[Show abstract][Hide abstract] ABSTRACT: Multipurpose technologies that simultaneously protect from sexually transmitted infections and unintended pregnancy are urgently
needed. Pod-intravaginal rings (IVRs) formulated with the antiretroviral agents (ARVs) tenofovir, nevirapine, and saquinavir
and the contraceptives etonogestrel and estradiol were evaluated in sheep. Steady-state concentrations were maintained for
28 days with controlled, sustained delivery. This proof-of-principle study demonstrates that pod IVRs can deliver three ARVs
from different mechanistic classes and a progestin-estrogen combination over the wide range needed for putative preventative
[Show abstract][Hide abstract] ABSTRACT: Antiretroviral-based microbicides applied topically to the vagina may play an important role in protecting women from HIV
infection. Incorporation of the nucleoside reverse transcriptase inhibitor tenofovir (TFV) into intravaginal rings (IVRs)
for sustained mucosal delivery may lead to increased microbicide product adherence and efficacy compared with those of conventional
vaginal formulations. Formulations of a novel “pod IVR” platform spanning a range of IVR drug loadings and daily release rates
of TFV were evaluated in a pig-tailed macaque model. The rings were safe and exhibited sustained release at controlled rates
over 28 days. Vaginal secretion TFV levels were independent of IVR drug loading and were able to be varied over 1.5 log units
by changing the ring configuration. Mean TFV levels in vaginal secretions were 72.4 ± 109 μg ml−1 (slow releasing) and 1.84 ± 1.97 mg ml−1 (fast releasing). The mean TFV vaginal tissue concentration from the slow-releasing IVRs was 76.4 ± 54.8 μg g−1 and remained at steady state 7 days after IVR removal, consistent with the long intracellular half-life of TFV. Intracellular
tenofovir diphosphate (TFV-DP), the active moiety in defining efficacy, was measured in vaginal lymphocytes collected in the
study using the fast-releasing IVR formulation. Mean intracellular TFV-DP levels of 446 ± 150 fmol/106 cells fall within a range that may be protective of simian-human immunodeficiency virus strain SF162p3 (SHIVSF162p3) infection in nonhuman primates. These data suggest that TFV-releasing IVRs based on the pod design have potential for the
prevention of transmission of human immunodeficiency virus type 1 (HIV-1) and merit further clinical investigation.
[Show abstract][Hide abstract] ABSTRACT: Intravaginal delivery of microbicide combinations is a promising approach for the prevention of sexually transmitted infections, but requires a method of providing simultaneous, independent release of multiple agents into the vaginal compartment. A novel intravaginal ring (IVR) platform has been developed for simultaneous delivery of the reverse-transcriptase inhibitor tenofovir (TFV) and the guanosine analogue antiviral acyclovir (ACV) with independent control of release rate for each drug. The IVR is based on a pod design, with up to 10 individual polymer-coated drug cores embedded in the ring releasing through preformed delivery channels. The release rate from each pod is controlled independently of the others by the drug properties, polymer coating, and size and number of delivery channels. Pseudo-zero-order in vitro release of TFV (144 ± 10 µg day) and ACV (120 ± 19 µg day⁻¹) from an IVR containing both drugs was sustained for 28 days. The mechanical properties of the pod IVR were evaluated and compared with the commercially available Estring® (Pfizer, NY, NY). The pod-IVR design enables the vaginal delivery of multiple microbicides with differing physicochemical properties, and is an attractive approach for the sustained intravaginal delivery of relatively hydrophilic drugs that are difficult to deliver using conventional matrix IVR technology.
[Show abstract][Hide abstract] ABSTRACT: Systemic aciclovir and its prodrug valaciclovir are effective in treating and reducing recurrences of genital herpes simplex virus (HSV) and reducing transmission. Local aciclovir delivery, if it can achieve and maintain comparable intracellular genital tract levels, may be equally effective in the treatment and suppression of genital HSV. Intravaginal ring (IVR) delivery of aciclovir may provide pre-exposure prophylaxis against HSV acquisition.
Tolerability and pharmacokinetics were evaluated in six HIV-negative women with recurrent genital HSV who switched their daily oral valaciclovir suppression to an aciclovir IVR for 7 days (n = 3) or 14 days (n = 3). Blood and cervicovaginal lavage (CVL) were collected after oral and IVR dosing to measure aciclovir concentrations and genital swabs were obtained to quantify HSV shedding by PCR.
The rings were well tolerated. Median plasma aciclovir concentrations were 110.2 ng/mL (IQR, 85.9-233.5) 12-18 h after oral valaciclovir. Little or no drug was detected in plasma following IVR dosing. Median (IQR) CVL aciclovir levels were 127.3 ng/mL (21-660.8) 2 h after oral valaciclovir, 154.4 ng/mL (60.7-327.5) 12-18 h after oral valaciclovir and 438 ng/mL (178.5-618.5) after 7 days and 393 ng/mL (31.6-1615) after 14 days of aciclovir ring use. Median CVL aciclovir levels 2 h after oral dosing were similar to levels observed 7 (P = 0.99) and 14 (P = 0.75) days after ring use. HSV DNA was not detected in genital swabs and there was no significant change in inflammatory mediators.
This first-in-human study demonstrated that an IVR could safely deliver mucosal levels of aciclovir similar to oral valaciclovir without systemic absorption. More intensive site-specific pharmacokinetic studies are needed to determine whether higher local concentrations are needed to achieve optimal drug distribution within the genital tract.
[Show abstract][Hide abstract] ABSTRACT: To compare the distribution of tenofovir in sheep vaginal lumen, tissue, and plasma following topical delivery of the antiretroviral drug from intravaginal rings, either as tenofovir or the disoproxil fumarate prodrug.
Comparative pharmacokinetic study in sheep.
Intravaginal rings formulated to achieve equivalent release rates of tenofovir and its disoproxil fumarate prodrug were evaluated for 28 days in sheep, with four animals in each group. Drug concentrations were measured by high-performance liquid chromatography-mass spectrometry.
Tenofovir levels in cervicovaginal lavage were indistinguishable (P > 0.30) in both groups, but tissue levels in animals receiving the prodrug were 86-fold higher than those receiving tenofovir, and approximately 50 times higher than the level shown to be protective of HIV infection in the CAPRISA 004 trial.
This is the first study to compare the pharmacokinetics of tenofovir and its disoproxil fumarate prodrug administered topically to the vaginal tract. These in-vivo data show that the prodrug leads to significantly higher drug tissue levels than tenofovir, a finding that may have important implications for the development of preexposure prophylaxis strategies based on topical delivery of antivirals to the female genital tract.
AIDS (London, England) 12/2011; 26(6):707-10. DOI:10.1097/QAD.0b013e3283509abb · 5.55 Impact Factor
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] ABSTRACT: Background:
Systemic acyclovir (ACV) and its prodrug valacyclovir (VCV) are effective in treating and reducing recurrences of genital herpes simplex virus (HSV). Once-daily oral VCV reduces the risk of genital HSV transmission among heterosexual, HSV-2-discordant couples. We hypothesize that local ACV delivery, if it can achieve and maintain comparable intracellular genital tract levels, will be equally effective in the treatment and suppression of genital HSV and avoid systemic exposure. Intravaginal ring (IVR) delivery of ACV may also protect against HSV acquisition.
Silicone rings, similar in size and shape to Estring, were designed to release ACV at a rate of 240 mg/day. Tolerability, pharmacokinetics and surrogate efficacy were evaluated in 6 women with recurrent genital HSV who switched their daily oral VCV suppression to an ACV IVR for 7 (n=3) or 14 days (n=3). Blood and cervicovaginal lavage (CVL) was collected after both oral and IVR dosing to measure ACV concentrations. As a surrogate of pharmacodynamics, the anti-HSV activity in CVL was measured in a plaque assay.
The rings were well tolerated with no adverse events or expulsions. Plasma ACV levels ranged from 12.6-529 ng/ml at 12 and 24 hours after oral VCV. Little or no drug was detected (below quantifiable limit 1 ng/ml) in plasma following IVR dosing. CVL ACV levels ranged from <25-1404 ng/ml after oral VCV and 45-1615 ng/ml at 1, 3, 7, 10 and 14 days after IVR dosing. There was 0.17-3.59 and 0.78-3.55 log reduction in HSV after oral and IVR dosing, respectively. Anti-HSV activity in CVL correlated modestly, but significantly with ACV levels (r=0.33, p<.02).
This first-in-human study demonstrated that an IVR could safely deliver ACV and achieve at least as good local mucosal levels as oral therapy without systemic absorption. These findings support further development and study of an ACV IVR.
Infectious Diseases Society of America 2011 Annual Meeting; 10/2011
[Show abstract][Hide abstract] ABSTRACT: Millions of intravaginal rings (IVRs) are used by women worldwide for contraception and for the treatment of vaginal atrophy. These devices also are suitable for local and systemic sustained release drug delivery, notably for antiviral agents in human immunodeficiency virus pre-exposure prophylaxis. Despite the widespread use of IVRs, no studies have examined whether surface-attached bacterial biofilms develop in vivo, an important consideration when determining the safety of these devices. The present study used scanning electron microscopy, fluorescence in situ hybridization and confocal laser scanning microscopy to study biofilms that formed on the surface of IVRs worn for 28 days by six female pig-tailed macaques, an excellent model organism for the human vaginal microbiome. Four of the IVRs released the nucleotide analogue reverse transcriptase inhibitor tenofovir at a controlled rate and the remaining two were unmedicated. Large areas of the ring surfaces were covered with monolayers of epithelial cells. Two bacterial biofilm phenotypes were found to develop on these monolayers and both had a broad diversity of bacterial cells closely associated with the extracellular material. Phenotype I, the more common of the two, consisted of tightly packed bacterial mats approximately 5 µm in thickness. Phenotype II was much thicker, typically 40 µm, and had an open architecture containing interwoven networks of uniform fibres. There was no significant difference in biofilm thickness and appearance between medicated and unmedicated IVRs. These preliminary results suggest that bacterial biofilms could be common on intravaginal devices worn for extended periods of time.
Journal of Medical Microbiology 03/2011; 60(Pt 6):828-37. DOI:10.1099/jmm.0.028225-0 · 2.25 Impact Factor