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

Overview

Journal Front Pharmacol

Date 2021 Feb 4

PMID 33536904

Citations 11

Authors

Manjula Gunawardana

Mariana Remedios-Chan

Debbie Sanchez

Simon Webster

Patricia Galvan

Rob Fanter

Amalia E Castonguay

Paul Webster

John A Moss

Joseph Kuo

Philippe A Gallay

Kathleen L Vincent

Massoud Motamedi

Dana Weinberger

Mark A Marzinke

Craig W Hendrix

Marc M Baum

Affiliations

Soon will be listed here.

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.

Citing Articles

An Ultra-Long-Acting Dimeric Bictegravir Prodrug Defined by a Short Pharmacokinetic Tail.

Edagwa B, Nayan M, Sillman B, Das S, Hanson B, Sultana A Res Sq. 2025; .

PMID: 40034436 PMC: 11875291. DOI: 10.21203/rs.3.rs-5959131/v1.

Data characterizing a panel of biodegradable cross-linked polyester implants for sustained delivery of an anti-viral drug.

Jung S, Bufton J, Bao Z, Cho W, Aguiar D, Allen C Data Brief. 2025; 58():111182.

PMID: 39802831 PMC: 11719335. DOI: 10.1016/j.dib.2024.111182.

Parenteral platforms for tunable, long-acting administration of a highly hydrophobic antiretroviral drug.

Akhavein N, Baum M, Gunawardana M, Moss J, Calvez S, Remedios-Chan M Sci Rep. 2024; 14(1):11573.

PMID: 38773172 PMC: 11109207. DOI: 10.1038/s41598-024-58583-w.

Chronic Hepatitis B Infection: New Approaches towards Cure.

Ogunnaike M, Das S, Raut S, Sultana A, Nayan M, Ganesan M Biomolecules. 2023; 13(8).

PMID: 37627273 PMC: 10452112. DOI: 10.3390/biom13081208.

Incorporating end-users' voices into the development of an implant for HIV prevention: a discrete choice experiment in South Africa and Zimbabwe.

Browne E, Manenzhe K, Makoni W, Nkomo S, Mahaka I, Ahmed K BMC Womens Health. 2023; 23(1):58.

PMID: 36765358 PMC: 9913002. DOI: 10.1186/s12905-023-02181-x.

References

Holt B, Bachus K, Beck J, Bloebaum R, Jeyapalina S . Immediate post-implantation skin immobilization decreases skin regression around percutaneous osseointegrated prosthetic implant systems. J Biomed Mater Res A. 2013; 101(7):2075-82. DOI: 10.1002/jbm.a.34510. View

Schlesinger E, Johengen D, Luecke E, Rothrock G, McGowan I, van der Straten A . A Tunable, Biodegradable, Thin-Film Polymer Device as a Long-Acting Implant Delivering Tenofovir Alafenamide Fumarate for HIV Pre-exposure Prophylaxis. Pharm Res. 2016; 33(7):1649-56. PMC: 4892981. DOI: 10.1007/s11095-016-1904-6. View

Gallay P, Chatterji U, Kirchhoff A, Gandarilla A, Gunawardana M, Pyles R . Prevention of vaginal and rectal HIV transmission by antiretroviral combinations in humanized mice. PLoS One. 2017; 12(9):e0184303. PMC: 5589224. DOI: 10.1371/journal.pone.0184303. View

Gallay P, Chatterji U, Kirchhoff A, Gandarilla A, Pyles R, Baum M . Protection Efficacy of C5A Against Vaginal and Rectal HIV Challenges in Humanized Mice. Open Virol J. 2018; 12:1-13. PMC: 5842390. DOI: 10.2174/1874357901812010001. View

Parsons T, Gwenden K, Marzinke M . Interspecies Differences in Tenofovir Alafenamide Fumarate Stability in Plasma. Antimicrob Agents Chemother. 2020; 64(9). PMC: 7449208. DOI: 10.1128/AAC.00930-20. View

Gunawardana M, Remedios-Chan M, Miller C, Fanter R, Yang F, Marzinke M . Pharmacokinetics of long-acting tenofovir alafenamide (GS-7340) subdermal implant for HIV prophylaxis. Antimicrob Agents Chemother. 2015; 59(7):3913-9. PMC: 4468692. DOI: 10.1128/AAC.00656-15. View

Hummert P, Parsons T, Ensign L, Hoang T, Marzinke M . Validation and implementation of liquid chromatographic-mass spectrometric (LC-MS) methods for the quantification of tenofovir prodrugs. J Pharm Biomed Anal. 2018; 152:248-256. PMC: 5835418. DOI: 10.1016/j.jpba.2018.02.011. View

Moyo D, Gomes M, Erlwanger K . Comparison of the histology of the skin of the Windsnyer, Kolbroek and Large White pigs. J S Afr Vet Assoc. 2018; 89(0):e1-e10. PMC: 6191761. DOI: 10.4102/jsava.v89i0.1569. View

Chua C, Jain P, Ballerini A, Bruno G, Hood R, Gupte M . Transcutaneously refillable nanofluidic implant achieves sustained level of tenofovir diphosphate for HIV pre-exposure prophylaxis. J Control Release. 2018; 286:315-325. PMC: 6345255. DOI: 10.1016/j.jconrel.2018.08.010. View

10.

Lykins W, Luecke E, Johengen D, van der Straten A, Desai T . Long acting systemic HIV pre-exposure prophylaxis: an examination of the field. Drug Deliv Transl Res. 2017; 7(6):805-816. DOI: 10.1007/s13346-017-0391-6. View

11.

Sartoretto S, Uzeda M, Miguel F, Nascimento J, Ascoli F, Calasans-Maia M . SHEEP AS AN EXPERIMENTAL MODEL FOR BIOMATERIAL IMPLANT EVALUATION. Acta Ortop Bras. 2017; 24(5):262-266. PMC: 5266658. DOI: 10.1590/1413-785220162405161949. View

12.

McEvoy F, Strathe A, Madsen M, Svalastoga E . Changes in the relative thickness of individual subcutaneous adipose tissue layers in growing pigs. Acta Vet Scand. 2007; 49:32. PMC: 2174490. DOI: 10.1186/1751-0147-49-32. View

13.

Su J, Simpson S, Sung S, Bryndza Tfaily E, Veazey R, Marzinke M . A Subcutaneous Implant of Tenofovir Alafenamide Fumarate Causes Local Inflammation and Tissue Necrosis in Rabbits and Macaques. Antimicrob Agents Chemother. 2019; 64(3). PMC: 7038301. DOI: 10.1128/AAC.01893-19. View

14.

Vegas A, Veiseh O, Doloff J, Ma M, Tam H, Bratlie K . Combinatorial hydrogel library enables identification of materials that mitigate the foreign body response in primates. Nat Biotechnol. 2016; 34(3):345-52. PMC: 4904301. DOI: 10.1038/nbt.3462. View

15.

Stricker-Krongrad A, Shoemake C, Bouchard G . The Miniature Swine as a Model in Experimental and Translational Medicine. Toxicol Pathol. 2016; 44(4):612-23. DOI: 10.1177/0192623316641784. View

16.

Gunawardana M, Baum M, Smith T, Moss J . An intravaginal ring for the sustained delivery of antibodies. J Pharm Sci. 2014; 103(11):3611-3620. PMC: 4206599. DOI: 10.1002/jps.24154. View

17.

Johnson L, Krovi S, Li L, Girouard N, Demkovich Z, Myers D . Characterization of a Reservoir-Style Implant for Sustained Release of Tenofovir Alafenamide (TAF) for HIV Pre-Exposure Prophylaxis (PrEP). Pharmaceutics. 2019; 11(7). PMC: 6680758. DOI: 10.3390/pharmaceutics11070315. View

18.

Asin J, Molin J, Perez M, Pinczowski P, Gimeno M, Navascues N . Granulomas Following Subcutaneous Injection With Aluminum Adjuvant-Containing Products in Sheep. Vet Pathol. 2018; 56(3):418-428. DOI: 10.1177/0300985818809142. View

19.

Rashid S, Salacinski H, Hamilton G, Seifalian A . The use of animal models in developing the discipline of cardiovascular tissue engineering: a review. Biomaterials. 2003; 25(9):1627-37. DOI: 10.1016/s0142-9612(03)00522-2. View

20.

Alexandre N, Ribeiro J, Gartner A, Pereira T, Amorim I, Fragoso J . Biocompatibility and hemocompatibility of polyvinyl alcohol hydrogel used for vascular grafting--In vitro and in vivo studies. J Biomed Mater Res A. 2014; 102(12):4262-75. DOI: 10.1002/jbm.a.35098. View