Genital Mucosal Drug Concentrations and anti-HIV Activity in Tenofovir-Based PrEP Products: Intravaginal Ring vs. Oral Administration

Abstract

Objective: To describe and compare systemic and local pharmacokinetics (PK) and cervicovaginal (CV) pharmacodynamics (PD) of oral tenofovir disoproxil fumarate (TDF) in combination with emtricitabine (FTC) with tenofovir (TFV) intravaginal ring (IVR).Design: Phase I, randomized, parallel-group study. Women (n = 22) used TDF/FTC oral tablets daily or TFV IVR continuously and were assessed at baseline and 14 days.Methods: TFV and FTC concentrations were measured in plasma, CV fluid (CVF), and CV tissue. TFV-diphosphate and FTCtriphosphate were assessed in CV tissue. In vitro PD antiviral activities of TFV and FTC (using in vivo concentration ranges) were modeled in the CVF and by infecting CV tissue explants ex vivo with HIV-1 BaL .Results: Adverse events (AEs) were more common with oral TDF/ FTC use (P , 0.01). The median CVF TFV concentrations were 10 6 ng/mL after use of TFV IVR vs. 10 2 ng/mL for TDF/FTC. The median TFV and TFV-diphosphate concentrations in CV tissue were .100-fold higher among IVR users. The median CVF FTC concentrations were 10 3 ng/mL. FTC and FTC-triphosphate were detected in all CV tissues from TDF/FTC users. HIV inhibitory activity of CVF increased significantly with treatment in both cohorts (P , 0.01) but was higher in TFV IVR users (P , 0.01). In vitro inhibition of tissue infection with ex vivo administration of TFV and FTC was dose dependent, with maximal efficacy achieved with 10 mg/mL TFV, 1 mg/mL FTC, and 0.1 mg/mL of TFV and FTC combined.Conclusions: Both products were safe and increased mucosal HIV inhibitory activity. In addition to systemic protection, oral TDF/FTC displays a PK/PD profile compatible with CV mucosal antiviral activity. TFV IVR resulted in fewer AEs, lower TFV plasma concentrations, higher CVF and tissue TFV and TFV-DP concentrations, and greater anti-HIV activity in CVF.

Vaginal Microbiota and Mucosal Pharmacokinetics of Tenofovir in Healthy Women Using a 90-Day Tenofovir/Levonorgestrel Vaginal Ring

“…CONRAD and our collaborators developed two MPT intravaginal rings (IVRs) which release tenofovir (TFV) alone (active against HIV-1 and HSV-2) and TFV in combination with levonorgestrel (LNG) (contraceptive) for 90 days ( Johnson et al., 2012 ; Clark et al., 2014 ). To date, the TFV and or TFV/LNG IVRs have been tested in 5 phase I studies (CONRAD 128 ClinicalTrials.gov NCT02235662 ( Thurman et al., 2018 ; Thurman et al., 2019 ), CONRAD 138 NCT03279120 ( Thurman et al., 2021 ), CONRAD 140 NCT02722343 ( Ouattara et al., 2022a ), CONRAD 144 NCT03762382 ( Mugo et al., 2021 ), and MTN038 NCT03670355, conducted in the United States, Dominican Republic, and Western Kenya.…”

Synthesis of protective PrEP adherence levels in cisgender women using convergent clinical and bottom-up modelling.

“…Local drug concentrations. We simulated dosing schedules and measurement time-points for 7 studies that report local TFV-DP or FTC-TP concentrations [36][37][38][39][40][41][42] using the pharmacokinetic models exemplified above. Based on the respective simulated concentrations in PBMCs, we computed local:PBMC concentrations at the study-specific measurement timepoints, as illustrated in Supplementary Text S3.…”

“…We identified 3 studies with 8 dosing regimens for FTC-TP and 5 studies reporting 10 dosing regimens for TFV-DP that report local TFV-DP or FTC-TP concentrations [36][37][38][39][40][41][42]. By simulating the respective dosing regimens using our pharmacokinetic models (Methods In summary, our simulations point out that the type of exposure, as well as local dNTP concentrations have little impact on PrEP efficacy when considered in isolation.…”

“…Notably, each of these 'building blocks' has been individually verified or developed based on available clinical and in vitro data [36][37][38][39][40][41][42], reflecting the current state-of-knowledge of the mechanisms of action of FTC/TDF-based PrEP at the multiple scales that determine PrEP efficacy.…”

Tenofovir-tethered gold nanoparticles as a novel multifunctional long-acting anti-HIV therapy to overcome deficient drug delivery-: an in vivo proof of concept

“…It is evident from the chemical structure of TNF that it exhibits a negative charge facilitating improved systemic transport and disposition to various tissues/organs [ 47 – 50 ]. Therefore, drug delivery strategies for TNF are the key to the low bioavailability and toxicity concerns [ 51 ].…”