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.
RCT Entities:
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.
Authors: Alonso Heredia; Charles Davis; Anthony Amoroso; Joyelle K Dominique; Nhut Le; Erin Klingebiel; Elise Reardon; Davide Zella; Robert R Redfield Journal: Proc Natl Acad Sci U S A Date: 2003-03-18 Impact factor: 11.205
Authors: D V Havlir; P B Gilbert; K Bennett; A C Collier; M S Hirsch; P Tebas; E M Adams; L J Wheat; D Goodwin; S Schnittman; M K Holohan; D D Richman Journal: AIDS Date: 2001-07-27 Impact factor: 4.177
Authors: Franco Lori; Davide De Forni; Elly Katabira; Denis Baev; Renato Maserati; Sandra A Calarota; Pedro Cahn; Marco Testori; Aza Rakhmanova; Michael R Stevens Journal: PLoS One Date: 2012-10-19 Impact factor: 3.240