Chemistry:Tenofovir disoproxil

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Short description: Antiviral drug used to treat or prevent HIV and hepatitis infections
Tenofovir disoproxil
Tenofovir disoproxil structure.svg
Clinical data
Pronunciation/ˌtəˈnoʊfəvɪər ˌdɪsəˈprɑːksəl/
Trade namesViread, others
Other namesBis(POC)PMPA
AHFS/Drugs.comMonograph
MedlinePlusa602018
License data
Pregnancy
category
  • AU: B3
Routes of
administration		By mouth (tablets)
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability25%
MetabolismEster hydrolysis
MetabolitesTenofovir
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
NIAID ChemDB
Chemical and physical data
FormulaC19H30N5O10P
Molar mass519.448 g·mol−1
3D model (JSmol)
Tenofovir
Mbg inc.Tenofovir.svg
Clinical data
Other names9-(2-Phosphonyl-methoxypropyly)adenine (PMPA)
MedlinePlusa602018
ATC code
  • None
Pharmacokinetic data
Protein binding< 1%
MetabolismPhosphorylation
MetabolitesTenofovir diphosphate (active metabolite)
Elimination half-life17 hours
ExcretionKidney
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC9H14N5O4P
Molar mass287.216 g·mol−1
3D model (JSmol)
  (verify)

Tenofovir disoproxil, sold under the trade name Viread among others, is a medication used to treat chronic hepatitis B and to prevent and treat HIV/AIDS.[1] It is generally recommended for use with other antiretrovirals.[1] It may be used for prevention of HIV/AIDS among those at high risk before exposure, and after a needlestick injury or other potential exposure.[1] It is sold both by itself and together in combinations such as emtricitabine/tenofovir, efavirenz/emtricitabine/tenofovir,[1] and elvitegravir/cobicistat/emtricitabine/tenofovir.[2] It does not cure HIV/AIDS or hepatitis B.[1][3] It is available by mouth as a tablet or powder.[1]

Common side effects include nausea, rash, diarrhea, headache, pain, depression, and weakness.[1] Severe side effects include high blood lactate and an enlarged liver.[1] There are no absolute contraindications.[1] It is often recommended during pregnancy and appears to be safe.[1] It is a nucleotide reverse transcriptase inhibitor and works by decreasing the ability of the viruses to replicate.[1]

Tenofovir was patented in 1996 and approved for use in the United States in 2001.[4] It is on the World Health Organization's List of Essential Medicines.[5] It is available in the United States as a generic medication as of 2017.[6]

Medical uses

Tenofovir disoproxil is used for HIV-1 infection and chronic hepatitis B treatment. For HIV-1 infection, tenofovir is indicated in combination with other antiretroviral agents for people 2 years of age and older. For chronic hepatitis B patients, tenofovir is indicated for patients 12 years of age and older.[7]

HIV risk reduction

Tenofovir can be used for HIV prevention in people who are at high risk for infection through sexual transmission or injecting drug use. A Cochrane review examined the use of tenofovir for prevention of HIV before exposure and found that both tenofovir alone and the tenofovir/emtricitabine combination decreased the risk of contracting HIV for high risk patients.[8] The U.S. Centers for Disease Control and Prevention (CDC) also 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 tenofovir as a prevention measure. The results 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.[9]

Adverse effects

Tenofovir disoproxil is generally well tolerated with low discontinuation rates among the HIV and chronic hepatitis B population.[10] There are no contraindications for use of this drug.[7] The most commonly reported side effects due to use of tenofovir disoproxil were dizziness, nausea, and diarrhea.[10] Other adverse effects include depression, sleep disturbances, headache, itching, rash, and fever. The US boxed warning cautions potential onset of lactic acidosis or liver damage due to use of tenofovir disoproxil.[11]

Long term use of tenofovir disoproxil is associated with nephrotoxicity and bone loss. Presentation of nephrotoxicity can appear as Fanconi syndrome, acute kidney injury, or decline of glomerular filtration rate (GFR).[12] Discontinuation of tenofovir disoproxil can potentially lead to reversal of renal impairment. Nephrotoxicity may be due to proximal tubules accumulation of Tenofovir disoproxil leading to elevated serum concentrations.[10]

Interactions

Tenofovir interacts with didanosine and HIV-1 protease inhibitors. Tenofovir increases didanosine concentrations and can result in adverse effects such as pancreatitis and neuropathy. Tenofovir also interacts with HIV-1 protease inhibitors such as atazanavir, by decreasing atazanavir concentrations while increasing tenofovir concentrations.[7] In addition, since tenofovir is excreted by the kidney, medications that impair renal function can also cause problems.[13]

Pharmacology

Mechanism of action

Tenofovir disoproxil is a nucleotide analog reverse-transcriptase inhibitor (NtRTI).[14] It selectively inhibits viral reverse transcriptase, a crucial enzyme in retroviruses such as human immunodeficiency virus (HIV), while showing limited inhibition of human enzymes, such as DNA polymerases α, β, and mitochondrial DNA polymerase γ.[7][14] In vivo tenofovir disoproxil fumarate is converted to tenofovir, an acyclic analog of deoxyadenosine 5'-monophosphate (dAMP). Tenofovir lacks a hydroxyl group in the position corresponding to the 3' carbon of the dAMP, preventing the formation of the 5′ to 3′ phosphodiester linkage essential for DNA chain elongation.[14] Once incorporated into a growing DNA strand, tenofovir causes premature termination of DNA transcription, preventing viral replication.[14]

Pharmacokinetics

Tenofovir disoproxil is a prodrug that is quickly absorbed from the gut and cleaved to release tenofovir.[7] Inside cells, tenofovir is phosphorylated to tenofovir diphosphate (which is analogous to a triphosphate, as tenofovir itself already has one phosphonate residue), the active compound that inhibits reverse transcriptase via chain termination.[13][14]

In fasting persons, bioavailability is 25%, and highest blood plasma concentrations are reached after one hour.[14] When taken with fatty food, highest plasma concentrations are reached after two hours, and the area under the curve is increased by 40%.[14] It is an inhibitor of cytochrome P450 1A2.[15]

Tenofovir is mainly excreted via the kidneys, both by glomerular filtration and by tubular secretion using the transport proteins OAT1, OAT3 and ABCC4.[13]

Detection in body fluids

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.[16][17][18]

Chemistry

Tenofovir is a derivative of adenine and this was the chemical starting point for its first published synthesis[19] which was included in patents to the compound.[20] During drug development, attention switched to the phosphonate ester derivative, tenofovir disoproxil, which was the subject of extensive process chemistry to provide a viable manufacturing route.

Tenofovir disoproxil synthesis.svg

Adenine is first reacted with a chiral version of propylene carbonate with R absolute configuration, using sodium hydroxide as base. Under these conditions, the reaction is regioselective, with alkylation occurring exclusively in the imidazole ring and at the less-hindered carbon of the dioxolane. In the second step, the hydroxyl group is reacted with a phosphonic acid derivative, using tert-butyllithium as base to ensure selective O-alkylation, with the formation of an ether bond. Tenofovir is formed when the diethyl phosphonate group is converted to its acid using trimethylsilyl chloride in the presence of sodium bromide, a further refinement of the original manufacturing route.[21][22][23] The synthesis of the alternative ester in tenofovir disoproxil is completed by alkylation with the appropriate chloromethyl ether derivative and this may be purified as its fumarate salt.[21]

History

Tenofovir was initially synthesized by Antonín Holý at the Institute of Organic Chemistry and Biochemistry of the Czechoslovak Academy of Sciences in Prague. The patent filed in 1986 makes no mention of the potential use of the compound for the treatment of HIV infection but claims activity against herpes simplex virus.[20]

In 1985, De Clercq and Holý described the activity of PMPA against HIV in cell culture.[24] 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.[25]

The initial form of tenofovir used in these studies had limited potential for widespread use because it poorly penetrated cells and was not absorbed when given by mouth. Gilead developed a pro-drug version of tenofovir, tenofovir disoproxil. 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 in the U.S. in 2001, for the treatment of HIV, and in 2008, for the treatment of chronic hepatitis B.[26][27]

Drug forms

Tenofovir disoproxil can be taken by mouth and is sold under the brand name Viread, among others.[28] Tenofovir disoproxil is a pro-drug form of tenofovir phosphonate, which is liberated intracellularly and converted to tenofovir disphophate.[29] It is marketed by Gilead Sciences (as the fumarate, abbreviated TDF).[30]

Tenofovir disoproxil is also available in pills which combine a number of antiviral drugs into a single dose. Well-known combinations include Atripla (tenofovir disoproxil/emtricitabine/efavirenz), Complera (tenofovir disoproxil/emtricitabine/rilpivirine), Stribild (tenofovir disoproxil/emtricitabine/elvitegravir/cobicistat), and Truvada (tenofovir disoproxil/emtricitabine).[28]

Gilead has created a second pro-drug form of the active drug, tenofovir diphosphate, called tenofovir alafenamide. It differs from tenofovir disoproxil due to its activation in the lymphoid cells. This allows the active metabolites to accumulate in those cells, leading to lower systemic exposure and potential toxicities.[10]

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 "Tenofovir Disoproxil Fumarate". The American Society of Health-System Pharmacists. https://www.drugs.com/monograph/tenofovir-disoproxil-fumarate.html. 
  2. ↑ "Stribild". PubChem. U.S. National Library of Medicine. https://pubchem.ncbi.nlm.nih.gov/compound/Stribild. 
  3. ↑ "A Treatment Algorithm for the Management of Chronic Hepatitis B Virus Infection in the United States: 2015 Update". Clinical Gastroenterology and Hepatology 13 (12): 2071–87.e16. November 2015. doi:10.1016/j.cgh.2015.07.007. PMID 26188135. 
  4. ↑ (in en) Analogue-based Drug Discovery. John Wiley & Sons. 2006. p. 505. ISBN 9783527607495. https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA505. 
  5. ↑ World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. 2019. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO. 
  6. ↑ "Teva Announces Exclusive Launch of a Generic version of Viread in the United States". https://www.tevapharm.com/news/teva_announces_exclusive_launch_of_generic_viread_in_the_united_states_12_17.aspx. 
  7. ↑ 7.0 7.1 7.2 7.3 7.4 "Tenofovirdisoproxil Prescribing Information.". Gilead Sciences, Inc.. November 2012. http://www.gilead.com/pdf/viread_pi.pdf. 
  8. ↑ "Antiretroviral pre-exposure prophylaxis (PrEP) for preventing HIV in high-risk individuals". The Cochrane Database of Systematic Reviews 7 (7): CD007189. July 2012. doi:10.1002/14651858.CD007189.pub3. PMID 22786505. 
  9. ↑ "Preventive drug could reduce HIV transmission among injecting drug users". The Conversation Australia. The Conversation Media Group. 14 June 2013. https://theconversation.com/preventive-drug-could-reduce-hiv-transmission-among-injecting-drug-users-15166. 
  10. ↑ 10.0 10.1 10.2 10.3 "Tenofovir: What We Have Learnt After 7.5 Million Person-Years of Use". Infectious Diseases and Therapy 4 (2): 145–57. June 2015. doi:10.1007/s40121-015-0070-1. PMID 26032649. 
  11. ↑ "Tenofovir: MedlinePlus Drug Information". MedlineP. U.S. National Library of Medicine. https://medlineplus.gov/druginfo/meds/a602018.html. 
  12. ↑ "Role of traditional risk factors and antiretroviral drugs in the incidence of chronic kidney disease, ANRS CO3 Aquitaine cohort, France, 2004-2012". PLOS ONE 8 (6): e66223. 2013-06-12. doi:10.1371/journal.pone.0066223. PMID 23776637. Bibcode: 2013PLoSO...866223M. 
  13. ↑ 13.0 13.1 13.2 Haberfeld, H, ed (2015) (in German). Austria-Codex. Vienna: Österreichischer Apothekerverlag. 
  14. ↑ 14.0 14.1 14.2 14.3 14.4 14.5 14.6 "Tenofovir". DrugBank. http://www.drugbank.ca/drugs/DB00300. 
  15. ↑ "Tenofovir disoproxil" (in en). Pubchem. U.S. National Library of Medicine. https://pubchem.ncbi.nlm.nih.gov/compound/5481350#section=DrugBank-Interactions&fullscreen=true. 
  16. ↑ "The simultaneous assay of tenofovir and emtricitabine in plasma using LC/MS/MS and isotopically labeled internal standards". Journal of Chromatography B 877 (20–21): 1907–14. July 2009. doi:10.1016/j.jchromb.2009.05.029. PMID 19493710. 
  17. ↑ "Pharmacokinetics and dosing recommendations of tenofovir disoproxil fumarate in hepatic or renal impairment". Clinical Pharmacokinetics 45 (11): 1115–24. 2006. doi:10.2165/00003088-200645110-00005. PMID 17048975. 
  18. ↑ Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Foster City, California: Biomedical Publications. 2008. pp. 1490–1492. 
  19. ↑ "Preparation of 5'-O-phosphonylmethyl analogues of nucleoside-5'-phosphates, 5'-diphosphates and 5'-triphosphates". Collection of Czechoslovak Chemical Communications 47 (12): 3447–3463. 1982. doi:10.1135/cccc19823447. 
  20. ↑ 20.0 20.1 Holy A, Rosenberg I, "9-(phosponylmethoxyalkyl) adenines, the method of preparation and utilization thereof", US patent 4808716, published 1989-02-28, assigned to Czech Academy of Sciences
  21. ↑ 21.0 21.1 "Process Improvements for the Manufacture of Tenofovir Disoproxil Fumarate at Commercial Scale". Organic Process Research & Development 14 (5): 1194–1201. 2010. doi:10.1021/op1001337. 
  22. ↑ "Rapid, mild method for phosphonate diester hydrolysis: Development of a one-pot synthesis of tenofovir disoproxil fumarate from tenofovir diethyl ester". Tetrahedron 66 (41): 8137–8144. 2010. doi:10.1016/j.tet.2010.08.037. 
  23. ↑ "34: Antiviral Drugs". Synthesis of Best-Seller Drugs. 2016. pp. 714–716. doi:10.1016/B978-0-12-411492-0.00034-1. ISBN 9780124114920. 
  24. ↑ De Clercq E, Holy A, Rosenberg I, "Therapeutical application of phosphonylmethoxyalkyl adenines", US patent 4724233
  25. ↑ "Safety, pharmacokinetics, and antiretroviral activity of intravenous 9-[2-(R)-(Phosphonomethoxy)propyladenine, a novel anti-human immunodeficiency virus (HIV) therapy, in HIV-infected adults"]. Antimicrobial Agents and Chemotherapy 42 (9): 2380–4. September 1998. doi:10.1128/aac.42.9.2380. PMID 9736567. 
  26. ↑ "FDA letter of approval (regarding treatment of hepatitis B)". https://www.fda.gov/cder/foi/appletter/2008/021356s025ltr.pdf. 
  27. ↑ Shwiff, Kathy (11 August 2008). "FDA Clears Viread for Hepatitis B". The Wall Street Journal (Dow Jones & Company, Inc.). https://www.wsj.com/articles/SB121849463154631469?mod=us_business_whats_news. 
  28. ↑ 28.0 28.1 "Drugs@FDA: FDA Approved Drug Products". http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.SearchAction&SearchTerm=tenofovir&SearchType=BasicSearch. 
  29. ↑ "Key toxicity issues with the WHO-recommended first-line antiretroviral therapy regimen". Expert Review of Clinical Pharmacology 9 (11): 1493–1503. November 2016. doi:10.1080/17512433.2016.1221760. PMID 27498720. 
  30. ↑ "Post-exposure prophylaxis for SIV revisited: animal model for HIV prevention". AIDS Research and Therapy 3: 29. November 2006. doi:10.1186/1742-6405-3-29. PMID 17132170. 

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