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Pharmacokinetic Interaction Study of Indinavir/Ritonavir and the Enteric-Coated Capsule Formulation of Didanosine in Healthy Volunteers

From the Department of Clinical Pharmacy, University Medical Centre, Nijmegen, the Netherlands (C. la Porte, C. Verweij-van Wissen, N. van Ewijk, R. Aarnoutse, Y. Hekster, D. Burger); Nijmegen University Centre for Infectious Diseases, Nijmegen, the Netherlands (C. la Porte, R. Aarnoutse, P. Koopmans, Y. Hekster, D. Burger); Department of General Medicine, University Medical Centre, Nijmegen, the Netherlands (P. Koopmans); Department of Infectious Diseases and National AIDS Therapy Evaluation Centre (NATEC), Academic Medical Center, Amsterdam, the Netherlands (P. Reiss); and Merck & Co, Whitehouse Station, New Jersey (M. Stek, Jr).

Didanosine enteric-coated should be taken on an empty stomach, but the once-daily combination of indinavir/ritonavir can be taken with food. Because these drugs are frequently included in 1 regimen, the food effects on the pharmacokinetics were evaluated. This was a randomized, 4-way crossover study of single doses of didanosine enteric-coated 400 mg and indinavir/ritonavir 1200/400 mg in 8 healthy subjects. The following regimens were given: didanosine enteric-coated 2 hours after breakfast (reference regimen A), indinavir/ritonavir with breakfast (reference regimen B), didanosine enteric-coated + indinavir/ritonavir 2 hours after breakfast (test regimen C), and didanosine enteric-coated + indinavir/ritonavir with breakfast (test regimen D). Breakfast was 550 kcal, 28% fat. Blood samples were drawn before and up to 24 hours after ingestion. Statistical comparisons of test regimens C and D with reference regimens A and B were made using the equivalence approach for indinavir and didanosine area under the curve and C_max (0.80-1.25). Eight subjects (5 men, 3 women) were enrolled and completed the study. Indinavir area under the curves were bioequivalent in test regimens C and D compared to reference regimen B. A 14% increased C_max was observed in test regimen C. Didanosine area under the curve in test regimen D was 4% lower and suggestive of bioequivalence compared to reference regimen A. However, test regimen C didanosine area under the curve was 23% lower and bioinequivalent compared to reference regimen A. Didanosine C_max decreased 42% and 46% in test regimens C and D, respectively, in comparison to reference regimen A. In this study, dosing didanosine enteric-coated 400 mg once daily + indinavir/ritonavir 1200/400 mg once daily with breakfast indicated no decrease in the amount of absorption for either didanosine and indinavir and that this regimen could be administered with food.

Key Words: Indinavir • ritonavir • didanosine • highly active antiretroviral therapy (HAART) • pharmacokinetics • drug interactions

Address for reprints: Charles J. L. la Porte, PharmD, Department of Clinical Pharmacy, University Medical Centre Nijmegen, PO Box 9101, 533 KF, 6500 HB, Nijmegen, the Netherlands.