title: Strategies to improve efficacy and safety of a novel class of antiviral hyper-activation-limiting therapeutic agents: the VS411 model in [corrected] HIV/AIDS.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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
  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.
authors.affiliation: ViroStatics, Sassari, Italy.
authors.forename: D
authors.initials: D
authors.lastname: De Forni
authors.forename: M R
authors.initials: MR
authors.lastname: Stevens
authors.forename: F
authors.initials: F
authors.lastname: Lori
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D018592:Cross-Over Studies; D016049:Didanosine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D005215:Fasting; D006801:Humans; D006918:Hydroxyurea / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D016018:Least-Squares Analysis; D019384:Nucleic Acid Synthesis Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D010865:Pilot Projects
chemical_list: D019380:Anti-HIV Agents; D004338:Drug Combinations; D019384:Nucleic Acid Synthesis Inhibitors; D016049:Didanosine; D006918:Hydroxyurea