Absence of clinically relevant drug interactions following simultaneous administration of didanosine-encapsulated, enteric-coated bead formulation with either itraconazole or fluconazole.
This open-label, two-way crossover study was undertaken to determine whether the enteric formulation of didanosine influences the pharmacokinetics of itraconazole or fluconazole, two agents frequently used to treat fungal infections that occur with HIV infection, and whose bioavailability may be influenced by changes in gastric pH. Healthy subjects were randomized to Treatment A (200-mg itraconazole or 200-mg fluconazole) or Treatment B (same dose of itraconazole or fluconazole with 400 mg of didanosine as an encapsulated, enteric-coated bead formulation). In the itraconazole study, 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-T) values of itraconazole and hydroxyitraconazole, the active metabolite of itraconazole, were contained entirely between 0.75 and 1.33. In the fluconazole study, the equivalence interval for C(max) and AUC(0-T) was 0.80-1.25. The data showed that for itraconazole the point estimate and 90% CI of the ratios of C(max) and AUC(0-T) values were 0.98 (0.79, 1.20) and 0.88 (0.71, 1.09), respectively; for hydroxyitraconazole the respective values were 0.91 (0.76, 1.08) and 0.85 (0.68, 1.06). In the fluconazole study, the point estimate and 90% CI of the ratios of C(max) and AUC(0-T) values were 0.98 (0.93, 1.03) and 1.01 (0.99, 1.03), respectively. The T(max) for itraconazole, hydroxyitraconazole, and fluconazole were similar between treatments. Both studies indicated a lack of clinically significant interactions of the didanosine formulation with itraconazole or fluconazole. These results showed that the encapsulated, enteric-coated bead formulation of didanosine can be concomitantly administered with drugs, such as the azole antifungal agents, whose bioavailability may be influenced by interaction with antacids.
Damle
B
B
Clinical Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543, USA. bharat.damle@bms.com
Hess
H
H
Kaul
S
S
Knupp
C
C
D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000935:Antifungal Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D002214:Capsules; D018592:Cross-Over Studies; D016049:Didanosine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004347:Drug Interactions; D005260:Female; D015725:Fluconazole / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006801:Humans; D017964:Itraconazole / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D013608:Tablets, Enteric-Coated
D019380:Anti-HIV Agents; D000935:Antifungal Agents; D002214:Capsules; D013608:Tablets, Enteric-Coated; D017964:Itraconazole; D015725:Fluconazole; D016049:Didanosine