Sustained delivery of microbicide dapivirine using intra-vaginal rings: an independent clinical assessment of safety and drug delivery in women.
BACKGROUND: Vaginal microbicides for the prevention of HIV transmission may be an important option for protecting women from infection. Intra-vaginal rings (IVR) are one approach to sustained release of microbicides that could provide increased flexibility for the user and increased product adherence. This report describes two independent phase I safety trials designed to evaluate delivery of the NNRTI microbicide dapivirine from IVR. METHODS: Each study involved a differently designed silicone elastomer core type IVR. Study 1 used IVR with 120 mg or 0 mg (placebo) of dapivirine in a cross-over design involving 12 sexually abstinent healthy volunteers. Each participant underwent 7 days of placebo and then 7 days of dapivirine ring use. Study 2 was a randomized, double blind placebo controlled study involving 7 day use of IVR with 25 mg (10 women) or 0 mg of dapivirine (3 women). Safety, tolerability, and drug distribution were assessed similarly in each study. RESULTS: All participants completed both studies. Safety was assessed in each study by measurement of clinical laboratory parameters, adverse events, and pelvic examinations. There were no deaths, serious adverse events, or adverse events (AE) resulting in study discontinuation in either trial. Similar AE were observed in the placebo and treatment groups of both studies. IVR in each study were found to be generally safe and well tolerated. Drug levels in different sample types collected on day 7 allow summary comparison between studies. Levels in vaginal fluids (Sno-strip collection) and in cervical and vaginal tissues (biopsy) at day 7 were compared at the cervix, introitus, and the vaginal ring areas. In study 1, mean vaginal fluid levels ranged from ~17 ng/strip (cervix) to ~74 ng/strip (ring area); mean tissue levels ranged from ~279 ng/gm (introitus) to ~703 ng/gm (ring area). In study 2, mean fluid levels ranged from 7 ng/strip (cervix) to ~94 ng/strip (ring area); mean tissue levels ranged from ~680 ng/gm (cervix) to 2480 ng/gm (ring area). Mean plasma levels in each study were
Romano, J.; Variano, B.; Coplan, P.; van Roey, J.; Douville, K.; Rosenberg, Z.; Temmerman, M.; van Bortel, L.; Weyers, S.; Mitchnick, M. Sustained delivery of microbicide dapivirine using intra-vaginal rings: an independent clinical assessment of safety and drug delivery in women. Presented at 14th Conference on retroviruses and opportunistic infections, Los Angeles, California, USA, 25-28 February 2007. (2007)