A safety and pharmacokinetic trial assessing delivery of dapivirine from a vaginal ring in healthy women

Abstract

The dapivirine vaginal ring has a safety and pharmacokinetic profile that supports its use as a sustained-release topical microbicide for HIV-1 prevention in women.

Pharmacokinetics and Safety Assessment of Anti-HIV Dapivirine Vaginal Microbicide Rings with Multiple Dosing

“…No differences in the incidence of TEAEs, genital symptoms or Nugent scores were observed between the dapivirine ring and the placebo ring group. These data are consistent with those from previous trials in which the use of a single Dapivirine Vaginal Ring-004 was investigated, and demonstrate a good safety profile for the use of multiple rings over approximately 56 days [15,26]. In addition, these data also correspond to the safety profile observed during a 3-month observational safety arm of an earlier IPM trial (IPM 011, unpublished data), when no device or investigational product was administered (ClinicalTrials.gov No NCT00469170).…”

“…Considering the known elimination half-life of dapivirine in vaginal fluids (mean values of approximately 12 -14 hours [26]), total 28-day exposure is not considered to differ much between a single ring insertion or repeated ring insertions.…”

Frequent Cross-Resistance to Dapivirine in HIV-1 Subtype C-Infected Individuals after First-Line Antiretroviral Therapy Failure in South Africa

“…The lowest IC 90 (1.74 ng/ml) of the 100 viruses tested was 6-fold higher than the mean plasma C max (0.29 ng/ml), indicating that plasma DPV concentrations were insufficient to block viral replication. In contrast, reported vaginal fluid concentration on day 28 of DPV ring use (prior to ring removal) of 14,900 to 65,000 ng/ml (15,16) exceeded the adjusted IC 90 of 75% of samples by a minimum of 15-fold. The exact IC 90 could not be determined for 25 samples that displayed Ͼ500-FC DPV resistance (Fig.…”

“…2). About 30 to 49% of the 100 viruses tested had adjusted IC 90 s higher than the estimated DPV concentrations found in vaginal fluid 3 days after ring removal (186 to 834 ng/ml) (15).…”

“…Risk of breakthrough HIV-1 infection based on plasma and vaginal fluid DPV concentrations during ring use and after ring removal. Adjusted DPV IC 90 of the first-line ART failure viruses were compared to published mean concentrations of DPV found in plasma and vaginal fluid in the cervix, introitus, and area near the ring from two studies (15,16). The lowest IC 90 (1.74 ng/ml) of the 100 viruses tested was 6-fold higher than the mean plasma C max (0.29 ng/ml), indicating that plasma DPV concentrations were insufficient to block viral replication.…”