Dataset Information

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

ABSTRACT: Preexposure prophylaxis (PrEP) against HIV using oral regimens based on the nucleoside reverse transcriptase inhibitor tenofovir disoproxil fumarate (TDF) has been effective to various degrees in multiple clinical trials, and the CCR5 receptor antagonist maraviroc (MVC) holds potential for complementary efficacy. The effectiveness of HIV PrEP is highly dependent on adherence. Incorporation of the TDF-MVC combination into intravaginal rings (IVRs) for sustained mucosal delivery could increase product adherence and efficacy compared with oral and vaginal gel formulations. A novel pod-IVR technology capable of delivering multiple drugs is described. The pharmacokinetics and preliminary local safety characteristics of a novel pod-IVR delivering a combination of TDF and MVC were evaluated in the ovine model. The device exhibited sustained release at controlled rates over the 28-day study and maintained steady-state drug levels in cervicovaginal fluids (CVFs). Dilution of CVFs during lavage sample collection was measured by ion chromatography using an inert tracer, allowing corrected drug concentrations to be measured for the first time. Median, steady-state drug levels in vaginal tissue homogenate were as follows: for tenofovir (TFV; in vivo hydrolysis product of TDF), 7.3 × 10(2) ng g(-1) (interquartile range [IQR], 3.0 × 10(2), 4.0 × 10(3)); for TFV diphosphate (TFV-DP; active metabolite of TFV), 1.8 × 10(4) fmol g(-1) (IQR, 1.5 × 10(4), 4.8 × 10(4)); and for MVC, 8.2 × 10(2) ng g(-1) (IQR, 4.7 × 10(2), 2.0 × 10(3)). No adverse events were observed. These findings, together with previous pod-IVR studies, have allowed several lead candidates to advance into clinical evaluation.

SUBMITTER: Moss JA

PROVIDER: S-EPMC4879417 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Moss John A JA Butkyavichene Irina I Churchman Scott A SA Gunawardana Manjula M Fanter Rob R Miller Christine S CS Yang Flora F Easley Jeremiah T JT Marzinke Mark A MA Hendrix Craig W CW Smith Thomas J TJ Baum Marc M MM

Antimicrobial agents and chemotherapy 20160523 6

Preexposure prophylaxis (PrEP) against HIV using oral regimens based on the nucleoside reverse transcriptase inhibitor tenofovir disoproxil fumarate (TDF) has been effective to various degrees in multiple clinical trials, and the CCR5 receptor antagonist maraviroc (MVC) holds potential for complementary efficacy. The effectiveness of HIV PrEP is highly dependent on adherence. Incorporation of the TDF-MVC combination into intravaginal rings (IVRs) for sustained mucosal delivery could increase pro ...[more]

PMID: 27067321

Similar Datasets

Project description:Globally, women bear an uneven burden for sexual HIV acquisition. Results from two clinical trials evaluating intravaginal rings (IVRs) delivering the antiretroviral agent dapivirine have shown that protection from HIV infection can be achieved with this modality, but high adherence is essential. Multipurpose prevention technologies (MPTs) can potentially increase product adherence by offering protection against multiple vaginally transmitted infections and unintended pregnancy. Here we describe a coitally independent, long-acting pod-IVR MPT that could potentially prevent HIV and HSV infection as well as unintended pregnancy. The pharmacokinetics of MPT pod-IVRs delivering tenofovir alafenamide hemifumarate (TAF2) to prevent HIV, acyclovir (ACV) to prevent HSV, and etonogestrel (ENG) in combination with ethinyl estradiol (EE), FDA-approved hormonal contraceptives, were evaluated in pigtailed macaques (N = 6) over 35 days. Pod IVRs were exchanged at 14 days with the only modification being lower ENG release rates in the second IVR. Plasma progesterone was monitored weekly to determine the effect of ENG/EE on menstrual cycle. The mean in vivo release rates (mg d-1) for the two formulations over 30 days ranged as follows: TAF2 0.35-0.40; ACV 0.56-0.70; EE 0.03-0.08; ENG (high releasing) 0.63; and ENG (low releasing) 0.05. Mean peak progesterone levels were 4.4 ± 1.8 ng mL-1 prior to IVR insertion and 0.075 ± 0.064 ng mL-1 for 5 weeks after insertion, suggesting that systemic EE/ENG levels were sufficient to suppress menstruation. The TAF2 and ACV release rates and resulting vaginal tissue drug concentrations (medians: TFV, 2.4 ng mg-1; ACV, 0.2 ng mg-1) may be sufficient to protect against HIV and HSV infection, respectively. This proof of principle study demonstrates that MPT-pod IVRs could serve as a potent biomedical prevention tool to protect women's sexual and reproductive health and may increase adherence to HIV PrEP even among younger high-risk populations.

Project description:BACKGROUND:Intravaginal rings (IVRs) can deliver antiretroviral (ARV) agents for HIV pre-exposure prophylaxis (PrEP), theoretically overcoming adherence concerns associated with frequent dosing. However, topical vaginal ARV drug delivery has not simultaneously led to sufficient rectal drug exposure to likely protect from HIV infection as a result of receptive anal intercourse (RAI). Unprotected RAI has a higher risk of infection per sex act and, for women, also can be associated with vaginal exposure during a single sexual encounter, especially in higher-risk subsets of women. The physiologically inflamed, activated, immune-cell dense colorectal mucosa is increasingly appreciated as the sexual compartment with highly significant risk; this risk is increased in the setting of co-infections. Ex vivo studies have shown that colorectal tissue and rectal fluid concentrations correlated with HIV protection. Given these important results, efforts to document colorectal compartment ARV drug concentration from pod-IVR delivery was assessed to determine if vaginal application could provide protective ARV levels in both compartments. METHODOLOGY/PRINCIPAL FINDINGS:A crossover clinical trial (N = 6) evaluated 7 d of continuous TDF pod-IVR use, a wash-out phase, followed by 7 d with a TDF-FTC pod-IVR. A subsequent clinical trial (N = 6) consisted of 7 d of continuous TDF-FTC-MVC pod-IVR use. Rectal fluids were collected on Day 7 at IVR removal in all three ARV-exposures (two Phase 1 trials) and drug concentrations quantified by LC-MS/MS. Median rectal fluid concentrations of TFV, the hydrolysis product of the prodrug TDF, were between 0.66 ng mg-1 (TDF pod-IVR group) and 1.11 ng mg-1 (TDF-FTC pod-IVR group), but below the analytical lower limit of quantitation in 5/6 samples in the TDF-FTC-MVC pod-IVR group. Unexpectedly, median FTC (TDF-FTC pod-IVR, 20.3 ng mg-1; TDF-FTC-MVC pod-IVR, 0.18 ng mg-1), and MVC rectal fluid concentrations (0.84 ng mg-1) were quantifiable and higher than their respective in vitro EC50 values in most samples. Due to participant burden in these exploratory trials, rectal fluid was used as a surrogate for rectal tissue, where drug concentrations are expected to be higher. CONCLUSIONS/SIGNIFICANCE:The concentrations of FTC and MVC in rectal fluids obtained in two exploratory clinical trials of IVRs delivering ARV combinations exceeded levels associated with in vitro efficacy in HIV inhibition. Unexpectedly, MVC appeared to depress the distribution of TFV and FTC into the rectal lumen. Here we show that vaginal delivery of ARV combinations may provide adherence and coitally independent dual-compartment protection from HIV infection during both vaginal and receptive anal intercourse.

Project description:Background: Effective HIV prevention requires efficient delivery of safe and efficacious drugs and optimization of user adherence. The user's experiences with the drug, delivery system, and use parameters are critical to product acceptability and adherence. Prevention product developers have the opportunity to directly control a drug delivery system and its impact on acceptability and adherence, as well as product efficacy. Involvement of potential users during preclinical design and development can facilitate this process. We embedded a mixed methods user evaluation study into a safety and pharmacokinetics (PK) trial of a pod-intravaginal ring delivering antiretroviral agents.Methodology: Women enrolled in two cohorts, ultimately evaluating the safety/PK of a pod-IVRs delivering TDF-alone, TDF-FTC, and/or TDF-FTC-MVC. A 7-day use period was targeted for each pod-IVR, regardless of drug or drug combination. During the clinical study, participants provided both quantitative (i.e., survey) and qualitative (i.e., in-depth interview) data capturing acceptability, perceptibility, and adherence behaviors. Initial sexual and reproductive health history surveys, daily diaries, a final acceptability and willingness to use survey, and a qualitative in-depth interview comprised the user evaluation data for each pod-IVR experienced by the participants.Findings: Overall, the majority of participants (N = 10) reported being willing to use the pod-IVR platform for HIV prevention should it advance to market. Confidence to use the pod-IVR (e.g., insertion, removal) was high. There were no differences noted in the user experience of the pod-IVR platform; that is, whether the ring delivered TDF-alone, TDF-FTC, or TDF-FTC-MVC, users' experiences of the ring were similar and acceptable. Participants did report specific experiences, both sensory and behavioral, that impacted their use behaviors with respect to the ring, and which could ultimately impact acceptability and adherence. These experiences, and user evaluations elicited by them, could both challenge use or be used to leverage use in future trials and product rollout once fully articulated.Conclusions: High willingness-to-use data and lack of salient differences in user experiences related to use of the pod-IVR platform (regardless of agents delivered) suggests that the pod-IVR is a feasible and acceptable drug delivery device in and of itself. This finding holds promise both for an anti-HIV pod-IVR and, potentially, a multipurpose prevention pod-IVR that could deliver both prevention for sexually transmitted infections (STIs) including HIV and contraception. Given the very early clinical trial context, further acceptability, perceptibility, and adherence data should continue to be explored, in the context of longer use periods (e.g., 28-day ring use), and in the contexts of sexual activity and menses. Using early design and development contexts to gain insights into potential challenges and facilitators of drug delivery systems such as the pod-IVR could save valuable resources and time as a potential biomedical technology moves through the clinical trial pipeline and into real-world use.

Project description:BACKGROUND:Intravaginal rings (IVRs) for HIV pre-exposure prophylaxis (PrEP) theoretically overcome some adherence concerns associated with frequent dosing that can occur with oral or vaginal film/gel regimens. An innovative pod-IVR, composed of an elastomer scaffold that can hold up to 10 polymer-coated drug cores (or "pods"), is distinct from other IVR designs as drug release from each pod can be controlled independently. A pod-IVR has been developed for the delivery of tenofovir (TFV) disoproxil fumarate (TDF) in combination with emtricitabine (FTC), as daily oral TDF-FTC is the only Food and Drug Administration (FDA)-approved regimen for HIV PrEP. A triple combination IVR building on this platform and delivering TDF-FTC along with the antiretroviral (ARV) agent maraviroc (MVC) also is under development. METHODOLOGY AND FINDINGS:This pilot Phase I trial conducted between June 23, 2015, and July 15, 2016, evaluated the safety, pharmacokinetics (PKs), and acceptability of pod-IVRs delivering 3 different ARV regimens: 1) TDF only, 2) TDF-FTC, and 3) TDF-FTC-MVC over 7 d. The crossover, open-label portion of the trial (N = 6) consisted of 7 d of continuous TDF pod-IVR use, a wash-out phase, and 7 d of continuous TDF-FTC pod-IVR use. After a 3-mo pause to evaluate safety and PK of the TDF and TDF-FTC pod-IVRs, TDF-FTC-MVC pod-IVRs (N = 6) were evaluated over 7 d of continuous use. Safety was assessed by adverse events (AEs), colposcopy, and culture-independent analysis of the vaginal microbiome (VMB). Drug and drug metabolite concentrations in plasma, cervicovaginal fluids (CVFs), cervicovaginal lavages (CVLs), and vaginal tissue (VT) biopsies were determined via liquid chromatographic-tandem mass spectrometry (LC-MS/MS). Perceptibility and acceptability were assessed by surveys and interviews. Median participant age was as follows: TDF/TDF-FTC group, 26 y (range 24-35 y), 2 White, 2 Hispanic, and 2 African American; TDF-FTC-MVC group, 24.5 y (range 21-41 y), 3 White, 1 Hispanic, and 2 African American. Reported acceptability was high for all 3 products, and pod-IVR use was confirmed by residual drug levels in used IVRs. There were no serious adverse events (SAEs) during the study. There were 26 AEs reported during TDF/TDF-FTC IVR use (itching, discharge, discomfort), with no differences between TDF alone or in combination with FTC observed. In the TDF-FTC-MVC IVR group, there were 12 AEs (itching, discharge, discomfort) during IVR use regardless of attribution to study product. No epithelial disruption/thinning was seen by colposcopy, and no systematic VMB shifts were observed. Median (IQR) tenofovir diphosphate (TFV-DP) tissue concentrations of 303 (277-938) fmol/10(6) cells (TDF), 289 (110-603) fmol/10(6) cells (TDF-FTC), and 302 (177.1-823.8) fmol/10(6) cells (TDF-FTC-MVC) were sustained for 7 d, exceeding theoretical target concentrations for vaginal HIV prevention. The study's main limitations include the small sample size, short duration (7 d versus 28 d), and the lack of FTC triphosphate measurements in VT biopsies. CONCLUSIONS:An innovative pod-IVR delivery device with 3 different formulations delivering different regimens of ARV drugs vaginally appeared to be safe and acceptable and provided drug concentrations in CVFs and tissues exceeding concentrations achieved by highly protective oral dosing, suggesting that efficacy for vaginal HIV PrEP is achievable. These results show that an alternate, more adherence-independent, longer-acting prevention device based on the only FDA-approved PrEP combination regimen can be advanced to safety and efficacy testing. TRIAL REGISTRATION:ClinicalTrials.gov NCT02431273.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets