A Phase 1 Trial to Assess the Safety, Acceptability, Pharmacokinetics, and Pharmacodynamics of a Novel Dapivirine Vaginal Film

Abstract

Background: Films may deliver antiretroviral drugs efficiently to mucosal tissues. In this first in-human trial of a vaginal film for delivering the nonnucleoside reverse transcriptase inhibitor dapivirine, safety, pharmacokinetics, and pharmacodynamics of film and gel formulations were compared with placebo.

Methods: Sixty-one healthy HIV-negative women were randomized to daily dapivirine (0.05%) or placebo gel, or dapivirine (1.25 mg) or placebo film for seven days. The proportion of participants experiencing grade 2 and higher adverse events related to study product were compared. Plasma dapivirine concentrations were quantified. Paired cervical and vaginal tissue biopsies obtained ∼2 hours after the last dose were measured for tissue drug concentration and exposed to HIV in an ex vivo challenge assay.

Results: Two grade 2 related adverse events occurred in the placebo film group. Women randomized to gel and film products had 4 log10 higher of dapivirine in cervical and vaginal tissues than plasma. Although gel and film users had comparable plasma dapivirine concentrations, tissue concentrations of dapivirine were 3-5 times higher in the gel users when compared with film users. HIV replication in the ex vivo challenge assay was significantly reduced in vaginal tissues from women randomized to dapivirine film or gel; furthermore, tissue drug concentrations were highly correlated with HIV protection. Women rated the film more comfortable with less leakage but found it more difficult to insert than gel.

Discussion: Both film and gel delivered dapivirine at concentrations sufficient to block HIV ex vivo. This proof-of-concept study suggests film formulations for microbicides merit further investigation.

Figure 1

Pharmacokinetic and pharmacodynamic correlations were defined between dapivirine (DPV) film and gel users in (A) tissue and (B) cervicovaginal lavage (CVL) compartments. A) Paired cervical (CVX) and vaginal (VAG) tissue were collected from participants 2-4 hours after their last dose of film or gel. In one set of biopsies, DPV was quantified by LC-MS/MS and expressed as ng/mL. In the other set of biopsies, DPV activity was evaluated using an ex vivo challenge assay and expressed as pg/mL of HIV p24gag. The dotted vertical line represents the lower limit of quantification (LLOQ) for DPV in tissue. Values below the LLOQ were imputed as ½ the LLOQ. B) CVL was collected 2-4 hours after the last dose of film (left) or gel (right) and DPV was quantified by LC-MS/MS and expressed as ng/mL and DPV activity was evaluated using a TZM-bl assay and expressed as %anti-HIV activity. The LLOQ for DPV in CVL was 2 ng/mL; ½ the LLOQ was imputed from CVL that was below the LLOQ. DPV product users are represented by a solid circle while placebo product users are represented by an open square. Solid lines represent linear least squared regression with a P value test for zero slope using subject as a covariate

Figure 2

Cervicovaginal lavage (CVL) innate anti-HIV activity in placebo film (left panels) and gel (right panels) users. Innate anti-HIV activity was quantified from CVL collected at visits 1, 3 (after product use), and 4 from placebo users using a TZM-bl assay. Viability was measured in lower panels to ensure changes in anti-HIV activity were not associated with deviations in cell line viability.