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Investigational

Tenofovir (microbicide)  Audio icon

Other Names: GS-1278, PMPA gel, tenofovir gel, TFV 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
Phase of Development: Phase III
Chemical Image:
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tenofovir
tenofovir
Molecular Weight: 287.2146
(Compound details obtained from ChemIDplus Advanced1, NIAID Therapeutics Database2, and Cold Spring Harbor Perspectives in Medicine article3)
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.3,4,5,6

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.5,7

A pharmacokinetic study compared daily dosing of tenofovir vaginal gel with daily dosing of 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.8

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.5

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.5

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.)9

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.10


Dosing in Clinical Trials


Topical tenofovir 1% gel is applied vaginally or rectally (reduced glycerin formulation).

Reduced glycerin tenofovir 1% gel (intrarectal):

Phase I
MTN-007 (HIV-uninfected men and women):
Reduced glycerin tenofovir 1% gel used once daily; 2% nonoxynol-9 gel used once daily; placebo used once daily; or no treatment.11,12

Phase II
MTN-017 (HIV-uninfected men and transgender women):
Reduced glycerin tenofovir 1% gel used once daily; reduced glycerin tenofovir 1% gel used before and after anal intercourse; or oral emtricitabine/tenofovir DF used once daily.13,14

Tenofovir 1% gel (intravaginal):

Phase IIb
CAPRISA 004 (HIV-uninfected women):
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.9,15

MTN-003 (VOICE study) (HIV-uninfected women):
Oral tenofovir DF used once daily; oral emtricitabine/tenofovir DF used once daily; or oral placebo used once daily. Tenofovir 1% gel (vaginal formulation) used once daily or placebo gel used once daily.16,17

Phase III
FACTS 001 (HIV-uninfected women):
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.9,18

Additional clinical trials of tenofovir 1% gel are ongoing or are planned.


Adverse Events


In the Phase I 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.12

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.9


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 planned.19 


References


1. United States National Library of Medicine. ChemIDplus Advanced. Last accessed on January 5, 2014.

2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. Last accessed on January 5, 2014.

3. Shattock RJ, Rosenberg Z. Microbicides: Topical Prevention against HIV. Cold Spring Harb Perspect Med. 2012 Feb;2(2):a007385. Last accessed on January 5, 2014.

4. National Institute of Allergy and Infectious Diseases (NIAID). Topical Microbicides. Last accessed on January 5, 2014.

5. 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. Last accessed on January 5, 2014.

6. Balzarini J, Van Damme L. Intravaginal and intrarectal microbicides to prevent HIV infection. CMAJ. 2005 Feb 15;172(4):461-4. Last accessed on January 5, 2014.

7. 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. Last accessed on January 5, 2014.

8. 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. Last accessed on January 5, 2014.

9. 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. Last accessed on January 5, 2014.

10. 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. Last accessed on January 5, 2014.

11. 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. Last accessed on January 5, 2014.

12. McGowan I, Hoesley C, Cranston RD, et al. A Phase 1 Randomized, Double Blind, Placebo Controlled Rectal Safety and Acceptability Study of Tenofovir 1% Tel (MTN-007). PLoS One. 2013;8(4):e60147. Last accessed on January 5, 2014.

13. 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. Last accessed on January 5, 2014.

14. Microbicide Trials Network (MTN): News Room. Researchers Launch First-Ever Phase II Safety Study of a Rectal Microbicide to Prevent HIV. Last accessed on January 5, 2014.

15. 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. Last accessed on January 5, 2014.

16. 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. Last accessed on January 5, 2014.

17. National Institute of Allergy and Infectious Diseases (NIAID): News Releases. Daily-Use HIV Prevention Approaches Prove Ineffective Among Women in NIH Study. Last accessed on January 5, 2014.

18. 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. Last accessed on January 5, 2014.

19. 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. Last accessed on December 3, 2013.


Last Reviewed: January 5, 2014

Last Updated: January 5, 2014


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