Tenofovir
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Tenofovir (top) and tenofovir disoproxil fumarate (bottom)
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| Systematic (IUPAC) name |
| ({[(2R)-1-(6-amino-9H-purin-9-yl)propan-2-yl]oxy}methyl)phosphonic acid |
| Clinical data |
| Trade names |
Viread |
| AHFS/Drugs.com |
monograph |
| MedlinePlus |
a602018 |
| Pregnancy cat. |
B3 (AU) B (US) |
| Legal status |
Prescription Only (S4) (AU) ℞-only (CA) POM (UK) ℞-only (US) |
| Routes |
Oral |
| Pharmacokinetic data |
| Bioavailability |
25% |
| Protein binding |
< 1% |
| Half-life |
17 hours |
| Excretion |
Renal |
| Identifiers |
| CAS number |
147127-20-6 Y |
| ATC code |
J05AF07 |
| PubChem |
CID 464205 |
| DrugBank |
DB00300 |
| ChemSpider |
408154 Y |
| UNII |
99YXE507IL Y |
| KEGG |
D01982 Y |
| ChEMBL |
CHEMBL483 Y |
| NIAID ChemDB |
080741 |
| Chemical data |
| Formula |
C9H14N5O4P |
| Mol. mass |
287.213 g/mol |
SMILES
- O=P(O)(O)CO[C@H](C)Cn1c2ncnc(c2nc1)N
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InChI
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InChI=1S/C9H14N5O4P/c1-6(18-5-19(15,16)17)2-14-4-13-7-8(10)11-3-12-9(7)14/h3-4,6H,2,5H2,1H3,(H2,10,11,12)(H2,15,16,17)/t6-/m1/s1 Y
Key:SGOIRFVFHAKUTI-ZCFIWIBFSA-N Y
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| Y (what is this?) (verify) |
Tenofovir disoproxil fumarate (TDF or PMPA[1]), marketed by Gilead Sciences under the trade name Viread, belongs to a class of antiretroviral drugs known as nucleotide analogue reverse transcriptase inhibitors (NRTIs), which block reverse transcriptase, a crucial virus enzyme in human immunodeficiency virus 1 (HIV-1) and hepatitis B virus infections.[2]
It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.[3]
Contents
- 1 Medical uses
- 2 Adverse effects
- 3 History
- 4 Drug forms
- 5 Increased yield
- 6 Therapeutic drug monitoring
- 7 References
- 8 External links
Medical uses
- HIV-1 infection: Tenofovir is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients 2 years of age and older.[2] This indication is based on analyses of plasma HIV-1 RNA levels and CD4 cell counts in controlled studies of tenofovir in treatment-naive and treatment-experienced adults.
- Tenofovir is indicated for the treatment of chronic hepatitis B in adults and pediatric patients 12 years of age and older.[2]
HIV risk reduction
A Cochrane review examined the use of tenofovir as a pre-exposure prophylaxis against HIV infection. It found that both tenofovir alone, as well as the tenofovir/emtricitabine combination, significantly decreased the risk of contracting HIV.[4]
The American Centers for Disease Control and Prevention (CDC) conducted a study in partnership with the Thailand Ministry of Public Health to ascertain the effectiveness of providing people who inject drugs illicitly with daily doses of the anti-retroviral drug Tenofovir as a prevention measure. The results of the study were released in mid-June 2013 and revealed a 48.9% reduced incidence of the virus among the group of subjects who received the drug, in comparison to the control group who received a placebo. The Principal Investigator of the study stated in the Lancet medical journal: “We now know that pre-exposure prophylaxis can be a potentially vital option for HIV prevention in people at very high risk for infection, whether through sexual transmission or injecting drug use.”[5]
Adverse effects
The most common side effects associated with tenofovir include nausea, vomiting, diarrhea, and asthenia. Less frequent side effects include hepatotoxicity, abdominal pain, and flatulence.[6] Tenofovir has also been implicated in causing renal toxicity, particularly at elevated concentrations.[7]
Tenofovir can cause acute renal failure, Fanconi syndrome, proteinuria or tubular necrosis. These side effects are due to accumulation of the drug in proximal tubules. Tenofovir can interact with didanosine by increasing didanosine's concentration. It also decreases the concentration of atazanavir sulfate.
History
Tenofovir was initially synthesized by Antonín Holý at the Institute of Organic Chemistry and Biochemistry (IOCB), Academy of Sciences of the Czech Republic (AS CR) in Prague. The patent[8] filed by Holý in 1985, makes no mention of the potential use of the compound for the treatment of HIV infection, which had only been discovered 2 years earlier. The only antiviral application of tenofovir described in the patent is its potential for use in the treatment of herpes simplex infections.
In 1993 Erik De Clercq and other researchers at the Rega Institute for Medical Research described the activity of tenofovir against HIV in cell culture. Shortly thereafter, a collaboration was initiated with the biotechnology company Gilead Sciences to investigate tenofovir's potential as a treatment for HIV infected patients. In 1997 researchers from Gilead and the University of California, San Francisco demonstrated that tenofovir exhibits anti-HIV effects in humans when dosed by subcutaneous injection.[9]
The initial form of tenofovir used in these studies had limited potential for widespread use because it was not absorbed when administered orally. A medicinal chemistry team at Gilead developed a modified version of tenofovir, tenofovir disoproxil fumarate.[10] This version of tenofovir, which is the only version used clinically today, is often referred to simply as "tenofovir". In this version of the drug, the two negative charges of the tenofovir phosphonic acid group are masked, thus enhancing oral absorption.
Tenofovir disoproxil fumarate was approved by the U.S. Food and Drug Administration (FDA) on October 26, 2001 for the treatment of HIV, and on August 11, 2008 for the treatment of chronic hepatitis B.[11][12]
Drug forms
Tenofovir disoproxil fumarate is a prodrug form of tenofovir. It is also marketed under the brand name Reviro by DRL. Tenofovir is also available in a fixed-dose combination with emtricitabine in a product with the brand name Truvada for once-a-day dosing. Atripla, a fixed-dose triple combination of tenofovir, emtricitabine and efavirenz, was approved by the FDA on 12 July 2006 and is now available, providing a single daily dose for the treatment of HIV.
Increased yield
A difficult step in the manufacture of tenofovir is near the end, when the mixture is "like oatmeal, making it very difficult to stir," said Joseph Fortunak, who left Abbott Laboratories to teach at Howard. That slows the next reaction, a problem because the intermediary is highly unstable and decomposes, thus lowering the yield.
A catalyst, TBAB (tetrabutylammonium bromide) sped up the reaction and thinned the oatmeal-like mixture into something "like milk," Williams said. But unexpectedly, it made the product more stable, which substantially increased the yield. This lowered the cost by about 20%.[13]
Therapeutic drug monitoring
Tenofovir may be measured in plasma by liquid chromatography. Such testing is useful for monitoring therapy and to prevent drug accumulation and toxicity in patients with renal or hepatic impairment.[14][15][16]
References
- ^ Emau P, Jiang Y, Agy MB et al. (2006). "Post-exposure prophylaxis for SIV revisited: Animal model for HIV infection". AIDS Res Ther 3: 29. doi:10.1186/1742-6405-3-29. PMC 1687192. PMID 17132170.
- ^ a b c Gilead Sciences, Inc. Prescribing Information. Revised: November 2012.
- ^ "WHO Model List of EssentialMedicines". World Health Organization. October 2013. Retrieved 22 April 2014.
- ^ Okwundu CI, Uthman OA, Okoromah CAN (2012). "Antiretroviral pre-exposure prophylaxis (PrEP) for preventing HIV in high-risk individuals". Cochrane Database Syst Rev (7): CD007189. doi:10.1002/14651858.CD007189.pub3. PMID 22786505.
- ^ Emma Bourke (14 June 2013). "Preventive drug could reduce HIV transmission among injecting drug users". The Conversation Australia. The Conversation Media Group. Retrieved 17 June 2013.
- ^ USPDI. Thompson. 2005. pp. 2741–2.
- ^ "Viread Prescribing Guidelines" (PDF). U.S. Food and Drug Administration. March 2006. Archived from the original on 2007-09-30. Retrieved 2007-02-12.
- ^ "Patent US4808716 - 9-(phosponylmethoxyalkyl) adenines, the method of preparation and ... - Google Patents".
- ^ Deeks SG, Barditch-Crovo P, Lietman PS, et al. (September 1998). "Safety, pharmacokinetics, and antiretroviral activity of intravenous 9-[2-(R)-(Phosphonomethoxy)propyl]adenine, a novel anti-human immunodeficiency virus (HIV) therapy, in HIV-infected adults". Antimicrob. Agents Chemother. 42 (9): 2380–4. PMC 105837. PMID 9736567.
- ^ "Patent US5977089 - Antiviral phosphonomethoxy nucleotide analogs having increased oral ... - Google Patents".
- ^ FDA letter of approval (regarding treatment of hepatitis B)
- ^ FDA Clears Viread for Hepatitis B
- ^ SCHOOFS, MARK (May 13, 2011). "Researchers Manipulate Drug's Chemistry in Bid to Lower Treatment Cost". Wall Street Journal.
- ^ Delahunty T, Bushman L, Robbins B, Fletcher CV (2009). "The simultaneous assay of tenofovir and emtricitabine in plasma using LC/MS/MS and isotopically labeled internal standards". J. Chrom. B 877 (20–21): 1907–1914. doi:10.1016/j.jchromb.2009.05.029.
- ^ Kearney BP, Yale K, Shah J, Zhong L, Flaherty JF (2006). "Pharmacokinetics and dosing recommendations of tenofovir disoproxil fumarate in hepatic or renal impairment". Clin. Pharmacokinet. 45 (11): 1115–24. doi:10.2165/00003088-200645110-00005. PMID 17048975.
- ^ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, California, 2008, pp. 1490–1492.
External links
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Microbicides for sexually transmitted diseases
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| types |
- Rectal microbicide
- Vaginal microbicide
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| products |
- Nonoxynol-9
- Tenofovir
- PRO 2000
- BufferGel
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| Organizations |
- International Rectal Microbicide Advocates
- International Partnership for Microbicides
- Global Campaign for Microbicides
- Microbicides Development Programme
- Microbicide Trials Network
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| Clinical trials |
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Antiviral drugs: antiretroviral drugs used against HIV (primarily J05)
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Entry/fusion inhibitors
(Discovery and development) |
- gp41 (Enfuvirtide)
- CCR5 (Maraviroc
- Vicriviroc†, Cenicriviroc†, PRO 140†)
- CD4 (Ibalizumab†)
- gp120 (BMS-663068§)
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Reverse-transcriptase
inhibitors (RTIs) |
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Nucleoside and
nucleotide (NRTI)
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- Nucleoside analogues/NARTIs: Abacavir (ABC)°#
- Emtricitabine (FTC)°#
- Lamivudine (3TC)°#
- Didanosine (ddI)#
- Zidovudine (AZT)#
- Apricitabine†
- Stampidine†
- Elvucitabine†
- Racivir†
- Amdoxovir†
- Stavudine (d4T)#
- Zalcitabine (ddC)◊
- Festinavir†
- Nucleotide analogues/NtRTIs: Tenofovir disoproxil fumarate (TDF)°#
- Tenofovir alafenamide fumarate (TAF)†
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Non-nucleoside (NNRTI)
(Discovery and development)
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- (1st generation) Efavirenz (EFV)°#
- Nevirapine (NVP)#
- Loviride◊
- Delavirdine (DLV)◊
(2nd generation) diarylpyrimidines (Etravirine- Rilpivirine)
- Lersivirine†
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| Integrase inhibitors |
- Raltegravir°
- Elvitegravir
- Dolutegravir
- Globoidnan A (experimental)
- MK-2048†
- BI 224436†
- GSK744†
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| Maturation inhibitors |
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Protease Inhibitors (PI)
(Discovery and development) |
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1st generation
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- Fosamprenavir°
- Lopinavir°#
- Nelfinavir#
- Ritonavir#
- Saquinavir#
- Amprenavir◊
- Indinavir◊#
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2nd generation
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- Atazanavir°
- Darunavir°
- Tipranavir
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| Combined formulations |
- Lamivudine/zidovudine
- Emtricitabine/tenofovir/efavirenz
- Abacavir/lamivudine/zidovudine
- Tenofovir/emtricitabine
- Lopinavir/ritonavir
- Abacavir/lamivudine
- Emtricitabine/rilpivirine/tenofovir
- Elvitegravir/cobicistat/emtricitabine/tenofovir
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| Experimental agents |
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Uncoating inhibitors
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Transcription inhibitors
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Translation inhibitors
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Other
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- Abzyme
- Calanolide A
- Ceragenin
- Cyanovirin-N
- Diarylpyrimidines
- Epigallocatechin gallate (EGCG)
- Foscarnet
- Griffithsin
- Hydroxycarbamide
- Miltefosine
- Portmanteau inhibitors
- Seliciclib†
- Synergistic enhancers
- Tre recombinase
- Zinc finger protein transcription factor
- KP-1461†
- Cobicistat†
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Failed agents
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- Dexelvucitabine
- Capravirine
- Emivirine
- Lodenosine
- Atevirdine
- Brecanavir
- Aplaviroc
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- #WHO-EM
- ‡Withdrawn from market
- Clinical trials:
- †Phase III
- §Never to phase III
°DHHS preferred first-line agent. ◊Formerly or rarely used agent.
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cutn/syst (hppv/hiva, infl/zost/zoon)/epon
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drug (dnaa, rnaa, rtva, vacc)
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