In Vivo Evaluation of a Gel Formulation of Stampidine, a Novel Nonspermicidal Broad-Spectrum Anti-HIV Microbicide

Abstract

IntroductionStampidine (2′,3′-didehydro-2′,3′-dideoxythymidine 5′-[p-bromophenyl methoxyalaninyl phosphate]), a novel aryl phosphate derivative of stavudine (STV/d4T), is a potent, broad-spectrum anti-HIV agent with potential as a new class of nonspermicidal microbicide. As part of an effort to develop an acceptable formulation for the clinical use of stampidine as a microbicide, we developed a vaginal gel formulation of stampidine and evaluated its potential to cause mucosal toxicity in the New Zealand white rabbit vaginal irritation model.MethodsStampidine was solubilized in a gel formulation composed of microcrystalline cellulose, xanthan gum, macrogol (polyethylene glycol [PEG]) 400, sorbitol, and polysorbate 80. Rabbits in groups of four were exposed intravaginally to a gel with 0.5, 1, or 2% stampidine or no active drug for 14 consecutive days. The rabbits were euthanized on day 15 and their vaginal tissues were evaluated for histologic evidence of mucosal toxicity and immunohistochemical evidence of cellular inflammation or hyperplasia. Additionally, rabbits in groups of three were exposed intravaginally to a 2% stampidine gel, and plasma samples collected at various timepoints were assayed for stampidine and its major metabolites, alaninyl-stavudine-monophosphate and stavudine by analytical high performance liquid chromatography (HPLC).ResultsWith application of 0.5–2.0% stampidine, only minimal-to-mild vaginal irritation was observed, which is within the acceptable range for clinical trials (total score <4 out of a possible 16). Repeated intravaginal treatment with stampidine gel caused no inflammation or hyperplasia in the vaginal epithelium and submucosa. Stampidine and its major metabolites were not detectable in the plasma of rabbits given 2% stampidine-containing gel intravaginally.ConclusionsThe favorable toxicity profile of intravaginally administered stampidine-containing gel may provide the foundation for its clinical development as a safe and effective broad-spectrum anti-HIV microbicide without contraceptive properties.