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 non-nucleoside reverse transcriptase inhibitor dapivirine, safety, pharmacokinetics, and pharmacodynamics of film and gel formulations were compared to placebo. Methods 61 healthy HIV negative women were randomized to daily dapivirine (0.05%) or placebo gel, or dapivirine (1.25mg) 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 following the last dose were measured for tissue drug concentration and exposed to HIV in an ex vivo challenge assay. Results Two Grade 2 related AEs 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. While gel and film users had comparable plasma dapivirine concentrations, tissue concentrations of dapivirine were 3 to 5 times higher in the gel users when compared to 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.

Safety and Pharmacokinetics of Quick-Dissolving Polymeric Vaginal Films Delivering the Antiretroviral IQP-0528 for Preexposure Prophylaxis

“…The recently completed phase I trial in women with dapivirine film and gels demonstrated a reduction in the innate anti-HIV activity of cervicovaginal lavage (CVL) fluid samples obtained from the gel users and not the film users (35). It was reported that dilution, due to the greater volume used with gels than with films, could likely account for the reduction in the innate anti-HIV activity.…”

“…This formulation compares well with other film formulation developments, where a dapivirine film showed high PK values in vaginal tissue. Concentrations were detected at levels that can protect against ex vivo HIV infection (35).…”

“…A number of promising ARVs and/or microbicides, such as dapivirine, TFV, dapivirine in combination with TFV and maraviroc, retrocyclin-101, and cellulose acetate phthalate, have been formulated into films (28)(29)(30)(31)(32)(33)(34). A few studies have evaluated the safety, pharmacokinetics (PK) and pharmacodynamics of films in macaques and humans (29,35).…”

Griffithsin-Modified Electrospun Fibers as a Delivery Scaffold To Prevent HIV Infection

“…However, user acceptance and adherence can be negatively impacted by the leakiness and corresponding untidiness experienced by some users. Similarly, for intravaginal films, user adherence is a common barrier to obtaining efficacy and is impacted by the perceived difficulty of film administration, as well as localized irritation after prolonged contact (76,77). Furthermore, the rapid and complete release of the incorporated agents from intravaginal films within hours of administration may result in transient protection against STIs, thereby remaining a major hurdle to obtaining long-term delivery and efficacy (78,79).…”

Vaginal film for prevention of HIV: using visual and tactile evaluations among potential users to inform product design

“…spermicidal film) and lubrication and are under investigation (Ham et al 2012; Akil et al 2014; Zhang et al 2015; Bunge et al 2016) as potential delivery systems for the prevention of sexually transmitted infections, including HIV (Garg et al 2010; Romano et al 2013). Drug delivery is critical, but prevention technology effectiveness ultimately depends on user behaviors.…”