the AUC by 19%, 27%, 20%, and 18%, respectively; statistical analyses indicated an indeterminate food effect, except for the Cmax for the high-fat meal. For 1 hour before meal, Cmax and AUC were lower by 15% and 24% and, for 2 hours after meal, were lower by 15% and 10%, respectively. There was an indeterminate food effect for 1 hour before the meal treatment; in addition, 2 hours after the meal, treatment approached statistical equivalence, missing narrowly on the lower bounds. For 1.5, 2, and 3 hours before meal treatments, Cmax values were unchanged, but AUC was lower by 10%, 4%, and 0%, respectively; lack of food effect was observed for all three treatments. Across studies, median time to Cmix ranged from 1.67 to 2.67 hours but was delayed by 2.5 to 3 hours with high-fat and light meals compared to fasting conditions. The half-life of didanosine was 1.5 to 2 hours. It was concluded that the bioavailability of didanosine from encapsulated enteric-coated beads was reduced by approximately 20% to 25% with food, which can be circumvented by taking didanosine on an empty stomach. The clinical significance of such moderate reductions in didanosine exposure with food, especially as part of a highly active antiretroviral therapy, is not clear.
authors.affiliation: Department of Clinical Discovery, Biostatistics, and Data Management, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543, USA.
authors.forename: Bharat D
authors.initials: BD
authors.lastname: Damle
authors.forename: Jing-He
authors.initials: JH
authors.lastname: Yan
authors.forename: Douglas
authors.initials: D
authors.lastname: Behr
authors.forename: Edward
authors.initials: E
authors.lastname: O'Mara
authors.forename: Peter
authors.initials: P
authors.lastname: Nichola
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Kaul
authors.forename: Catherine
authors.initials: C
authors.lastname: Knupp
mesh_terms: D000284:Administration, Oral; D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood; D019540:Area Under Curve; D001682:Biological Availability; D016001:Confidence Intervals; D018592:Cross-Over Studies; D016049:Didanosine / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood*; D004041:Dietary Fats / Q000097:blood; D005215:Fasting / Q000097:blood; D005260:Female; D018565:Food-Drug Interactions / Q000502:physiology*; D006801:Humans; D008297:Male; D008863:Microspheres; D013608:Tablets, Enteric-Coated
chemical_list: D019380:Anti-HIV Agents; D004041:Dietary Fats; D013608:Tablets, Enteric-Coated; D016049:Didanosine