Tenofovir disoproxil

From Wikipedia, the free encyclopedia
  (Redirected from Tenofovir)
Jump to: navigation, search
"Tenofovir" redirects here. For the other prodrug of tenofovir, see Tenofovir alafenamide.
Tenofovir disoproxil
Tenofovir disoproxil structure.svg
Systematic (IUPAC) name
Bis{[(isopropoxycarbonyl)oxy]methyl} ({[(2R)-1-(6-amino-9H-purin-9-yl)-2-propanyl]oxy}methyl)phosphonate
Clinical data
Trade names Viread
AHFS/Drugs.com Monograph
Pregnancy
category
  • AU: B3
  • US: B (No risk in non-human studies)
Routes of
administration
By mouth (tablets)
Legal status
Legal status
Pharmacokinetic data
Bioavailability 25%
Identifiers
CAS Number 201341-05-1
ATC code J05AF07 (WHO)
PubChem CID 5481350
ChemSpider 4587262
UNII F4YU4LON7I
ChEBI CHEBI:63717
NIAID ChemDB 080741
Chemical data
Formula C19H30N5O10P
Molar mass 519.443 g/mol
Tenofovir
Tenofovir structure.svg
Systematic (IUPAC) name
({[(2R)-1-(6-amino-9H-purin-9-yl)propan-2-yl]oxy}methyl)phosphonic acid
Clinical data
MedlinePlus a602018
Routes of
administration
Oral
Pharmacokinetic data
Protein binding < 1%
Biological half-life 17 hours
Excretion Kidney
Identifiers
CAS Number 147127-20-6 YesY
ATC code None
PubChem CID 464205
DrugBank DB00300 YesY
ChemSpider 408154 YesY
UNII 99YXE507IL YesY
KEGG D06074 YesY
ChEBI CHEBI:63625
ChEMBL CHEMBL483 YesY
Synonyms 9-(2-Phosphonyl-methoxypropyly)adenine (PMPA)
Chemical data
Formula C9H14N5O4P
Molar mass 287.213 g/mol
  (verify)

Tenofovir disoproxil is an antiretroviral medication used to prevent and treat HIV/AIDS and to treat chronic hepatitis B.[1] The active substance is tenofovir, while tenofovir disoproxil is a prodrug that is used because of its better absorption in the gut.

The drug is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.[2] It is marketed by Gilead Sciences under the trade name Viread (as the fumarate, TDF).[3] As of 2015 the cost for a typical month of medication in the United States is more than 200 USD.[4]

Medical uses[edit]

  • 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.[5] 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.[5][6]

HIV risk reduction[edit]

A Cochrane review examined the use of tenofovir for prevention of HIV before exposure. It found that both tenofovir alone and the tenofovir/emtricitabine combination decreased the risk of contracting HIV.[7]

The U. S. 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 antiretroviral 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: "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."[8]

Adverse effects[edit]

The most common side effects associated with tenofovir include nausea, vomiting, diarrhea, and asthenia. Less frequent side effects include hepatotoxicity, abdominal pain, and flatulence.[9] Tenofovir has also been implicated in causing kidney toxicity, particularly at elevated concentrations.[10]

In rare cases, tenofovir can cause acute kidney failure, Fanconi syndrome, proteinuria, or tubular necrosis.[11] These side effects are due to accumulation of the drug in proximal tubules.[citation needed] Tenofovir kidney toxicity from proximal tubular injury was observed, involving mitochondrial structural/histological abnormalities found in kidney biopsies.[12] After discontinuation of tenofovir, 3 of 3 patients with proteinuria completely recovered, 4 of 4 patients with acute kidney injury (but without dialysis) made substantial or complete recoveries, and 4 of 5 patients who required dialysis were able to discontinue dialysis within 4 months.

Interactions[edit]

Tenofovir increases didanosine plasma levels by 40 to 60%, which in some cases resulted in adverse effects related to didanosine such as lactic acidosis and pancreatitis; fatalities have been described. It also decreases concentrations of atazanavir by 25%, but without clinical consequences. As tenofovir is excreted via the kidney, drugs that impair renal function or are nephrotoxic can theoretically cause problems. No interactions related to the cytochrome P450 liver enzymes are expected.[11]

Pharmacology[edit]

Mechanism of action[edit]

Tenofovir is a defective adenosine nucleotide that selectively inhibits the action of reverse transcriptase, while only weakly interfering with mammalian DNA polymerases α, β, and mitochondrial DNA polymerase γ.[13] Tenofovir prevents the formation of the 5′ to 3′ phosphodiester linkage essential for DNA chain elongation. A phosphodiester bond cannot be formed because the tenofovir molecule lacks an –OH group on the 3′ carbon of its deoxyribose sugar.[13] Once incorporated into a growing DNA strand, tenofovir causes premature termination of DNA transcription. The drug is classified as a nucleotide analogue reverse transcriptase inhibitor (NtRTI).[13] Reverse transcriptase is a crucial viral enzyme in retroviruses such as human immunodeficiency virus (HIV) and in hepatitis B virus infections.[5]

Pharmacokinetics[edit]

Tenofovir disoproxil is quickly absorbed from the gut and cleaved to tenofovir, formaldehyde, and presumably isopropyl alcohol and carbon dioxide. In fasting persons, bioavailability is 25%, and highest blood plasma concentrations are reached after one hour. When taken with fatty food, highest plasma concentrations are reached after two hours, and the area under the curve is increased by 40%. In vitro, less than 0.7% of tenofovir is bound to plasma proteins and 7.2% to serum proteins. It does not relevantly interact with cytochrome P450 enzymes.[11]

Inside cells, tenofovir is phosphorylated to tenofovir diphosphate (which is actually a triphosphate, as tenofovir itself already has one phosphate residue), the active compound that is incorporated into viral DNA.[11]

The substance is mainly excreted via the kidneys, both by glomerular filtration and by tubular secretion using the transport proteins OAT1, OAT3 and ABCC4.[11]

History[edit]

Tenofovir was initially synthesized by Antonín Holý at the Institute of Organic Chemistry and Biochemistry of the Academy of Sciences of the Czech Republic in Prague. The patent[14] filed by Holý in 1984 makes no mention of the potential use of the compound for the treatment of HIV infection, which had only been discovered one year earlier.

In 1985, De Clercq and Holý described the activity of PMPA against HIV in cell culture.[15] Shortly thereafter, a collaboration with the biotechnology company Gilead Sciences led to the investigation of PMPA'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.[16]

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.[17] This version of tenofovir 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 was approved by the U.S. FDA on October 26, 2001, for the treatment of HIV, and on August 11, 2008, for the treatment of chronic hepatitis B.[18][19]

Drug forms[edit]

Tenofovir disoproxil is a prodrug form of tenofovir. It is also marketed under the brand name Reviro by Dr. Reddy's Laboratories. Tenofovir is also available in a fixed-dose combination with emtricitabine in a product with the brand name Truvada for once-a-day dosing. Efavirenz/emtricitabine/tenofovir disoproxil (brand name 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.

Physical and chemical properties[edit]

Tenofovir has a melting point of 279 °C (534 °F).[20] Tenofovir disoproxil fumarate is a white to off-white crystalline powder that is soluble in methanol, slightly soluble in water (13.4 mg/ml[21]), and very slightly soluble in dichloromethane.[22]

Detection in body fluids[edit]

Tenofovir may be measured in plasma by liquid chromatography. Such testing is useful for monitoring therapy and to prevent drug accumulation and toxicity in people with kidney or liver problems.[23][24][25]

References[edit]

  1. ^ "Viread". The American Society of Health-System Pharmacists. Retrieved 31 July 2015. 
  2. ^ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014. 
  3. ^ 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 1687192free to read. PMID 17132170. 
  4. ^ Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 66. ISBN 9781284057560. 
  5. ^ a b c Gilead Sciences, Inc. Prescribing Information. Revised: November 2012.
  6. ^ Guidelines for the prevention, care and treatment of persons with chronic hepatitis B infection, WHO, Publication details:Pages: 166 Publication date: March 2015 Languages: English ISBN 978 92 4 154905 9
  7. ^ Okwundu CI, Uthman OA, Okoromah CA (2012). "Antiretroviral pre-exposure prophylaxis (PrEP) for preventing HIV in high-risk individuals". Cochrane Database Syst Rev. 7 (7): CD007189. doi:10.1002/14651858.CD007189.pub3. PMID 22786505. 
  8. ^ 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. 
  9. ^ USPDI. Thompson. 2005. pp. 2741–2. 
  10. ^ "Viread Prescribing Guidelines" (PDF). U.S. Food and Drug Administration. March 2006. Archived from the original (PDF) on 2007-09-30. Retrieved 2007-02-12. 
  11. ^ a b c d e Haberfeld, H, ed. (2015). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag. 
  12. ^ Herlitz, Leal C.; Mohan, Sumit; Stokes, Michael B.; Radhakrishnan, Jai; D’Agati, Vivette D.; Markowitz, Glen S. (2010). "Tenofovir nephrotoxicity: acute tubular necrosis with distinctive clinical, pathological, and mitochondrial abnormalities". Kidney International. 78: 1171–1175. doi:10.1038/ki.2010.318. PMID 20811330. 
  13. ^ a b c Drugbank: Tenofovir
  14. ^ "Patent US4808716 - 9-(phosponylmethoxyalkyl) adenines, the method of preparation and ... - Google Patents". 
  15. ^ A US 4724233 A, De Clercq, Erik; Antonin Holy & Ivan Rosenberg, "Therapeutical application of phosphonylmethoxyalkyl adenines", published 1985-04-25 
  16. ^ 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 105837free to read. PMID 9736567. 
  17. ^ "Patent US5977089 - Antiviral phosphonomethoxy nucleotide analogs having increased oral ... - Google Patents". 
  18. ^ FDA letter of approval (regarding treatment of hepatitis B)
  19. ^ FDA Clears Viread for Hepatitis B
  20. ^ Dinnendahl, V; Fricke, U, eds. (2011). Arzneistoff-Profile (in German). 9 (25 ed.). Eschborn, Germany: Govi Pharmazeutischer Verlag. ISBN 978-3-7741-9846-3. 
  21. ^ "AIDSinfo Drug Database: Tenofovir disoproxil fumarate". National Institutes of Health. Retrieved 4 August 2016. 
  22. ^ "Tenofovir disoproxil fumarate" (PDF). World Health Organization. June 2010. 
  23. ^ 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. 
  24. ^ 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. 
  25. ^ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, California, 2008, pp. 1490–1492.

External links[edit]