Simultaneous delivery of tenofovir and acyclovir via an intravaginal ring

Abstract

Vaginal microbicides may play an important role in protecting women from HIV infection. A strong synergy between HSV and HIV has been observed, and epidemiological studies demonstrate that HSV infection increases the risk of HIV acquisition. Incorporation of the antiretroviral tenofovir (TFV) along with the antiherpetic acyclovir (ACV) into combination intravaginal rings (IVRs) for sustained mucosal delivery of both compounds could lead to increased microbicide product adherence and efficacy compared with conventional vaginal formulations. A novel, dual-protection "pod IVR" platform developed in-house and delivering ACV and TFV was evaluated in rabbit and sheep models. The devices were safe and exhibited sustained release of both drugs independently and at controlled rates over the 28-day studies. Daily release rates were estimated based on residual drug content of the used devices: rabbits, 343 ± 335 μg day(-1) (ACV) and 321 ± 207 μg day(-1) (TFV); sheep, 174 ± 14 μg day(-1) (ACV) and 185 ± 34 μg day(-1) (TFV). Mean drug levels in sheep vaginal samples were as follows: secretions, 5.25 ± 7.31 μg ml(-1) (ACV) and 20.6 ± 16.2 μg ml(-1) (TFV); cervicovaginal lavage fluid, 118 ± 113 ng ml(-1) (ACV) and 191 ± 125 ng ml(-1) (TFV); tissue, 173 ng g(-1) (ACV) and 93 ng g(-1) (TFV). An in vitro-in vivo correlation was established for both drugs and will allow the development of future formulations delivering target levels for prophylaxis and therapy. These data suggest that the IVR based on the pod design has potential in the prevention of transmission of HIV-1 and other sexually transmitted pathogens.

Fig 1

Photographs of two-pod rabbit (A) and four-pod sheep (B) intravaginal devices.

Fig 2

Animal study timelines and biological sample collection points. (A) Rabbit study. Arrows indicate times of blood and vaginal secretion (Weck-Cel) collection (a) and blood, vaginal secretion (Weck-Cel), and tissue collection (b). There was one predose sample collection point (day 0). (B) Sheep study. Arrows indicate times of blood, vaginal secretion (Weck-Cel), and cervicovaginal lavage (CVL) fluid collection (a) and blood, vaginal secretion (Weck-Cel), CVL fluid, and tissue collection (b). There was one predose sample collection point (day 0).

Fig 3

In vitro cumulative release (means; n = 5) of ACV (solid circles) and TFV (open circles) from combination pod IVRs (16 mg loading for each drug) into VFS.

Fig 4

Rabbit plasma ACV levels (means and standard deviations; n = 5) from the in vivo study. TFV levels mostly were below the LLOQ.

Fig 5

Levels of ACV (circles) and TFV (triangles) in vaginal secretions (blue, distal; red, proximal) measured via Weck-Cel from sheep in vivo study. Data are means and standard deviations (n = 4).

Fig 6

Levels of ACV (solid circles) and TFV (open circles) in cervicovaginal lavage fluid from the sheep in vivo study. Data are means and standard deviations (n = 4).