Dataset Information

FAME-04: A Phase 1 trial to assess the safety, acceptability, pharmacokinetics and pharmacodynamics of film and gel formulations of tenofovir.

ABSTRACT: INTRODUCTION:Fast-dissolving vaginal film formulations release antiretroviral drugs directly into vaginal fluid and may be as efficient at drug delivery yet more acceptable to women than gels. In this Phase 1 vaginal film study, the safety, acceptability, pharmacokinetics and pharmacodynamics of two doses of tenofovir (TFV) film and TFV 1% gel were compared to corresponding placebo formulations. METHODS:Seventy-eight healthy HIV negative women were randomized to self-insert daily vaginal film (10 mg TFV, 40 mg TFV or placebo) or 4 mL of vaginal gel (TFV 1% [40 mg] or placebo) for seven days. Grade 2 and higher adverse events (AEs) related to study product were compared across study arms using Fisher's exact test. Plasma TFV concentrations were measured before and 2 hours after last product use. Paired cervical and vaginal tissue biopsies obtained 2 hours after the last dose were measured to determine tenofovir diphosphate (TFV-DP) concentrations and exposed to HIV in an ex vivo challenge assay. Acceptability was assessed through questionnaire. RESULTS:There was only one grade 2 or higher related AE, the primary endpoint; it occurred in the placebo gel arm. AEs occurred in 90% of participants; the majority (91%) were grade 1. AEs were similar across study arms. TFV concentrations in plasma and TFV-DP concentrations in cervical and vaginal tissues were comparable between 40 mg TFV film and the TFV gel groups. There was a significant relationship between reduced viral replication and TFV-DP concentrations in cervical tissues. Film users were less likely to report product leakage than gel users (66% vs. 100%, p < 0.001). CONCLUSIONS:Films were safe and well tolerated. Furthermore, films delivered TFV to mucosal tissues at concentrations similar to gel and were sufficient to block HIV infection of genital tissue ex vivo.

SUBMITTER: Bunge KE

PROVIDER: S-EPMC6088248 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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FAME-04: A Phase 1 trial to assess the safety, acceptability, pharmacokinetics and pharmacodynamics of film and gel formulations of tenofovir.

Bunge Katherine E KE Dezzutti Charlene S CS Hendrix Craig W CW Marzinke Mark A MA Spiegel Hans M L HML Moncla Bernard J BJ Schwartz Jill L JL Meyn Leslie A LA Richardson-Harman Nicola N Rohan Lisa C LC Hillier Sharon L SL

Journal of the International AIDS Society 20180801 8

<h4>Introduction</h4>Fast-dissolving vaginal film formulations release antiretroviral drugs directly into vaginal fluid and may be as efficient at drug delivery yet more acceptable to women than gels. In this Phase 1 vaginal film study, the safety, acceptability, pharmacokinetics and pharmacodynamics of two doses of tenofovir (TFV) film and TFV 1% gel were compared to corresponding placebo formulations.<h4>Methods</h4>Seventy-eight healthy HIV negative women were randomized to self-insert daily ...[more]

PMID: 30101439

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Project description:To prevent the global health burdens of human immunodeficiency virus [HIV] and unintended/mistimed pregnancies, we developed an intravaginal ring [IVR] that delivers tenofovir [TFV] at ~10mg/day alone or with levonorgestrel [LNG] at ~20μg/day for 90 days. We present safety, pharmacokinetics, pharmacodynamics, acceptability and drug release data in healthy women. CONRAD A13-128 was a randomized, placebo controlled phase I study. We screened 86 women; 51 were randomized to TFV, TFV/LNG or placebo IVR [2:2:1] and 50 completed all visits, using the IVR for approximately 15 days. We assessed safety by adverse events, colposcopy, vaginal microbiota, epithelial integrity, mucosal histology and immune cell numbers and phenotype, cervicovaginal [CV] cytokines and antimicrobial proteins and changes in systemic laboratory measurements, and LNG and TFV pharmacokinetics in multiple compartments. TFV pharmacodynamic activity was measured by evaluating CV fluid [CVF] and tissue for antiviral activity using in vitro models. LNG pharmacodynamic assessments were timed based on peak urinary luteinizing hormone levels. All IVRs were safe with no significant colposcopic, mucosal, immune and microbiota changes and were acceptable. Among TFV containing IVR users, median and mean CV aspirate TFV concentrations remained above 100,000 ng/mL 4 hours post IVR insertion and mean TFV-diphosphate [DP] concentrations in vaginal tissue remained above 1,000 fmol/mg even 3 days post IVR removal. CVF of women using TFV-containing IVRs completely inhibited [94-100%] HIV infection in vitro. TFV/LNG IVR users had mean serum LNG concentrations exceeding 300 pg/mL within 1 hour, remaining high throughout IVR use. All LNG IVR users had a cervical mucus Insler score <10 and the majority [95%] were anovulatory or had abnormal cervical mucus sperm penetration. Estimated in vivo TFV and LNG release rates were within expected ranges. All IVRs were safe with the active ones delivering sustained high concentrations of TFV locally. LNG caused changes in cervical mucus, sperm penetration, and ovulation compatible with contraceptive efficacy. The TFV and TFV/LNG rings are ready for expanded 90 day clinical testing. Trial registration ClinicalTrials.gov #NCT02235662.

Project description:OBJECTIVE:To evaluate the safety and pharmacokinetics of MIV-150 and zinc acetate in a carrageenan gel (PC-1005). Acceptability, adherence, and pharmacodynamics were also explored. DESIGN:A 3-day open-label safety run-in (n = 5) preceded a placebo-controlled, double-blind trial in healthy, HIV-negative, abstinent women randomized (4:1) to vaginally apply 4 mL of PC-1005 or placebo once daily for 14 days. METHODS:Assessments included physical examinations, safety labs, colposcopy, biopsies, cervicovaginal lavages (CVLs), and behavioral questionnaires. MIV-150 (plasma, CVL, tissue), zinc (plasma, CVL), and carrageenan (CVL) concentrations were determined with LC-MS/MS, ICP-MS, and ELISA, respectively. CVL antiviral activity was measured using cell-based assays. Safety, acceptability, and adherence were analyzed descriptively. Pharmacokinetic parameters were calculated using noncompartmental techniques and actual sampling times. CVL antiviral EC50 values were calculated using a dose-response inhibition analysis. RESULTS:Participants (n = 20) ranged from 19-44 years old; 52% were black or African American. Among those completing the trial (13/17, PC-1005; 3/3, placebo), 11/17 reported liking the gel overall; 7 recommended reducing the volume. Adverse events, which were primarily mild and/or unrelated, were comparable between groups. Low systemic MIV-150 levels were observed, without accumulation. Plasma zinc levels were unchanged from baseline. Seven of seven CVLs collected 4-hour postdose demonstrated antiviral (HIV, human papillomavirus) activity. High baseline CVL anti-herpes-simplex virus type-2 (HSV-2) activity precluded assessment of postdose activity. CONCLUSIONS:PC-1005 used vaginally for 14 days was well tolerated. Low systemic levels of MIV-150 were observed. Plasma zinc levels were unchanged. Postdose CVLs had anti-HIV and anti-human papillomavirus activity. These data warrant further development of PC-1005 for HIV and sexually transmitted infection prevention.

Project description:CHARM-02 is a crossover, double-blind, randomized trial to compare the safety and pharmacokinetics of three rectally applied tenofovir 1% gel candidate rectal microbicides of varying osmolalities: vaginal formulation (VF) (3111?mOsmol/kg), the reduced glycerin vaginal formulation (RGVF) (836?mOsmol/kg), and an isoosmolal rectal-specific formulation (RF) (479?mOsmol/kg). Participants (n?=?9) received a single, 4?ml, radiolabeled dose of each gel twice, once with and once without simulated unprotected receptive anal intercourse (RAI). The safety, plasma tenofovir pharmacokinetics, colonic small molecule permeability, and SPECT/CT imaging of lower gastrointestinal distribution of drug and virus surrogate were assessed. There were no Grade 3 or 4 adverse events reported for any of the products. Overall, there were more Grade 2 adverse events in the VF group compared to RF (p?=?0.006) and RGVF (p?=?0.048). In the absence of simulated unprotected RAI, VF had up to 3.8-fold greater systemic tenofovir exposure, 26- to 234-fold higher colonic permeability of the drug surrogate, and 1.5- to 2-fold greater proximal migration in the colonic lumen, when compared to RF and RGVF. Similar trends were observed with simulated unprotected RAI, but most did not reach statistical significance. SPECT analysis showed 86% (standard deviation 19%) of the drug surrogate colocalized with the virus surrogate in the colonic lumen. There were no significant differences between the RGVF and RF formulation, with the exception of a higher plasma tenofovir concentration of RGVF in the absence of simulated unprotected RAI. VF had the most adverse events, highest plasma tenofovir concentrations, greater mucosal permeability of the drug surrogate, and most proximal colonic luminal migration compared to RF and RGVF formulations. There were no major differences between RF and RGVF formulations. Simultaneous assessment of toxicity, systemic and luminal pharmacokinetics, and colocalization of drug and viral surrogates substantially informs rectal microbicide product development.

Dataset Information

FAME-04: A Phase 1 trial to assess the safety, acceptability, pharmacokinetics and pharmacodynamics of film and gel formulations of tenofovir.

Publications

FAME-04: A Phase 1 trial to assess the safety, acceptability, pharmacokinetics and pharmacodynamics of film and gel formulations of tenofovir.

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