TY - JOUR
T1 - Safety and pharmacokinetics of single, dual, and triple antiretroviral drug formulations delivered by pod-intravaginal rings designed for HIV-1 prevention
T2 - A Phase I trial
AU - Vincent, Kathleen L.
AU - Moss, John A.
AU - Marzinke, Mark A.
AU - Hendrix, Craig W.
AU - Anton, Peter A.
AU - Pyles, Richard B.
AU - Guthrie, Kate M.
AU - Dawson, Lauren
AU - Olive, Trevelyn J.
AU - Butkyavichene, Irina
AU - Churchman, Scott A.
AU - Cortez, John M.
AU - Fanter, Rob
AU - Gunawardana, Manjula
AU - Miller, Christine S.
AU - Yang, Flora
AU - Rosen, Rochelle K.
AU - Vargas, Sara E.
AU - Baum, Marc M.
N1 - Funding Information:
This work was funded by the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health (https://www.nichd.nih.gov/ Award Number R44HD075636); National Institute of Allergy and Infectious Diseases of the National Institutes of Health (https://www.niaid.nih.gov/; Award Number U19AI113048, MMB); Institute for Translational Sciences at the University of Texas Medical Branch, from the National Center for Advancing Translational Sciences, National Institutes of Health (https://ncats.nih.gov/; Award number UL1 TR001439); Institute for Clinical and Translational Research (ICTR) at Johns Hopkins University, from the National Center for Advancing Translational Sciences, National Institutes of Health (https://ncats.nih.gov/; Award Number UL1 TR001079); and Johns Hopkins Center for AIDS Research (http://hopkinscfar.org/; Award Number P30AI094189). The above funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Auritec Pharmaceuticals, Inc. was the sponsor of the study and prime recipient of the NIH grant (Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health under Award Number R44HD075636) that funded part of the study. Study materials (e.g., IVRs) were provided to UTMB (clinical site) by Oak Crest in collaboration with Auritec under that Award; however, there was no direct funding provided by Auritec. Auritec played a role in study design but had no role in data collection or analysis (with the possible exception pertaining to MG in the competing interest disclosure) or manuscript preparation. We would like to acknowledge Jamal Saada, Audrie Colorado, and Megan Amerson-Brown for assistance with collection of samples, Massoud Motamedi for imaging support, and Amy Adler for editing support. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2018 Vincent et al. http://creativecommons.org/licenses/by/4.0/.
PY - 2018/9
Y1 - 2018/9
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pmed.1002655
DO - 10.1371/journal.pmed.1002655
M3 - Article
C2 - 30265679
AN - SCOPUS:85054635041
VL - 15
JO - PLoS Medicine
JF - PLoS Medicine
SN - 1549-1277
IS - 9
M1 - e1002655
ER -