Abstract

BACKGROUND AND PURPOSE. Antiviral hyper-activation-limiting therapeutic agents (AV-HALTs) are a novel experimental drug class designed to both decrease viral replication and down-regulate excessive immune system activation for the treatment of chronic infections, including human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome. VS411, a first-in-class AV-HALT, is a single-dosage form combining didanosine (ddI, 400 mg), an antiviral (AV), and hydroxyurea (HU, 600 mg), a cytostatic agent, designed to provide a slow release of ddI to reduce its maximal plasma concentration (C_max) to potentially reduce toxicity while maintaining total daily exposure (AUC) and the AV activity.
EXPERIMENTAL APPROACH. This was a pilot phase I, open-label, randomized, single-dose, four-way crossover trial to investigate the fasted and non-fasted residual variance of AUC, Cmax and the oral bioavailability of ddI and HU, co-formulated as VS411, and administered as two different fixed-dose combination formulations compared to commercially available ddI (Videx EC) and HU (Hydrea) when given simultaneously.
KEY RESULTS. Formulation VS411-2 had a favourable safety profile, displayed a clear trend for lower ddI C_max (P= 0.0603) compared to Videx EC, and the 90% confidence intervals around the least square means ratio of C_max did not include 100%. ddI AUC∞ was not significantly decreased compared to Videx EC. HU pharmacokinetic parameters were essentially identical to Hydrea, although there was a decrease in HU exposure under fed versus fasted conditions.
CONCLUSIONS AND IMPLICATIONS A phase IIa trial utilizing VS411-2 formulation has been fielded to identify the optimal doses of HU plus ddI as an AV-HALT for the treatment of HIV disease.

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