P18.08
Background: Two reformulated gels designed to deliver tenofovir (TFV) in a mucosa friendly manner for use as dual compartment microbicides were assessed in the pigtail macaque model. A reduced glycerin (RGVF), an iso-osmolar (TFIO), and matched placebo gels were assessed for safety and drug absorption with vaginal use.
Methods: Six macaques completed each study arm, receiving one of the TFV or placebo gels, daily for four days. Safety of repeated, daily exposures was measured by repeated colposcopic assessment, vaginal pH, vaginal smear and microbiology tracking. In addition, vaginal swabs and blood samples were collected daily for TFV detection. Rectal swabs were also collected to determine whether TFV crossed from the site of delivery to the rectum. Finally, vaginal and cervical biopsies were collected on study day 5 to document TFV and its active metabolite tenofovir diphosphate (TFV-DP) levels in the local tissue.
Results: RGVF and TFIO caused no discernible irritation to cervicovaginal tissues in the standardized safety study. RGVF was tolerated slightly better than its placebo, while TFIO was indistinguishable from its placebo gel by parameters assessed here. Both TFV gels resulted in heightened plasma TFV levels (RGVF 125ng/mL; TFIO 40ng/mL) 30-minutes after the initial exposure (T30 only measured on day 1), and in much lower concentration (1-2ng/mL) through day 5. TFV accumulated in the vaginal secretions, peaking on day 5 for both gels (RGVF 39,372 (157-138,000)ng/sample; TFIO 28,808 (2500-106,750)ng/sample), and dropping precipitously (<610ng/sample) on day 8, four days after the last gel application. Rectal secretions tested positive for TFV at greatly reduced levels. TFV and TFV-DP were detected in cervical and vaginal biopsies; TVF-DP was available in higher concentrations in the vaginal tissues compared to cervix.
Conclusions: Both of these alternate formulations of tenofovir gel are safe to the mucosal environment and efficacious in delivering tenofovir drug, with vaginal use.
