Strategies to improve efficacy and safety of a novel class of antiviral hyper‐activation‐limiting therapeutic agents: the VS411 model HIV/AIDS

Abstract

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 (Cmax) to potentially reduce toxicity while maintaining total daily exposure (AUC) and the AV activity. EXPERIMENTAL APPROACHThis 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 RESULTSFormulation VS411-2 had a favourable safety profile, displayed a clear trend for lower ddI Cmax (P = 0.0603) compared to Videx EC, and the 90% confidence intervals around the least square means ratio of Cmax 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 IMPLICATIONSA 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. Abbreviations3TC, lamivudine; ACTG, AIDS Clinical Trials Group; AIDS, acquired immunodeficiency syndrome; AUC, area under the plasma concentration-time curve; AUC•, area under the plasma concentration-time curve extrapolated to infinity; AUClast, area under the plasma concentration-time curve from time of administration up to the last time point with a measurable concentration post

Acute hemolytic vascular inflammatory processes are prevented by nitric oxide replacement or a single dose of hydroxyurea

“…HU is commonly used for the treatment of SCD, among other hematologic and nonhematologic diseases [14][15][16] in a chronic regime, because of its ability to increase levels of HbF and reduce platelet and leukocyte counts, 17,19 with consequent clinical benefits for patients. 43 However, HU may have important effects that are independent of HbF elevation, as this molecule can donate NO.…”

“…13 Hydroxyurea (HU) is a cytostatic drug, frequently used in the treatment of hematologic diseases such as SCD, beta thalassemia, polycythemia vera, essential thrombocythemia, and myelofibrosis, as well as nonhematologic diseases such as HIV/AIDS. [14][15][16] In SCD, HU modifies the disease process, improving hematologic parameters and reducing hospitalization and mortality. 17 One of the major mechanisms of action of HU in SCD is believed to be its ability to induce the production of fetal Hb (HbF) in erythrocytes, reducing hemoglobin S (HbS) polymerization and red cell sickling.…”

VS411 Reduced Immune Activation and HIV-1 RNA Levels in 28 Days: Randomized Proof-of-Concept Study for AntiViral-HyperActivation Limiting Therapeutics

“…These tablets were combined with HC 150 mg tablets designed to duplicate the previous plasma concentration-time profile of HC [39]. The use of individual tablets of didanosine and HC allowed differing numbers of didanosine and HC tablets, as well as placebos for both, to be placed into blinded capsules for each cohort of the five-arm dose-ranging study.…”

“…The dosages of the two drugs historically used to treat HIV-1 infection are now recognized as having been too high, generating immunosuppressive effects and toxicities that were further exacerbated by the frequent addition of a second nucleoside analogue, stavudine [39] , [40] , [41] . Since the side effects were largely dose dependent, we decided to investigate whether lower doses of both didanosine and HC could maintain antiviral efficacy while reducing toxicity during short-term (28 day) administration.…”

“…The five VS411 FDC formulations used in this dose-ranging study were developed using proprietary slow release, enterically-coated 100 mg didanosine tablets designed to modify the drug’s release profile, and thereby the didanosine plasma concentration-time profile, to further reduce potential toxicity. These tablets were combined with HC 150 mg tablets designed to duplicate the previous plasma concentration-time profile of HC [39] . The use of individual tablets of didanosine and HC allowed differing numbers of didanosine and HC tablets, as well as placebos for both, to be placed into blinded capsules for each cohort of the five-arm dose-ranging study.…”