Preclinical safety assessments of UC781 anti-human immunodeficiency virus topical microbicide formulations

Abstract

The nonnucleoside reverse transcriptase inhibitor UC781 is under development as a potential microbicide to prevent sexual transmission of human immunodeficiency virus type 1 (HIV-1). Two gel formulations of UC781 (0.1% and 1.0%) were evaluated in a range of preclinical safety assessments, including systemic absorption analysis following topical application in the pig-tailed macaque models for vaginally and rectally applied topical microbicides. High-sensitivity high-performance liquid chromatography analysis of serum samples showed that no systemic absorption of UC781 was detected after repeated vaginal or rectal application of either product. However, high levels of UC781 were detectable in the cervicovaginal lavage samples up to 6 h after product exposure. Both formulations were safe to the vaginal microenvironment, even with repeated daily use, as evidenced by colposcopy, cytokine analysis, and lack of impact on vaginal microflora. By contrast, rectal application of the 1.0% UC781 formulation caused an increased expression of numerous cytokines not observed after rectal application of the 0.1% UC781 formulation. These results provide additional support for the continued development of UC781 formulations as anti-HIV microbicides.

FIG. 1.

(a to c) Ectocervical tissue prior to UC781 gel exposure (a) and 2 hours after exposure (2-hrs Post Exposure) to control DMEM (b) and 2 h after exposure to 0.1% UC781 (c). No histologic changes were noted. (d) Pretreatment control for 2 h after exposure to 4.0% nonoxynol-9 (Non-9) (e).

FIG. 2.

Tissue viability as assessed using the MTT assay. N-9, nonoxynol-9.

FIG. 3.

(a) Vaginal application. Mean vaginal pH in the macaque showed increased variability after product use compared to placebo but consistently remained within the normal range for macaques. The vaginal pH values at 0 and 30 minutes on days 1 to 4 are shown. Vaginal pHs that were significantly different from the values for the placebo group are indicated by asterisks. (b) Rectal application. Mean rectal pH in the macaque showed transient pH shifts with product use. There were no significant differences between the baseline pH and follow-up pH in any group. The rectal pH values at 0 and 30 minutes on days 1 to 4 are shown.

FIG. 4.

Detection of UC781 in macaque vaginal lavage samples. The concentration of 1.0% UC781 in cervicovaginal lavage samples was highest at the 1-hour (60-min) sampling interval, although at 6 h postexposure, detectable levels were still at a high concentration of >1 mM or 10,000 times greater than the 50% inhibitory concentration.