Characterization of a Reservoir-Style Implant for Sustained Release of Tenofovir Alafenamide (TAF) for HIV Pre-Exposure Prophylaxis (PrEP)

Johnson, Lewis D.; Krovi, Sai Archana; Li, Linying; Girouard, Natalie; Demkovich, Zach; Myers, Daniel T.; Creelman, Ben; Straten, Ariane van der

doi:10.3390/pharmaceutics11070315

Cited by 69 publications

(66 citation statements)

References 57 publications

(60 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PCL has been described previously as a good candidate to prepare rate controlling membranes for drug delivery applications [9]. PEG membranes have been used before to release tenofovir alafenamide for HIV pre-exposure prophylaxis [56]. These systems achieved prolonged releases between 100 and 200 days.…”

Section: In Vitro Drug Release From Coated Implantsmentioning

confidence: 99%

Development of a Biodegradable Subcutaneous Implant for Prolonged Drug Delivery Using 3D Printing

et al. 2020

View full text Add to dashboard Cite

Implantable drug delivery devices offer many advantages over other routes of drug delivery. Most significantly, the delivery of lower doses of drug, thus, potentially reducing side-effects and improving patient compliance. Three dimensional (3D) printing is a flexible technique, which has been subject to increasing interest in the past few years, especially in the area of medical devices. The present work focussed on the use of 3D printing as a tool to manufacture implantable drug delivery devices to deliver a range of model compounds (methylene blue, ibuprofen sodium and ibuprofen acid) in two in vitro models. Five implant designs were produced, and the release rate varied, depending on the implant design and the drug properties. Additionally, a rate controlling membrane was produced, which further prolonged the release from the produced implants, signalling the potential use of these devices for chronic conditions.

show abstract

Section: In Vitro Drug Release From Coated Implantsmentioning

confidence: 99%

Development of a Biodegradable Subcutaneous Implant for Prolonged Drug Delivery Using 3D Printing

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Currently, LA ARV strategies for HIV PrEP are largely geared towards developing single-agent drugs for prevention instead of combinatorial formulations. [7][8][9][10][11][12][13][14][15] Focusing on a single drug allows for maximal drug loading, while minimizing injection volumes (for injectables). In the case of LA ARV implants, a single drug formulation affords smaller size dimensions for minimally-invasive and discreet implantation.…”

Section: Introductionmentioning

confidence: 99%

Preventive efficacy of a tenofovir alafenamide fumarate nanofluidic implant in SHIV-challenged nonhuman primates

Pons‐Faudoa

Sizovs

Shelton

et al. 2020

Preprint

View full text Add to dashboard Cite

36Pre-exposure prophylaxis (PrEP) using antiretroviral oral drugs is effective at preventing HIV 37 transmission when individuals adhere to the dosing regimen. Tenofovir alafenamide (TAF) is a 38 potent antiretroviral drug, with numerous long-acting (LA) delivery systems under development 39 to improve PrEP adherence. However, none has undergone preventive efficacy assessment. Here 40 we show that LA TAF using a novel subcutaneous nanofluidic implant (nTAF) confers 41 protection from HIV transmission. We demonstrate that sustained subcutaneous delivery through 42 nTAF in rhesus macaques maintained tenofovir diphosphate concentration at a median of 390.00 43 fmol/10 6 peripheral blood mononuclear cells, 9 times above clinically protective levels. In a non-44 blinded, placebo-controlled rhesus macaque study with repeated low-dose rectal SHIVSF162P3 45 3 challenge, the nTAF cohort had a 62.50% reduction in risk of infection per exposure compared 46 to the control. Our finding mirrors that of tenofovir disoproxil fumarate (TDF) monotherapy, 47 where 60.00% protective efficacy was observed in macaques, and clinically, 67% reduction in 48 risk with 86.00% preventive efficacy in individuals with detectable drug in the plasma. Overall, 49 our nanofluidic technology shows potential as a subcutaneous delivery platform for long-term 50PrEP and provides insights for clinical implementation of LA TAF for HIV prevention. 51 52 65 Long-acting (LA) antiretroviral (ARV) formulations and delivery systems offer systemic 66 delivery for prolonged periods, obviating the need for frequent dosing. Currently, LA ARV 67 strategies for HIV PrEP are largely geared towards developing single-agent drugs for prevention 68 mg of TAF over 10 days (Fig. 1i). However, an increase of TAF degradation products was 131 observed throughout the study, attributable to decrease in TAF stability ( Supplementary Fig. 1). 132 133 nTAF pharmacokinetic profile in NHP 134For in vivo evaluation of pharmacokinetic (PK) and PrEP efficacy, rhesus macaques were 135 subcutaneously implanted with either nTAF (n=8) or control nPBS (n=6) in the dorsum for 4 136 months. We used TFV-DP concentration in PBMC of 100.00 fmol/10 6 cells as the benchmark 137 phase 2a trial. Lancet HIV 4, e331-e340 (2017). 595

show abstract

“…TAF exhibited an improved antiviral activity and safety profile related to renal and bone toxicity [30][31][32]. Therefore, TFV, TDF and in particular TAF represent key compounds for the treatment of chronic hepatitis B and HIV infections and are thus a subject of intense research in the area of new drug delivery systems [33][34][35][36][37][38][39][40].…”

Section: Introductionmentioning

confidence: 99%

Co-crystals, Salts or Mixtures of Both? The Case of Tenofovir Alafenamide Fumarates

Lengauer

Makuc

Šterk³

et al. 2020

Pharmaceutics

View full text Add to dashboard Cite

Tenofovir alafenamide fumarate (TAF) is the newest prodrug of tenofovir that constitutes several drug products used for the treatment of HIV/AIDS. Although the solid-state properties of its predecessor tenofovir disoproxil fumarate have been investigated and described in the literature, there are no data in the scientific literature on the solid state properties of TAF. In our report, we describe the preparation of two novel polymorphs II and III of tenofovir alafenamide monofumarate (TA MF2 and TA MF3). The solid-state structure of these compounds was investigated in parallel to the previously known tenofovir alafenamide monofumarate form I (TA MF1) and tenofovir alafenamide hemifumarate (TA HF). Interestingly, the single-crystal X-ray diffraction of TA HF revealed that this derivative exists as a co-crystal form. In addition, we prepared a crystalline tenofovir alafenamide free base (TA) and its hydrochloride salt (TA HCl), which enabled us to determine the structure of TA MF derivatives using 15N-ssNMR (15N-solid state nuclear magnetic resonance). Surprisingly, we observed that TA MF1 exists as a mixed ionization state complex or pure salt, while TA MF2 and TA MF3 can be obtained as pure co-crystal forms.

show abstract

Characterization of a Reservoir-Style Implant for Sustained Release of Tenofovir Alafenamide (TAF) for HIV Pre-Exposure Prophylaxis (PrEP)

Cited by 69 publications

References 57 publications

Development of a Biodegradable Subcutaneous Implant for Prolonged Drug Delivery Using 3D Printing

Development of a Biodegradable Subcutaneous Implant for Prolonged Drug Delivery Using 3D Printing

Preventive efficacy of a tenofovir alafenamide fumarate nanofluidic implant in SHIV-challenged nonhuman primates

Co-crystals, Salts or Mixtures of Both? The Case of Tenofovir Alafenamide Fumarates

Contact Info

Product

Resources

About