Brid Devlin

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

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.

Future strategies in microbicide development

The reduction in human immunodeficiency virus (HIV) infection in women demonstrated by pericoital use of tenofovir gel has encouraged the continued development of microbicides. Novel approaches include new ways to deliver tenofovir, as well as products that contain different antiretroviral drugs, either as single agents or as combinations of antiretroviral drugs. Indeed, emphasis has renewed on the development of multipurpose prevention technologies, products designed to address multiple sexually transmitted infections. Dual-purpose contraceptive antiretroviral products are also being designed to prevent HIV and pregnancy. Since consistent and correct use of these products will be critical to their effectiveness, the active pharmaceutical ingredients must be delivered in acceptable vaginal dosage forms, such as gels, films and sustained-release vaginal rings. The development of different dosage forms will help ensure that women can find a method to protect themselves from HIV, pregnancy, and potentially other sexually transmitted infections.

Increased Dapivirine tissue accumulation through vaginal film codelivery of dapivirine and Tenofovir.

The HIV-1 replication inhibitor dapivirine (DPV) is one of the most promising drug candidates being used in topical microbicide products for prevention of HIV-1 sexual transmission. To be able to block HIV-1 replication, DPV must have access to the viral reverse transcriptase enzyme. The window for DPV to access the enzyme happens during the HIV-1 cellular infection cycle. Thus, in order for DPV to exert its anti-HIV activity, it must be present in the mucosal tissue or cells where HIV-1 infection occurs. A dosage form containing DPV must be able to deliver the drug to the tissue site of action. Polymeric films are solid dosage forms that dissolve and release their payload upon contact with fluids. Films have been used as vaginal delivery systems of topical microbicide drug candidates including DPV. For use in topical microbicide products containing DPV, polymeric films must prove their ability to deliver DPV to the target tissue site of action. Ex vivo exposure studies of human ectocervical tissue to DPV film revealed that DPV was released from the film and did diffuse into the tissue in a concentration dependent manner indicating a process of passive diffusion. Analysis of drug distribution in the tissue revealed that DPV accumulated mostly at the basal layer of the epithelium infiltrating the upper part of the stroma. Furthermore, as a combination microbicide product, codelivery of DPV and TFV from a polymeric film resulted in a significant increase in DPV tissue concentration [14.21 (single entity film) and 31.03 μg/g (combination film)], whereas no impact on TFV tissue concentration was found. In vitro release experiments showed that this observation was due to a more rapid DPV release from the combination film as compared to the single entity film. In conclusion, the findings of this study confirm the ability of polymeric films to deliver DPV and TFV to human ectocervical tissue and show that codelivery of the two agents has a significant impact on DPV tissue accumulation. These findings support the use of polymeric films for topical microbicide products containing DPV and/or TFV.

Matrix and reservoir-type multipurpose vaginal rings for controlled release of dapivirine and levonorgestrel

A matrix-type silicone elastomer vaginal ring providing 28-day continuous release of dapivirine (DPV) - a lead candidate human immunodeficiency virus type 1 (HIV-1) microbicide compound - has recently demonstrated moderate levels of protection in two Phase III clinical studies. Here, next-generation matrix and reservoir-type silicone elastomer vaginal rings are reported for the first time offering simultaneous and continuous in vitro release of DPV and the contraceptive progestin levonorgestrel (LNG) over a period of between 60 and 180days. For matrix-type vaginal rings comprising initial drug loadings of 100, 150 or 200mg DPV and 0, 16 or 32mg LNG, Day 1 daily DPV release values were between 4132 and 6113μg while Day 60 values ranged from 284 to 454μg. Daily LNG release ranged from 129 to 684μg on Day 1 and 2-91μg on Day 60. Core-type rings comprising one or two drug-loaded cores provided extended duration of in vitro release out to 180days, and maintained daily drug release rates within much narrower windows (either 75-131μg/day or 37-66μg/day for DPV, and either 96-150μg/day or 37-57μg/day for LNG, depending on core ring configuration and ignoring initial lag release effect for LNG) compared with matrix-type rings. The data support the continued development of these devices as multi-purpose prevention technologies (MPTs) for HIV prevention and long-acting contraception.

Development of a multi-layered vaginal tablet containing dapivirine levonorgestrel and acyclovir for use as a multipurpose prevention technology.

Multipurpose prevention technologies (MPTs) are preferably single dosage forms designed to simultaneously address multiple sexual and reproductive health needs, such as unintended pregnancy, HIV infection and other sexually transmitted infections (STIs). This manuscript describes the development of a range of multi-layered vaginal tablets, with both immediate and sustained release layers capable of delivering the antiretroviral drug dapivirine, the contraceptive hormone levonorgestrel, and the anti-herpes simplex virus drug acyclovir at independent release rates from a single dosage form. Depending on the design of the tablet in relation to the type (immediate or sustained release) or number of layers, the dose of each drug could be individually controlled. For example one tablet design was able to provide immediate release of all three drugs, while another tablet design was able to provide immediate release of both acyclovir and levonorgestrel, while providing sustained release of Dapivirine for up to 8h. A third tablet design was able to provide immediate release of both acyclovir and levonorgestrel, a large initial burst of Dapivirine, followed by sustained release of Dapivirine for up to 8h. All of the tablets passed the test for friability with a percent friability of less than 1%. The hardness of all tablet designs was between 115 and 153N, while their drug content met the European Pharmacopeia 2.9.40 Uniformity of Dosage units acceptance value at levels 1 and 2. Finally, the accelerated stability of all three actives was significantly enhanced in comparison with a mixed drug control.

Post-use assay of vaginal rings (VRs) as a potential measure of clinical trial adherence.

Highlights • Simulated use of dapivirine VRs showed no content changes after storage at RT or −20 °C.• On average, about 4 mg of dapivirine is released in vivo after 28 days of VR use.• Both in vivo and in vitro drug release conform to the Higuchi equation.• Residual ring data should be used in conjunction with other PK measures for modeling adherence.

Current Status of Multipurpose Prevention Technology (MPT) Development

Multipurpose prevention technologies (MPTs) are pharmaceutical products being developed for multiple indications, primarily prevention of HIV, pregnancy, and/or sexually transmitted infections. MPT products could be a combination of multiple drugs co-formulated for separate indications, or a single product with multiple indications. This paper reviews MPT work published since 2013, including technical papers on aspects of product development, papers focused on issues that will be critical to future MPT clinical research and introduction, and selected papers concerning products for prevention of pregnancy or HIV/STIs. Collaborative efforts between researchers and funders aim to provide efficiencies in the product development process, building on experiences from both the contraceptive and vaginal microbicide fields.