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

2020 ◽  
Vol 11 ◽  
Author(s):  
Manjula Gunawardana ◽  
Mariana Remedios-Chan ◽  
Debbie Sanchez ◽  
Simon Webster ◽  
Patricia Galvan ◽  
...  
Keyword(s):  
Animal Models ◽  
Active Agent ◽  
The Body ◽  
Dermal Tissue ◽  
Metabolite Concentrations ◽  
Tenofovir Alafenamide ◽  
Long Acting ◽  
Exposure Prophylaxis ◽  
Hiv 1 ◽  
Subdermal Implant

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.

scholarly journals Pharmacokinetics of Long-Acting Tenofovir Alafenamide (GS-7340) Subdermal Implant for HIV Prophylaxis

2015 ◽  
Vol 59 (7) ◽  
pp. 3913-3919 ◽  
Author(s):  
Manjula Gunawardana ◽  
Mariana Remedios-Chan ◽  
Christine S. Miller ◽  
Rob Fanter ◽  
Flora Yang ◽  
...  
Keyword(s):  
Sustained Release ◽  
Vulnerable Populations ◽  
Mononuclear Cells ◽  
Systemic Exposure ◽  
Systemic Delivery ◽  
Tenofovir Alafenamide ◽  
Long Acting ◽  
Pharmacologically Active ◽  
Hiv 1 ◽  
Subdermal Implant

ABSTRACTOral or topical daily administration of antiretroviral (ARV) drugs to HIV-1-negative individuals in vulnerable populations is a promising strategy for HIV-1 prevention. Adherence to the dosing regimen has emerged as a critical factor determining efficacy outcomes of clinical trials. Because adherence to therapy is inversely related to the dosing period, sustained release or long-acting ARV formulations hold significant promise for increasing the effectiveness of HIV-1 preexposure prophylaxis (PrEP) by reducing dosing frequency. A novel, subdermal implant delivering the potent prodrug tenofovir alafenamide (TAF) with controlled, sustained, zero-order (linear) release characteristics is described. A candidate device delivering TAF at 0.92 mg day−1in vitrowas evaluated in beagle dogs over 40 days for pharmacokinetics and preliminary safety. No adverse events related to treatment with the test article were noted during the course of the study, and no significant, unusual abnormalities were observed. The implant maintained a low systemic exposure to TAF (median, 0.85 ng ml−1; interquartile range [IQR], 0.60 to 1.50 ng ml−1) and tenofovir (TFV; median, 15.0 ng ml−1; IQR, 8.8 to 23.3 ng ml−1), the product ofin vivoTAF hydrolysis. High concentrations (median, 512 fmol/106cells over the first 35 days) of the pharmacologically active metabolite, TFV diphosphate, were observed in peripheral blood mononuclear cells at levels over 30 times higher than those associated with HIV-1 PrEP efficacy in humans. Our report on the first sustained-release nucleoside reverse transcriptase inhibitor (NRTI) for systemic delivery demonstrates a successful proof of principle and holds significant promise as a candidate for HIV-1 prophylaxis in vulnerable populations.

scholarly journals Long-acting rilpivirine as potential pre-exposure prophylaxis for HIV-1 prevention (the MWRI-01 study): an open-label, phase 1, compartmental, pharmacokinetic and pharmacodynamic assessment

2016 ◽  
Vol 3 (12) ◽  
pp. e569-e578 ◽  
Author(s):  
Ian McGowan ◽  
Charlene S Dezzutti ◽  
Aaron Siegel ◽  
Jarret Engstrom ◽  
Alexiy Nikiforov ◽  
...  
Keyword(s):  
Phase 1 ◽  
Open Label ◽  
Open Label Phase ◽  
Long Acting ◽  
Exposure Prophylaxis ◽  
Hiv 1

Safety and pharmacokinetics of islatravir subdermal implant for HIV-1 pre-exposure prophylaxis: a randomized, placebo-controlled phase 1 trial

2021 ◽  
Vol 27 (10) ◽  
pp. 1712-1717
Author(s):  
Randolph P. Matthews ◽  
Munjal Patel ◽  
Stephanie E. Barrett ◽  
Liesbeth Haspeslagh ◽  
Tom Reynders ◽  
...  
Keyword(s):  
Phase 1 ◽  
Phase 1 Trial ◽  
Exposure Prophylaxis ◽  
Hiv 1 ◽  
Subdermal Implant

scholarly journals Tenofovir alafenamide and elvitegravir loaded nanoparticles for long-acting prevention of HIV-1 vaginal transmission

AIDS ◽  
2017 ◽  
Vol 31 (4) ◽  
pp. 469-476 ◽  
Author(s):  
Subhra Mandal ◽  
Pavan K. Prathipati ◽  
Guobin Kang ◽  
You Zhou ◽  
Zhe Yuan ◽  
...  
Keyword(s):  
Vaginal Transmission ◽  
Tenofovir Alafenamide ◽  
Long Acting ◽  
Hiv 1 ◽  
Prevention Of Hiv

scholarly journals Viral load Reduction in SHIV-Positive Nonhuman Primates via Long-Acting Subcutaneous Tenofovir Alafenamide Fumarate Release from a Nanofluidic Implant

Pharmaceutics ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 981
Author(s):  
Fernanda P. Pons-Faudoa ◽  
Nicola Di Trani ◽  
Antons Sizovs ◽  
Kathryn A. Shelton ◽  
Zoha Momin ◽  
...  
Keyword(s):  
Viral Load ◽  
Nonhuman Primates ◽  
Mononuclear Cells ◽  
Target Cells ◽  
People Living With Hiv ◽  
Peripheral Blood Mononuclear ◽  
Treatment Regimens ◽  
Tenofovir Alafenamide ◽  
Long Acting ◽  
Hiv 1

HIV-1 is a chronic disease managed by strictly adhering to daily antiretroviral therapy (ART). However, not all people living with HIV-1 have access to ART, and those with access may not adhere to treatment regimens increasing viral load and disease progression. Here, a subcutaneous nanofluidic implant was used as a long-acting (LA) drug delivery platform to address these issues. The device was loaded with tenofovir alafenamide (TAF) and implanted in treatment-naïve simian HIV (SHIV)-positive nonhuman primates (NHP) for a month. We monitored intracellular tenofovir-diphosphate (TFV-DP) concentration in the target cells, peripheral blood mononuclear cells (PBMC). The concentrations of TFV-DP were maintained at a median of 391.0 fmol/106 cells (IQR, 243.0 to 509.0 fmol/106 cells) for the duration of the study. Further, we achieved drug penetration into lymphatic tissues, known for persistent HIV-1 replication. Moreover, we observed a first-phase viral load decay of −1.14 ± 0.81 log10 copies/mL (95% CI, −0.30 to −2.23 log10 copies/mL), similar to −1.08 log10 copies/mL decay observed in humans. Thus, LA TAF delivered from our nanofluidic implant had similar effects as oral TAF dosing with a lower dose, with potential as a platform for LA ART.

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