Combination Pod-Intravaginal Ring Delivers Antiretroviral Agents for HIV Prophylaxis: Pharmacokinetic Evaluation in an Ovine Model

Abstract

P reexposure prophylaxis (PrEP) using FDA-approved antiretroviral (ARV) drugs holds significant promise as a strategy in the prevention of HIV infection. By analogy to highly active antiretroviral therapy (HAART), a combination of ARV agents likely is essential for optimally effective HIV PrEP (1, 2). Multiple HIV PrEP clinical trials have demonstrated that vaginal and oral ARV regimens based on the nucleoside reverse transcriptase inhibitor (NRTI) tenofovir (TFV) can be effective in susceptible men, women, and partners of HIV-infected individuals (3-9), but other studies based on analogous drug regimens were unsuccessful at reducing the rates of HIV acquisition (10-12). A critical factor driving success in these trials appears to involve sustaining high adherence to frequent dosing (13).Adherence to therapy was found to be inversely related to dosing periods across different delivery methods (14-17). Topical delivery of ARV drugs using intravaginal rings (IVRs) is believed to improve adherence (18) while maintaining sustained mucosal microbicide levels independently of coitus and daily dosing (19). A recent phase 3, randomized, double-blind, placebo-controlled trial involving 2,629 African women evaluating a monthly IVR delivering the nonnucleoside HIV-1 reverse transcriptase inhibitor dapivirine (DPV) showed that this dosing modality can be effective at preventing HIV-1 infection (20). Overall, the incidence of HIV-1 infection in the DPV group was lower by 37% than that in the placebo group, following the exclusion of data from two sites that exhibited lower-than-expected protocol and product adherence. The efficacy of HIV-1 prevention was as high as 61% among women 25 years of age or older. However, the delivery of two or more ARV drugs by the use of conventional IVR designs, such as the DPV IVR, involves significant technological and manufacturing hurdles. To meet these challenges, we have developed a novel IVR technology, the pod-IVR (19,21), that enables rapid development of devices capable of delivering multiple agents over a wide range of target delivery rates and levels of aqueous solubility (22)(23)(24)(25).Here, we report on the pharmacokinetics (PK) and preliminary local safety in an ovine model of a pod-IVR delivering the prodrug TFV disoproxil fumarate (TDF) in combination with maraviroc (MVC), an entry inhibitor/antagonist of chemokine receptor CCR5. Steady-state drug levels for both ARV agents in cervicovaginal fluids (CVFs) were sustained over the 28-day study with corresponding vaginal tissue (VT) concentrations above the levels required for putative efficacy in preventing HIV infection.

Pharmacokinetics of the Protein Microbicide 5P12-RANTES in Sheep following Single-Dose Vaginal Gel Administration

“…5P12-RANTES has previously been shown to be stable by an in vitro cell fusion assay (i) when exposed to elevated temperatures (up to 55°C in water for 24 h and 40°C for 1 week), (ii) at the normal vaginal pH for 24 h, (iii) and when incubated with human cervicovaginal lavage fluid or human semen at 37°C for 24 h (39). The data presented here suggest for the first time that 5P12-RANTES is also sufficiently stable in vivo to allow detection and measurement of the protein by sampling of sheep vaginal fluid with a Weck-Cel sponge, as reported previously for various small-molecule HIV microbicides (12,(60)(61)(62). However, as previously noted for the in vitro fusion assay (39), enzyme-linked immunosorbent assay (ELISA) may not detect protein modifications that affect 5P12-RANTES activity, and therefore more appropriate analytical techniques should be considered when undertaking further preclinical development.…”

Mechanical testing methods for drug-releasing vaginal rings

“…A seventh ring product -Annovera™offering long-acting release of the contraceptive hormones, Nestorone ® and ethinyl estradiol, for a period of 1 year has recently been approved by the U.S. Food and Drug Agency (FDA) and is expected to be commercially available in late 2019 or early 2020. Interest in VR technology has surged in the last ten years, mostly due to extensive developments around antiretroviral-releasing rings for reduced sexual transmission of human immunodeficiency virus (HIV) (Baum et al, 2012;Fetherston et al, 2013b;Johnson et al, 2012;Moss et al, 2016). One such microbicidal ring devicethe dapivirine (DPV) silicone elastomer vaginal ringis currently under review for approval by the European Medicines Agency (EMA).…”

Development and pharmacokinetics of a combination vaginal ring for sustained release of dapivirine and the protein microbicide 5P12-RANTES

“…Maraviroc is an established antiretroviral used in HIV treatment that inhibits entry of HIV into host cells by targeting the CCR5 receptor (Chen et al, 2015;; darunavir is a protease inhibitor already used in combination with other antiretrovirals in the treatment of HIV infection (Mallolas, n.d.). Other combination microbicide vaginal rings have also been reported, including dapivirine and tenofovir (Johnson et al, 2010), tenofovir disoproxil fumarate and maraviroc (Moss et al, 2016), MIV-150 and zinc acetate (plus other drugs) (Ugaonkar et al, 2015), and tenofovir, nevirapine, and saquinavir (plus other drugs) (Moss et al, 2013).…”