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Strategies to improve efficacy and safety of a novel class of antiviral hyper‐activation‐limiting therapeutic agents: the VS411 model HIV/AIDS
Author(s) -
De Forni D,
Stevens MR,
Lori F
Publication year - 2010
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2010.00940.x
Subject(s) - pharmacokinetics , bioavailability , pharmacology , crossover study , toxicity , confidence interval , medicine , bioequivalence , didanosine , therapeutic index , viral load , in vivo , drug , human immunodeficiency virus (hiv) , immunology , biology , antiretroviral therapy , microbiology and biotechnology , alternative medicine , pathology , placebo
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, C max 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.