Background: Previous PK studies have identified increased drug exposure when didanosine (ddI) buffered tablet or enteric-coated capsule formulations are co-administered with tenofovir DF (TDF). These increases are such that ddI dose reduction may be appropriate to reduce the risk for ddI-associated adverse events. The objective of this study was to evaluate ddI PK following a dose reduction when ddI is administered in the fasted state and TDF is administered with a meal per current dosage and administration instructions (regulatory labeling). This study also evaluated the PK of ddI following a simplified dosing regimen of simultaneous co-administration with TDF in both the fasted and fed state.

Methods: Healthy subjects weighing > 60 kg received ddI EC 400 mg alone in the fasted state as a reference treatment. TDF 300 mg was dosed to steady state, after which ddI EC 250 mg was administered on 3 consecutive days. First, in the fasted state 2 hrs prior (staggered) to TDF and a light meal (373 kcal, 20% fat); second, simultaneously with TDF and a light meal, and third simultaneously with TDF in the fasted state. For each test treatment, ddI exposures (AUC and C_max) were compared to those from 400 mg by generation of 90% confidence intervals (CI) about the ratio of geometric means (GMR [90% CI]).

Results: When administered in a staggered fashion (per regulatory labeling), a 250 mg dose of ddI EC + TDF resulted in an equivalent AUC to 400 mg dosed alone. ddI AUCs were slightly higher (+14%) and lower (-11%) when simultaneously co-administered with TDF in the fasted and fed states, respectively. Observed ddI C_max values were only slightly lower following 250 mg + TDF versus a 400 mg dose alone. Within the interaction with TDF, ddI exposures were minimally affected by staggering of doses or the effect of food.

Conclusions: Administration of ddI EC 250 mg with TDF staggered or simultaneously with or without a meal results in similar drug exposures to a 400 mg dose of ddI EC alone.