Drugs

Tenofovir Alafenamide

Other Names: GS-7340, TAF, TFV alafenamide, prodrug of tenofovir, tenofovir alafenamide fumarate Drug Class: Nucleoside Reverse Transcriptase Inhibitors
Molecular Formula: C21 H29 N6 O5 P
Registry Number: 379270-37-8 (CAS) Chemical Name: isopropyl (2S)-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphoryl]amino]propanoate Chemical Class: Purine Nucleotides Organization: Gilead Sciences, Inc. Phase of Development: Five fixed-dose combination (FDC) tablets containing tenofovir alafenamide are U.S. Food and Drug Administration (FDA)-approved for HIV treatment: 1) elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (brand name: Genvoya), 2) emtricitabine/rilpivirine/tenofovir alafenamide (brand name: Odefsey), 3) emtricitabine/tenofovir alafenamide (brand name: Descovy), 4) bictegravir/emtricitabine/tenofovir alafenamide (brand name: Biktarvy), and 5) darunavir/cobicistat/emtricitabine/tenofovir alafenamide (brand name: Symtuza).

Descovy is also FDA-approved for use in certain at-risk individuals as an agent for HIV pre-exposure prophylaxis (PrEP).

As a stand-alone agent, tenofovir alafenamide (brand name: Vemlidy) is FDA-approved for chronic HBV infection treatment. It does not appear that stand-alone tenofovir alafenamide will be developed for HIV treatment, although there are two trials that are utilizing stand-alone tenofovir alafenamide to form antiretroviral regimens for treating HIV.

Chemical Image:

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tenofovir alafenamide

tenofovir alafenamide

Molecular Weight: 476.4711

(Compound details obtained from ChemIDplus Advanced,1 NIAID Therapeutics Database,2 Full Prescribing Information for Genvoya, Odefsey, Descovy, Biktarvy, Symtuza, and Vemlidy,3-8 and ClinicalTrials.gov9,10)

Pharmacology


Mechanism of Action: Nucleotide reverse transcriptase inhibitor. Tenofovir alafenamide (TAF) is a phosphonoamidate prodrug of the nucleotide analog tenofovir (TFV). TAF was designed to circulate systemically as the prodrug and undergo conversion to TFV intracellularly, achieving higher active metabolite concentrations in peripheral blood mononuclear cells and lower plasma TFV exposures than tenofovir disoproxil fumarate (tenofovir DF; TDF) does.11-13

TAF is predominantly metabolized intracellularly to TFV. This intracellular metabolism is primarily catalyzed by cathepsin A (CatA). Inside cells, TAF is initially hydrolyzed to a partially stable metabolite, from which the phenol group is spontaneously released, forming a cell-impermeable tenofovir-alanine (TFV-Ala) intermediate. TFV-Ala is converted to parent TFV, which undergoes subsequent phosphorylations to yield the active tenofovir diphosphate (TFV-DP) metabolite.14-16 TFV-DP inhibits the activity of HIV reverse transcriptase by competing with natural substrates and causing DNA chain termination after being incorporated into viral DNA.17

TAF has also demonstrated in vitro and in vivo activity against HBV.18,19

Half-life (T½): The median terminal half-life of TAF is 0.51 hours. The active metabolite, TFV-DP, has an intracellular half-life of 150 to 180 hours.3

Metabolism/Elimination: More than 80% of an oral dose of TAF is metabolized. In vitro, TAF is intracellularly metabolized to TFV by the CES1 enzyme (in hepatocytes) and by CatA (in PBMCs and macrophages). CYP3A-mediated metabolism of TAF is minor. Following single-dose administration of radiolabeled TAF, less than 1% of the dose is excreted in the urine and 31.7% of the dose is excreted in feces.3

Resistance: In vitro, HIV-1 isolates with reduced susceptibility to TAF have been selected, including virus with the K65R substitution (sometimes with S68N or L429I substitutions) and virus with the K70E substitution.3

The K65R and K70E TFV resistance substitutions can result in reduced susceptibility to abacavir, didanosine, emtricitabine, lamivudine, and TFV. HIV-1 containing multiple thymidine analog mutations (TAMs; M41L, D67N, K70R, L210W, T215F/Y, K219Q/E/N/R) have shown resistance to TAF in cell culture. In addition, multi-nucleoside resistant virus with a T69S double insertion mutation or with a Q151M mutation complex including K65R has exhibited in vitro resistance to tenofovir alafenamide.3

Additional information on HIV resistance mutations associated with TAF may be described in the following FDA-approved full prescribing labels: Genvoya, Odefsey, DescovyBiktarvy, and Symtuza.3-7


Select Clinical Trials


Tenofovir alafenamide for HIV treatment

FDC tablets

Five FDC tablets containing TAF are FDA-approved for HIV treatment: Genvoya, Odefsey, Descovy, Biktarvy, and Symtuza.3–7

FDA has also granted tentative approval of a dolutegravir/emtricitabine/tenofovir alafenamide FDC tablet and a dolutegravir/lamivudine/tenofovir alafenamide FDC tablet. These single-tablet regimens were approved under the U.S. President’s Emergency Plan for AIDS Relief (PEPFAR) and are available in PEPFAR focus countries for the treatment of HIV.20,21

Stand-alone TAF

Stand-alone TAF is not FDA-approved for HIV but is approved for treating chronic HBV infection under the brand name Vemlidy.8

This stand-alone version of TAF is being used in a Phase 2 trial (NCT03472326) that is evaluating the investigational NRTI GS-9131 for HIV treatment in women who are failing their current ART regimen. Participants will first receive GS-9131 functional monotherapy and will later switch to one of two ART regimens: either 1) GS-9131, bictegravir, darunavir, and ritonavir, or 2) GS-9131, bictegravir, and stand-alone TAF.9

The stand-alone version of TAF will also be used in a Phase 2 trial (NCT04143594) evaluating the efficacy of GS-6207, an investigational capsid inhibitor, in combination with other antiretrovirals for the treatment of HIV.10

Tenofovir alafenamide for HIV prevention

Descovy is FDA-approved for use in certain at-risk adults and adolescents as HIV PrEP to reduce the risk of HIV-1 infection from sexual acquisition. This approved use excludes individuals at risk of HIV infection from receptive vaginal sex.5

There are several early-phase HIV prevention studies involving TAF-containing products that are ongoing or planned, including:
  • MTN-039 (NCT04047420): A Phase 1 safety and pharmacokinetic trial evaluating the rectal administration of a tenofovir alafenamide/elvitegravir (TAF/EVG) insert (at two dose levels) in individuals without HIV. See the ClinicalTrials.gov record for this study’s status.22
  • NCT03976752: A Phase 1 pharmacokinetic study to evaluate Genvoya as a potential regimen to prevent HIV infection soon after potential exposure. Participants are men who have sex with men and who do not have HIV. This study is currently recruiting participants.23
  • NCT03472963: A Phase 1 pharmacokinetic study to evaluate Genvoya and darunavir as potential regimens to prevent HIV infection soon after potential exposure. Participants are men who have sex with men and who do not have HIV. This study is currently recruiting participants.24
  • NCT03499483: A Phase 4 trial evaluating the use of Biktarvy for the prevention of HIV infection in adults without HIV after high-risk sexual contact (non-occupational post exposure prophylaxis). This study is currently recruiting participants.25


Adverse Events


Adverse events associated with TAF may be described in the following FDA-approved full prescribing labels: Genvoya, Odefsey, Descovy, VemlidyBiktarvy, and Symtuza.3-8


Drug Interactions


At clinically relevant concentrations, TAF does not have inhibitory effects on the following transporters and enzymes: P-gp, BCRP (drug transporters); OAT1B1, OAT1B3, OCT1, BSEP (hepatic transporters); OAT1, OAT3, OCT2, MATE1 (renal transporters); or CYP, including CYP3A, and UGT1A1 (enzymes). TAF is a substrate of P-gp, BCRP, OATP1B1, and OATP1B3. Drugs that inhibit P-gp and BCRP may increase the absorption of TAF and result in increased plasma concentrations of TAF, while drugs that induce P-gp activity may decrease the absorption of TAF leading to decreased plasma concentrations of TAF.4,6

Specific drug-drug interactions associated with TAF may be described in the following FDA-approved full prescribing labels: Genvoya, Odefsey, Descovy, Vemlidy, Biktarvy, and Symtuza.3-8


References


  1. United States National Library of Medicine. ChemIDplus Advanced: Tenofovir Alafenamide. https://chem.sis.nlm.nih.gov/chemidplus/rn/379270-37-8. Accessed November 20, 2019
  2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. https://chemdb.niaid.nih.gov/DrugDevelopmentHIV.aspx. Accessed November 20, 2019
  3. Gilead Sciences, Inc. Genvoya: full prescribing information, February 11, 2019. DailyMed. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=34784acf-15ed-4715-b504-eb30430518e9. Accessed November 20, 2019
  4. Gilead Sciences, Inc. Odefsey: full prescribing information, October 1, 2018. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ea3b9ec8-e04a-412c-8b3f-e5cbc7e641d5. Accessed November 20, 2019
  5. Gilead Sciences, Inc. Descovy: full prescribing information, October 6, 2017. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=06f66e98-e6ee-4538-9506-6c1282cc14c1. Accessed November 20, 2019
  6. Gilead Sciences, Inc. Biktarvy: full prescribing information, September 17, 2018. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=664cb8f0-1f65-441b-b0d9-ba3d798be309. Accessed November 20, 2019
  7. Janssen Products LP. Symtuza: full prescribing information, February 4, 2019. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=85a17d00-6b7c-41ea-a6b3-5ad924820dab. Accessed November 20, 2019
  8. Gilead Sciences, Inc. Vemlidy: full prescribing information, February 11, 2019. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=72e6b33c-0351-4070-9172-eeaa186c01d2. Accessed November 20, 2019
  9. Gilead Sciences. A Phase 2 study to evaluate the efficacy of GS-9131 functional monotherapy in HIV-1-infected adults failing a nucleos(t)Ide reverse transcriptase inhibitor-containing regimen with nucleos(t)Ide reverse transcriptase inhibitor resistant virus, followed by continued treatment with a GS-9131+bictegravir+darunavir+ritonavir regimen. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 8, 2018. NLM Identifier: NCT03472326. https://clinicaltrials.gov/ct2/show/NCT03472326. Accessed November 20, 2019
  10. Gilead Sciences. A Phase 2 randomized, open label, active controlled study evaluating the safety and efficacy of long-acting capsid inhibitor GS-6207 in combination with other antiretroviral agents in people living with HIV. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on October 28, 2019. NLM Identifier: NCT04143594. https://clinicaltrials.gov/ct2/show/NCT04143594. Accessed November 20, 2019
  11. Birkus G, Bam RA, Frey CR, et al. Intracellular activation pathways for GS-7340 and the effect of antiviral protease inhibitors. Poster presented at: 19th Conference on Retroviruses and Opportunistic Infections (CROI); March 5-8, 2012; Seattle, WA. Poster 577. http://www.retroconference.org/2012b/PDFs/577.pdf. Accessed May 23, 2013.
  12. Lee WA, He G-X, Eisenberg E, et al. Selective intracellular activation of a novel prodrug of the human immunodeficiency virus reverse transcriptase inhibitor tenofovir leads to preferential distribution and accumulation in lymphatic tissue. Antimicrob Agents Chemother. 2005;49(5):1898-1906. doi:10.1128/AAC.49.5.1898-1906.2005
  13. Ruane PJ, DeJesus E, Berger D, et al. Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of tenofovir alafenamide as 10-day monotherapy in HIV-1-positive adults. J Acquir Immune Defic Syndr 1999. 2013;63(4):449-455. doi:10.1097/QAI.0b013e3182965d45
  14. Birkus G, Kutty N, He GX, et al. Activation of 9-[(R)-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino] phenoxyphosphinyl]-methoxy]propyl]adenine (GS-7340) and other tenofovir phosphonoamidate prodrugs by human proteases. Mol Pharmacol. 2008;74(1):92-100.
  15. Herman BD and Sluis-Cremer N. Molecular pharmacology of nucleoside and nucleotide HIV-1 reverse transcriptase inhibitors. In: Gallelli L, ed. In: Pharmacology. InTech; 2012:63-81. doi:10.5772/32969
  16. Sax PE, Zolopa A, Brar I, et al. Tenofovir alafenamide vs. tenofovir disoproxil fumarate in single tablet regimens for initial HIV-1 therapy: a randomized Phase 2 study. J Acquir Immune Defic Syndr. 2014;67(1):52-58.
  17. García-Lerma JG, Aung W, Cong M, et al. Natural substrate concentrations can modulate the prophylactic efficacy of nucleotide HIV reverse transcriptase inhibitors. J Virol. 2011;85(13):6610-6617. doi:10.1128/JVI.00311-11
  18. Gilead. Press Release, dated November 10, 2016. U.S. Food and Drug Administration approves Gilead’s Vemlidy® (tenofovir alafenamide) for the treatment of chronic hepatitis B virus infection. https://www.gilead.com/news-and-press/press-room/press-releases/2016/11/us-food-and-drug-administration-approves-gileads-vemlidy-tenofovir-alafenamide-for-the-treatment-of-chronic-hepatitis-b-virus-infection. Accessed November 20, 2019
  19. Lee W, He G, Mulato A, et al. In vivo and in vitro characterization of GS 7340, an isopropylalaninyl phenyl ester prodrug of tenofovir: selective intracellular activation of GS 7340 leads to preferential distribution in lymphatic tissues. Poster presented at: 9th Conference on Retroviruses and Opportunistic Infections (CROI); February 24-28, 2002; Seattle, WA. Poster 384-T. https://web.archive.org/web/20070316030446/http://retroconference.org/2002/Posters/13864.pdf. Accessed November 20, 2019
  20. Mylan: Press Release, dated February 20, 2018. Mylan receives tentative approval for combination HIV treatment DTG/FTC/TAF under FDA’s PEPFAR program. http://newsroom.mylan.com/2018-02-20-Mylan-Receives-Tentative-Approval-for-Combination-HIV-Treatment-DTG-FTC-TAF-Under-FDAs-PEPFAR-Program. Accessed November 20, 2019
  21. U.S. Food and Drug Administration (FDA). Tentatively approved and approved antiretrovirals eligible for procurement under the President’s Emergency Plan for AIDS Relief. http://www.fda.gov/international-programs/presidents-emergency-plan-aids-relief-pepfar/tentatively-approved-and-approved-antiretrovirals-eligible-procurement-under-presidents-emergency. Accessed November 20, 2019
  22. National Institute of Allergy and Infectious Diseases (NIAID). A Phase 1 open label safety and pharmacokinetic study of rectal administration of a tenofovir alafenamide/elvitegravir insert at two dose levels. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on August 5, 2019. NLM Identifier: NCT04047420. https://clinicaltrials.gov/ct2/show/NCT04047420. Accessed November 20, 2019
  23. Emory University. Body compartment pharmacokinetics of anti-retroviral agents that may be considered for future on-demand peri-exposure HIV prophylaxis regimens. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on June 4, 2019. NLM Identifier: NCT03976752. https://clinicaltrials.gov/ct2/show/NCT03976752. Accessed November 20, 2019
  24. Emory University. Body compartment pharmacokinetics of anti-retroviral agents that may be used for future HIV post-exposure prophylaxis regimens. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 15, 2018. NLM Identifier: NCT03472963. https://clinicaltrials.gov/ct2/show/NCT03472963. Accessed November 20, 2019
  25. Fenway Community Health. A Phase IV open-label evaluation of safety, tolerability, and acceptability of a fixed-dose formulation of bictegravir, emtricitabine/tenofovir alafenamide (B/F/TAF) for non-occupational prophylaxis following potential exposure to HIV-1. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on April 9, 2018. NLM Identifier: NCT03499483. https://clinicaltrials.gov/ct2/show/NCT03499483. Accessed November 20, 2019


Last Reviewed: November 20, 2019