Multispecies Evaluation of a Long-Acting Tenofovir Alafenamide Subdermal Implant for HIV Prophylaxis.

Manjula Gunawardana,John A Moss,Marc M Baum,Debbie Sanchez,Patricia Galvan,Mariana Remedios-Chan,Mark A Marzinke,Dana Weinberger,Philippe A Gallay,Paul Webster,Rob Fanter,Craig W Hendrix,Simon Webster,Kathleen L Vincent,Amalia E Castonguay,Massoud Motamedi,Joseph Kuo

doi:10.3389/fphar.2020.569373

Abstract

New HIV-1 infection rates far outpace the targets set by global health organizations, despite important progress in curbing the progression of the epidemic. Long-acting (LA) formulations delivering antiretroviral (ARV) agents for HIV-1 pre-exposure prophylaxis (PrEP) hold significant promise, potentially facilitating adherence due to reduced dosing frequency compared to oral regimens. We have developed a subdermal implant delivering the potent ARV drug tenofovir alafenamide that could provide protection from HIV-1 infection for 6 months, or longer. Implants from the same lot were investigated in mice and sheep for local safety and pharmacokinetics (PKs). Ours is the first report using these animal models to evaluate subdermal implants for HIV-1 PrEP. The devices appeared safe, and the plasma PKs as well as the drug and metabolite concentrations in dermal tissue adjacent to the implants were studied and contrasted in two models spanning the extremes of the body weight spectrum. Drug and drug metabolite concentrations in dermal tissue are key in assessing local exposure and any toxicity related to the active agent. Based on our analysis, both animal models were shown to hold significant promise in LA product development.

Highlights

Long-acting (LA) biomedical devices delivering antiretroviral (ARV) drugs locally or systemically reduce dosing frequency and, may lead to increased product adherence (Krogstad et al, 2019) and effectiveness
tenofovir alafenamide (TAF) Implants formulated for preclinical evaluation afforded linear drug release in vitro
The availability of suitable animal models is of paramount importance in the preclinical development of biomedical drug delivery devices

Summary

Introduction

Long-acting (LA) biomedical devices delivering antiretroviral (ARV) drugs locally or systemically reduce dosing frequency and, may lead to increased product adherence (Krogstad et al, 2019) and effectiveness. The prodrug tenofovir alafenamide (TAF) has the potency required to make a subdermal implant theoretically feasible (Gunawardana et al, 2015), and the clinical pharmacology of the parent drug tenofovir (TFV) and its active metabolite against HIV-1, TFV diphosphate (TFV-DP) are well understood. The choice of animal model and realistic human scaling of pharmacokinetic (PK) and pharmacodynamic (PD) measures are critical for successful preclinical development of LA drug delivery products for HIV-1 PrEP. We compared the PKs of TAF delivery from a subdermal implant in two animal models at opposite ends of the body weight spectrum: mice and sheep. This is the first report of the application of these models to the evaluation of TAF implants

Methods

Results

Conclusion