Preclinical Safety and Efficacy Assessments of Dendrimer-Based (SPL7013) Microbicide Gel Formulations in a Nonhuman Primate Model

Abstract

Three gel formulations (1%, 3%, and 5% [wt/wt]) of SPL7013, a dendrimer known to have antiviral (anti-human immunodeficiency virus and anti-herpes simplex virus) activities, completed a range of preclinical tests in the pigtailed macaque models for vaginally and rectally applied topical microbicide safety assessments. The vaginal safety profile of the 3% SPL7013 gel formulation was equal to that of the 1% formulation but was superior to that of the 5% formulation. The 3% SPL7013 gel was further evaluated for rectal safety and for antichlamydial efficacy with cervical challenge with Chlamydia trachomatis. This first-generation dendrimerbased product was shown to be safe to the vaginal and rectal microenvironments with repeated daily use. However, a single intravaginal application of the 3% (wt/wt) SPL7013 gel did not provide protection from the acquisition of cervical chlamydial infection.The use of topical microbicides is an emerging strategy for the prevention of transmission of human immunodeficiency virus (HIV) and other sexually transmitted infections. Topical microbicide products should optimally be safe and effective for repeated vaginal and/or rectal use.Dendrimers are a novel class of macromolecules characterized by highly branched three-dimensional structures (15). Dendrimers have good antiviral activities against both HIV and herpesvirus and physical properties appropriate for microbicide applications (2,3,5,(7)(8)(9)17). SPL7013, a dendrimerbased microbicide developed by Starpharma Pty Ltd., Melbourne, Australia, has emerged as a candidate for such a product (10,15).In this study, three gel formulations (1%, 3%, and 5% [wt/ wt]) of SPL7013 were assessed in a range of preclinical safety tests performed with the established pigtailed macaque models of repeated vaginal and rectal application (11-13). The vaginal safety profile of the 3% SPL7013 gel formulation was equal to that of the 1% formulation but was superior to that of the 5% formulation. Unformulated SPL7013 has been shown in separate mouse models to protect against genital herpes simplex virus type 2 infection and significantly reduce the incidence of ascending genital tract infection caused by Chlamydia trachomatis (2, 3). Thus, the 3% SPL7013 gel formulation was further evaluated for rectal safety and antichlamydial efficacy with a cervical challenge of C. trachomatis. MATERIALS AND METHODSTest products. Dendrimer gel formulations containing 1%, 3%, and 5% (wt/ wt) SPL7013 and a placebo gel were provided by Starpharma Pty Ltd.Animals. Sexually mature, female Macaca nemestrina macaques were obtained from a colony of animals at the Washington National Primate Research Center. Prior approval for use of the monkeys in this protocol was obtained from the Institutional Animal Care and Use Committee at the University of Washington. The animals were handled humanely, and experiments were performed within the National Institutes of Health's animal use guidelines. Experimental safety protocols. (i) Vaginal safety.Three concentrations of SPL7013 in a wa...

Designing Dendrimers for Drug Delivery and Imaging: Pharmacokinetic Considerations

“…Vivagel®, developed by Starpharma (Melbourne, Australia), is a formulation of polyanionic lysine G4 dendrimers with an anionic surface of naphthalene-disulfonate (SPL7013) in a Carbopol® gel. It exhibits antiviral activity against HIV and HSV for the treatment of sexually transmitted infections and is given by intravaginal administration (152). Complete preclinical and phase I clinical studies have shown that 0.5-3% SPL7013 formulations are safe and well tolerated after seven-day vaginal application without systemic absorption (151)(152)(153).…”

“…It exhibits antiviral activity against HIV and HSV for the treatment of sexually transmitted infections and is given by intravaginal administration (152). Complete preclinical and phase I clinical studies have shown that 0.5-3% SPL7013 formulations are safe and well tolerated after seven-day vaginal application without systemic absorption (151)(152)(153). A phase II clinical trial of Vivagel® is ongoing with fast track status.…”

Enhancement of Human Immunodeficiency Virus Type 1 Replication Is Not Intrinsic to All Polyanion-Based Microbicides

“…SPL7013 has demonstrated low toxicity in cervical and colorectal epithelial cell lines, peripheral blood mononuclear cells (PBMCs), and macrophages and does not impair the resistance of polarized epithelial cells (6). VivaGel has demonstrated favorable safety profiles when administered vaginally and rectally in macaques (16) (4). It is effective in preventing the vaginal transmission of the CXCR4 SHIV89.6P strain in macaques and SHIV162P3 infection of macaque PBMCs (11).…”

Microbicides for the Prevention of HPV, HIV-1, and HSV-2: Sexually Transmitted Viral Infections

“…Several trials have been conducted to evaluate the safety and eicacy of this product. These studies unanimously describe that SPL7013 is nontoxic and safe to use even at very high concentrations of (1000 μg/ml) [112,114]. Likewise, in …”