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Investigational

Tenofovir (microbicide)  Audio icon

Other Names: GS-1278, PMPA gel, TFV gel, tenofovir gel
Drug Class: Microbicides
Molecular Formula: C9 H14 N5 O4 P
Registry Number: 147127-20-6 (CAS)
Chemical Name: [(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methylphosphonic acid
Chemical Class: Purine Nucleotides
Company: Gilead Sciences, Inc.
Phase of Development: Phase III (Tenofovir vaginal gel is in Phase III testing. Other tenofovir-based microbicide products are in Phase I and II studies.)
Chemical Image:
Click image to enlarge
tenofovir
tenofovir
Molecular Weight: 287.2146
(Compound details obtained from ChemIDplus Advanced,1 NIAID Therapeutics Database,2 and AIDS Vaccine Advocacy Coalition [AVAC] publication3)
Patent Version Content

Pharmacology


Mechanism of Action: Microbicide; nucleoside reverse transcriptase inhibitor. HIV-specific topical microbicides formulated with antiretroviral (ARV) drugs, such as tenofovir, are being developed as a pre-exposure prophylaxis (PrEP) strategy to prevent the sexual transmission of HIV. ARV-based topical microbicides are designed to inhibit the infection process at the vaginal or rectal mucosa and directly interfere with the HIV replication cycle.4-7

Tenofovir, an adenosine nucleoside monophosphate (nucleotide) analog, is intracellularly phosphorylated to the active metabolite tenofovir diphosphate (TFV-DP). TFV-DP competitively inhibits the activity of HIV reverse transcriptase and causes DNA chain termination.6,8

A pharmacokinetic study compared daily dosing of tenofovir vaginal gel with daily dosing of tenofovir disoproxil fumarate (TDF) oral tablets. When compared to the oral daily dosing regimen, daily dosing of the vaginal gel resulted in vaginal tissue TFV-DP concentrations that were more than 100-fold higher and systemic tenofovir exposures that were 56-fold lower.9

In a study of rectally applied tenofovir gel versus oral TDF, tenofovir plasma concentrations were 24- to 33-fold lower after a single application of the gel than after a single oral dose. Rectal tissue concentrations of both tenofovir and TFV-DP were 2-4 log10 higher after single rectal dosing than after single oral dosing.10

Half-life (T½): Following a single oral dose, the plasma elimination half-life of tenofovir is approximately 17 hours, while the intracellular half-life is greater than 60 hours.6 In a study that compared rectally applied tenofovir gel to oral TDF, the tenofovir plasma half-life was noted to be at least 5 hours shorter with single and multiple rectal dosing than with single oral dosing.10

Metabolism/Elimination: Tenofovir is not a substrate of cytochrome P450 enzymes. Following intravenous (IV) administration of tenofovir, approximately 70 to 80% of the dose is recovered in the urine as unchanged drug. Tenofovir is eliminated renally.6

Resistance: In a Phase IIb study (CAPRISA 004) of tenofovir 1% vaginal gel, no tenofovir-related resistance mutations, thymidine analog mutations (TAMs), or mutations conferring multi-NRTI resistance were detected among HIV seroconverters. (HIV seroconverters were exposed to tenofovir gel for approximately 3 to 4 weeks after infection, and resistance testing was performed approximately 20 weeks after the date of infection.)11

In the VOICE trial, which assessed the effectiveness of a topical HIV prevention method (tenofovir 1% vaginal gel) and two different oral HIV prevention methods (TDF and emtricitabine/TDF), one participant in the emtricitabine/TDF group who underwent HIV-1 seroconversion 11 months after enrollment developed the M184V HIV resistance mutation.12

In the context of suboptimal use of microbicides, an in vitro study examined the effects of suboptimal concentrations of tenofovir, dapivirine, and dapivirine in combination with tenofovir on the development of drug-resistant HIV over 25 weeks. Results indicated that suboptimal doses of dapivirine alone permitted the emergence of more reverse transcriptase mutations than did the suboptimal doses of dapivirine in combination with tenofovir or the suboptimal doses of tenofovir alone. Suboptimal concentrations of tenofovir alone resulted in the development of one NRTI mutation, K65R.13


Dosing in Clinical Trials


Reduced Glycerin Tenofovir 1% Gel (Intrarectal):

Study Identifiers: MTN-007; NCT0123280314
Phase: I
Study Purpose: Study to assess the safety and acceptability of reduced glycerin tenofovir 1% gel applied rectally
Study Population: HIV-uninfected, healthy men and women
Dosing: Participants were randomized to one of the following four study groups:

  • Reduced glycerin tenofovir 1% gel
  • Hydroxyethyl cellulose placebo gel
  • 2% nonoxynol-9 gel
  • No treatment

Each gel was rectally applied, initially as a single dose administered by the clinic staff, and then followed by 7 daily self-administered doses.14,15
(See references cited above for information on study results.)

Study Identifiers: MTN-017; NCT0168721816
Phase: II
Study Purpose: Study to evaluate the safety and acceptability of oral emtricitabine/TDF (Truvada) and reduced glycerin tenofovir 1% gel applied rectally
Study Population: HIV-uninfected men and transgender women
Dosing: Participants are randomized to one of six groups. The order in which participants receive each study product differs by group. All participants receive the following study products for 8 weeks each, with a 1-week washout between products:

  • Reduced glycerin tenofovir 1% gel applied rectally and daily
  • Reduced glycerin tenofovir 1% gel applied rectally, used within 12 hours prior to receptive anal intercourse (RAI) and as soon as possible within 12 hours after RAI, and no more than two doses used in a 24-hour period (dosing strategy also known as BAT24)
  • Truvada (200 mg emtricitabine/300 mg TDF) taken orally and once daily.16-18

 

Tenofovir 1% Gel (Intravaginal):

Study Identifiers: CAPRISA 004; NCT0044129819
Phase: IIb
Study Purpose: Study to assess the safety and effectiveness of tenofovir 1% vaginal gel for preventing HIV infection in women
Study Population: HIV-uninfected women in South Africa
Dosing: Tenofovir 1% gel (vaginal formulation) used within 12 hours prior to intercourse and as soon as possible within 12 hours after intercourse, and no more than two doses used in a 24-hour period (dosing strategy also known as BAT24); or placebo used in the same manner.11,19,20
(See references cited above for information on study results.)

Study Identifiers: MTN-003; VOICE trial; NCT0070567921
Phase: IIb
Study Purpose: Study to assess the safety and effectiveness of oral TDF (Viread), oral emtricitabine/TDF (Truvada), and tenofovir 1% vaginal gel for the prevention of HIV infection in women
Study Population: HIV-uninfected women in South Africa, Uganda, and Zimbabwe
Dosing: Participants were randomized to one of the following five groups:

  • TDF 300 mg plus Truvada placebo, both taken orally and once daily
  • Truvada (200 mg emtricitabine/300 mg TDF) plus TDF placebo, both taken orally and once daily
  • TDF placebo plus Truvada placebo, both taken orally and once daily
  • Tenofovir 1% gel (vaginal formulation) applied once daily
  • Vaginal placebo gel applied once daily12,21-23

(See references cited above for information on study results.)

Study Identifiers: FACTS 001; NCT0138629424
Phase: III
Study Purpose: Study to assess the safety and effectiveness of tenofovir 1% vaginal gel for preventing HIV infection and HSV-2 infection in women
Study Population: HIV-uninfected women in South Africa
Dosing: Tenofovir 1% gel (vaginal formulation) used within 12 hours prior to intercourse and as soon as possible within 12 hours after intercourse, and no more than two doses used in a 24-hour period (dosing strategy also known as BAT24); or placebo used in the same manner.24-26
(See references cited above for information on study results.)

Additional clinical trials of tenofovir 1% gel are ongoing or are planned. Other forms of tenofovir-based microbicides are also being studied, including vaginal tablets, vaginal films, and intravaginal rings.27-30

 


Adverse Events


In the MTN-007 study of rectally applied reduced glycerin tenofovir 1% gel over 7 days in men and women, adverse events were generally mild or moderate. The most common adverse events were gastrointestinal symptoms, including abdominal pain, rectal urgency, diarrhea, and flatulence. Tenofovir gel use was not associated with mucosal damage. Changes in mucosal gene expression occurred in the tenofovir gel arm of the study; however, the significance of these changes is unclear and will require further evaluation.15

In the CAPRISA 004 study, tenofovir 1% vaginal gel that was used over a 30-month period by women demonstrated no evidence of increased renal, hepatic, pregnancy-related, or genital adverse events when compared with placebo. Mild and self-limiting diarrhea was reported more frequently in the tenofovir gel group than in the placebo group.11

In the VOICE trial, elevations in serum creatinine levels (all mild, except one) occurred more frequently among participants in the oral Truvada group than among participants in the oral placebo group. No other significant differences in safety concerns were noted in the study.12 


Drug Interactions


Drug interactions related to topical tenofovir gel are currently unknown. An in vivo drug interaction study of tenofovir 1% vaginal gel and three commonly used vaginal products is ongoing.31


References


  1. United States National Library of Medicine. ChemIDplus Advanced. Available at: http://chem.sis.nlm.nih.gov/chemidplus/rn/147127-20-6. Last accessed on March 10, 2015.
  2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. Available at: http://chemdb.niaid.nih.gov/DrugDevelopmentHIV.aspx. Last accessed on March 10, 2015.
  3. AIDS Vaccine Advocacy Coalition (AVAC). Microbicides by the Numbers: Science, products, money and more. Available at: http://www.avac.org/sites/default/files/resource-files/Microbicides_by_the_Numbers_Oct%202014.pdf. Last accessed on March 10, 2015.
  4. Shattock RJ, Rosenberg Z. Microbicides: Topical Prevention against HIV. Cold Spring Harb Perspect Med. 2012 Feb;2(2):a007385. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3281595/. Last accessed on March 10, 2015.
  5. National Institute of Allergy and Infectious Diseases (NIAID). Topical Microbicides. Available at: http://www.niaid.nih.gov/topics/hivaids/research/prevention/pages/topicalmicrobicides.aspx. Last accessed on March 10, 2015.
  6. Gengiah TN, Baxter C, Mansoor LE, Kharsany AB, Abdool Karim SS. A drug evaluation of 1% tenofovir gel and tenofovir disoproxil fumarate tablets for the prevention of HIV infection. Expert Opin Investig Drugs. 2012 May;21(5):695-715. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3460694/. Last accessed on March 15, 2015.
  7. Balzarini J, Van Damme L. Intravaginal and intrarectal microbicides to prevent HIV infection. CMAJ. 2005 Feb 15;172(4):461-4. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC548403/. Last accessed on March 10, 2015.
  8. Verma NA, Lee AC, Herold BC, Keller MJ. Topical Prophylaxis for HIV Prevention in Women: Becoming a Reality. Curr HIV/AIDS Rep. 2011 Jun;8(2):104-13. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3110084/. Last accessed on March 10, 2015.
  9. Hendrix CW, Chen BA, Guddera V, et al. MTN-001: Randomized Pharmacokinetic Cross-Over Study Comparing Tenofovir Vaginal Gel and Oral Tablets in Vaginal Tissue and Other Compartments. PLoS One. 2013;8(1):e55013. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3559346/. Last accessed on March 10, 2015.
  10. Yang KH, Hendrix C, Bumpus N, et al. A Multi-Compartment Single and Multiple Dose Pharmacokinetic Comparison of Rectally Applied Tenofovir 1% Gel and Oral Tenofovir Disoproxil Fumarate. PLoS One. 2014 Oct 28;9(10):e106196. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4211672/. Last accessed on March 10, 2015.
  11. Abdool Karim Q, Abdool Karim SS, Frohlich JA, et al. Effectiveness and Safety of Tenofovir Gel, an Antiretroviral Microbicide, for the Prevention of HIV Infection in Women. Science. 2010 Sep 3;329(5996):1168-74. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3001187/. Last accessed on March 10, 2015.
  12. Marrazzo JM, Ramjee G, Richardson BA, et al. Tenofovir-Based Preexposure Prophylaxis for HIV Infection among African Women. N Engl J Med. 2015 Feb 5;372(6):509-18. Available at: http://www.nejm.org/doi/pdf/10.1056/NEJMoa1402269. Last accessed on March 10, 2015.
  13. Schader SM, Oliveira M, Ibanescu RI, Moisi D, Colby-Germinario SP, Wainberg MA. In Vitro Resistance Profile of the Candidate HIV-1 Microbicide Drug Dapivirine. Antimicrob Agents Chemother. 2012 Feb;56(2):751-6. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3264246/. Last accessed on March 10, 2015.
  14. CONRAD. A Phase 1 Randomized, Double-Blinded, Placebo-Controlled Rectal Safety and Acceptability Study of Tenofovir 1% Gel. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on November 1, 2010. NLM Identifier: NCT01232803. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01232803. Last accessed on March 10, 2015.
  15. McGowan I, Hoesley C, Cranston RD, et al. A Phase 1 Randomized, Double Blind, Placebo Controlled Rectal Safety and Acceptability Study of Tenofovir 1% Gel (MTN-007). PLoS One. 2013;8(4):e60147. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3616022/. Last accessed on March 10, 2015.
  16. CONRAD. A Phase 2 Randomized Sequence Open Label Expanded Safety and Acceptability Study of Oral Emtricitabine/Tenofovir Disoproxil Fumarate Tablet and Rectally-Applied Tenofovir Reduced-Glycerin 1% Gel. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on August 27, 2012. NLM Identifier: NCT01687218. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01687218. Last accessed on March 10, 2015.
  17. Microbicide Trials Network (MTN): News Room. Backgrounder: MTN-017: Phase II Safety and Acceptability Study of Tenofovir Gel Reformulated for Rectal Use. Available at: http://www.mtnstopshiv.org/news/studies/mtn017/backgrounder. Last accessed on March 10, 2015.
  18. Microbicide Trials Network (MTN). MTN-017 Study Protocol: A Phase 2 Randomized Sequence Open Label Expanded Safety and Acceptability Study of Oral Emtricitabine/Tenofovir Disoproxil Fumarate Tablet and Rectally-Applied Tenofovir Reduced-Glycerin 1% Gel. Available at: http://www.mtnstopshiv.org/sites/default/files/attachments/MTN-017%20Protocol%20V%201.0%20%2017July2012_FINAL.pdf. Last accessed on March 10, 2015.
  19. Centre for the AIDS Programme of Research in South Africa. Phase IIb Trial to Assess the Safety and Effectiveness of the Vaginal Microbicide 1% Tenofovir Gel for the Prevention of HIV Infection in Women in South Africa. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on February 27, 2007. NLM Identifier: NCT00441298. Available at: https://www.clinicaltrials.gov/ct2/show/NCT00441298. Last accessed on March 10, 2015.
  20. Abdool Karim Q and Abdool Karim SS. CAPRISA 004: Effectiveness & safety of vaginal microbicide 1% tenofovir gel for prevention of HIV infection in women. 18th International AIDS Conference; July 18-23, 2010; Vienna, Austria. Sourced from: Contraceptive Research and Development (CONRAD): News & Press Releases, dated July 18, 2010. CAPRISA 004 Trial Results Presentation From AIDS 2010 Conference. Available at: http://www.conrad.org/media/news/92_CAPRISA%20004%20Results.pdf. Last accessed on March 10, 2015.
  21. National Institute of Allergy and Infectious Diseases (NIAID). Phase 2B Safety and Effectiveness Study of Tenofovir 1% Gel, Tenofovir Disproxil Fumarate Tablet and Emtricitabine/Tenofovir Disoproxil Fumarate Tablet for the Prevention of HIV Infection in Women. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on June 24, 2008. NLM Identifier: NCT00705679. Available at: https://www.clinicaltrials.gov/ct2/show/NCT00705679. Last accessed on March 10, 2015.
  22. National Institute of Allergy and Infectious Diseases (NIAID): News Release, dated March 4, 2013. Daily-Use HIV Prevention Approaches Prove Ineffective Among Women in NIH Study. Available at: http://www.niaid.nih.gov/news/newsreleases/2013/Pages/VOICEwomen.aspx. Last accessed on March 10, 2015.
  23. Marrazzo J, Rabe L, Kelly C, et al. Association of Tenofovir (TFV) Detection with Reduced Risk of Herpes Simplex virus Type-2 (HSV-2) Acquisition in the VOICE (MTN 003) Study. Abstract presented at: HIV Research for Prevention 2014: AIDS Vaccine, Microbicide and ARV-based Prevention Science (HIVR4P); October 28-31, 2014; Cape Town, South Africa. Abstract OA10.06 LB. Available at: http://hivr4p.org/abstracts-and-conference-materials?download=191:complete-abstract-book. Last accessed on March 10, 2015.
  24. CONRAD. A Phase III, Multi-Centre, Randomized Controlled Trial to Assess the Safety and Effectiveness of the Vaginal Microbicide 1% Tenofovir Gel in the Prevention of Human Immunodeficiency Virus Type 1 Infection in Women, and to Examine Effects of the Microbicide on the Incidence of Herpes Simplex Virus Type 2 Infection. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on June 28, 2011. NLM Identifier: NCT01386294. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01386294. Last accessed on March 10, 2015.
  25. Contraceptive Research and Development (CONRAD): Press Release, dated February 24, 2015. FACTS 001 Results Presented at CROI 2015. Available at: http://www.conrad.org/news-pressreleases-107.html. Last accessed on March 10, 2015.
  26. Rees H, Delany-Moretlwe SA, Lombard C, et al. FACTS 001 Phase III Trial of Pericoital Tenofovir 1% Gel for HIV Prevention in Women. Abstract presented at: 22nd Conference on Retroviruses and Opportunistic Infections (CROI); February 23-26, 2015; Seattle, Washington. Abstract 26LB. Available at: http://www.croiconference.org/sites/default/files/uploads/croi2015-program-abstracts.pdf. Last accessed on March 10, 2015.
  27. CONRAD. A Phase I Clinical Trial Assessing the Safety, Pharmacokinetics, Pharmacodynamics, and Disintegration Time of Vaginal Tablets Containing Tenofovir and/or Emtricitabine. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on July 17, 2012. NLM Identifier: NCT01694407. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01694407. Last accessed on March 10, 2015.
  28. CONRAD. A Phase I Trial to Assess the Safety of Tenofovir Gel and Film Formulations: FAME 04. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on November 5, 2013. NLM Identifier: NCT01989663. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01989663. Last accessed on March 10, 2015.
  29. Albert Einstein College of Medicine of Yeshiva University. Phase 1 Safety and Pharmacokinetic Study of Polyurethane Tenofovir Disoproxil Fumarate Vaginal Ring. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on November 19, 2013. NLM Identifier: NCT02006264. Available at: https://www.clinicaltrials.gov/ct2/show/NCT02006264. Last accessed on March 10, 2015.
  30. CONRAD. Phase I One-Month Safety, Pharmacokinetic, Pharmacodynamic, and Acceptability Study of Intravaginal Rings Releasing Tenofovir and Levonorgestrel or Tenofovir Alone. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on July 14, 2014. NLM Identifier: NCT02235662. Available at: https://www.clinicaltrials.gov/ct2/show/NCT02235662. Last accessed on March 10, 2015.
  31. CONRAD. In Vivo Drug Interaction Pharmacokinetic Study of Tenofovir 1% Gel and Three Commonly Used Vaginal Products. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 11, 2013. NLM Identifier: NCT01813162. Available at: https://clinicaltrials.gov/show/NCT01813162. Last accessed on March 10, 2015.
 


Last Reviewed: March 10, 2015

Last Updated: March 10, 2015


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