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

Katherine E Bunge, Charlene S Dezzutti, Craig W Hendrix, Mark A Marzinke, Hans M L Spiegel, Bernard J Moncla, Jill L Schwartz, Leslie A Meyn, Nicola Richardson-Harman, Lisa C Rohan, Sharon L Hillier, Katherine E Bunge, Charlene S Dezzutti, Craig W Hendrix, Mark A Marzinke, Hans M L Spiegel, Bernard J Moncla, Jill L Schwartz, Leslie A Meyn, Nicola Richardson-Harman, Lisa C Rohan, Sharon L Hillier

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.

Trial registration: ClinicalTrials.gov NCT01989663.

Keywords: microbicide; prevention; tenofovir; vaginal film; vaginal gel.

© 2018 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.

Figures

Figure 1
Figure 1
The disposition of participants and how each participant contributed to different analyses.
Figure 2
Figure 2
Tenofovir‐diphosphate (TFV‐DP) pharmacokinetic and pharmacodynamic activity in female genital tract tissue. Paired biopsy tissues were exposed to HIV‐1BaLex vivo; there was a significant relationship between HIV p24 antigen production and TFV‐DP concentrations for cervical (a) (p < 0.01), but not vaginal (b) (p = 0.52) tissue. The non‐linear 4‐parameter model (black line) defined the EC 90 of TFV‐DP in cervical tissue for all treatment groups (c) (vertical dotted line). Triangle, TFV 40 mg film; square, TFV 10 mg film; circle, TFV gel

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