title: Lack of effect of simultaneously administered didanosine encapsulated enteric bead formulation (Videx EC) on oral absorption of indinavir, ketoconazole, or ciprofloxacin.
abstract: Didanosine formulation that contains a buffer to prevent it from acid-mediated degradation can result in a significant decrease in the oral absorption of certain drugs because of interactions with antacids. An enteric formulation of didanosine is unlikely to cause such drug interactions because it lacks antacids. This study was undertaken to determine whether the enteric bead formulation of didanosine (Videx EC) influences the bioavailability of indinavir, ketoconazole, and ciprofloxacin, three drugs that are representative of a broader class of drugs affected by interaction with antacids. Healthy subjects of either gender were enrolled in three separate open-label, single-dose, two-way crossover studies. Subjects were randomized to treatment A (800 mg of indinavir, 200 mg of ketoconazole, or 750 mg of ciprofloxacin) or treatment B (same dose of indinavir, ketoconazole, or ciprofloxacin, but with 400 mg of didanosine as an encapsulated enteric bead formulation). A lack of interaction was concluded if the 90% confidence interval (CI) of the ratio of the geometric means of log-transformed C(max) and AUC(0-infinity) values (i.e., values for the area under the concentration-time curve from time zero to infinity) of indinavir, ketoconazole, and ciprofloxacin were contained entirely between 0.75 and 1.33. For indinavir (n = 23), the point estimate (90% CI; minimum, maximum) of the ratios of C(max) and AUC(0-infinity) values were 0.99 (0.91, 1.06) and 0.96 (0.91, 1.02), respectively. In the ketoconazole study, 3 of 24 subjects showed anomalous absorption of ketoconazole (i.e., an approximately 8-fold-lower AUC compared to historical data), which was the reference treatment. A post hoc analysis performed after these three subjects were excluded indicated that the point estimates (90% CI) of the ratios of C(max) and AUC(0-infinity) values were 0.99 (0.86, 1.14) and 0.97 (0.85, 1.10), respectively. For ciprofloxacin (n = 16), the point estimate (90% CI) of the ratios of C(max) and AUC(0-infinity) values were 0.92 (0.79, 1.07) and 0.91 (0.76, 1.08), respectively. All three studies clearly indicated a lack of interaction. The T(max) and t(1/2) for indinavir, ketoconazole, and ciprofloxacin were similar between treatments. Our results showed that the lack of interaction of didanosine encapsulated enteric bead formulation with indinavir, ketoconazole, and ciprofloxacin indicates that this enteric formulation of didanosine can be concomitantly administered with drugs whose bioavailability is known to be reduced by interaction with antacids.
authors.affiliation: Clinical Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Bristol-Myers Squibb Company, Princeton, New Jersey 08543, USA. bharat.damle@bms.com
authors.forename: Bharat D
authors.initials: BD
authors.lastname: Damle
authors.forename: Vanaja
authors.initials: V
authors.lastname: Mummaneni
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Kaul
authors.forename: Catherine
authors.initials: C
authors.lastname: Knupp
mesh_terms: D000042:Absorption; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000890:Anti-Infective Agents / Q000009:adverse effects / Q000493:pharmacokinetics; D000935:Antifungal Agents / Q000009:adverse effects / Q000493:pharmacokinetics; D000963:Antimetabolites / Q000494:pharmacology*; D002214:Capsules; D002626:Chemistry, Pharmaceutical; D002939:Ciprofloxacin / Q000009:adverse effects / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D016049:Didanosine / Q000494:pharmacology*; D004347:Drug Interactions; D004361:Drug Tolerance; D005260:Female; D017320:HIV Protease Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics; D006801:Humans; D019469:Indinavir / Q000009:adverse effects / Q000493:pharmacokinetics*; D007654:Ketoconazole / Q000009:adverse effects / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged
chemical_list: D000890:Anti-Infective Agents; D000935:Antifungal Agents; D000963:Antimetabolites; D002214:Capsules; D017320:HIV Protease Inhibitors; D002939:Ciprofloxacin; D019469:Indinavir; D016049:Didanosine; D007654:Ketoconazole