Tenofovir disoproxil

Last updated

Tenofovir disoproxil
Tenofovir disoproxil structure.svg
Clinical data
Pronunciation /ˌtəˈnoʊfəvɪərˌdɪsəˈprɑːksəl/
Trade names Viread, others
Other namesBis(POC)PMPA
AHFS/Drugs.com Monograph
MedlinePlus a602018
License data
Pregnancy
category
  • AU:B3
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 25%
Metabolism Ester hydrolysis
Metabolites Tenofovir
Identifiers
  • Bis{[(isopropoxycarbonyl)oxy]methyl} ({[(2R)-1-(6-amino-9H-purin-9-yl)-2-propanyl]oxy}methyl)phosphonate
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
NIAID ChemDB
CompTox Dashboard (EPA)
ECHA InfoCard 100.129.993 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C19H30N5O10P
Molar mass 519.448 g·mol−1
3D model (JSmol)
  • C[C@H](Cn1cnc2c1ncnc2N)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C
  • InChI=1S/C19H30N5O10P/c1-12(2)33-18(25)28-9-31-35(27,32-10-29-19(26)34-13(3)4)11-30-14(5)6-24-8-23-15-16(20)21-7-22-17(15)24/h7-8,12-14H,6,9-11H2,1-5H3,(H2,20,21,22)/t14-/m1/s1
  • Key:JFVZFKDSXNQEJW-CQSZACIVSA-N
Tenofovir
Mbg inc.Tenofovir.svg
Clinical data
Other names9-(2-Phosphonyl-methoxypropyly)adenine (PMPA)
MedlinePlus a602018
ATC code
  • None
Legal status
Legal status
Pharmacokinetic data
Protein binding < 1%
Metabolism Phosphorylation
Metabolites Tenofovir diphosphate (active metabolite)
Elimination half-life 17 hours
Excretion Kidney
Identifiers
  • ({[(2R)-1-(6-amino-9H-purin-9-yl)propan-2-yl]oxy}methyl)phosphonic acid
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.129.993 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C9H14N5O4P
Molar mass 287.216 g·mol−1
3D model (JSmol)
  • O=P(O)(O)CO[C@H](C)Cn1c2ncnc(c2nc1)N
  • 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 Yes check.svgY
  • Key:SGOIRFVFHAKUTI-ZCFIWIBFSA-N Yes check.svgY
   (verify)

Tenofovir disoproxil, sold under the brand name Viread among others, is a medication used to treat chronic hepatitis B and to prevent and treat HIV/AIDS. [4] It is generally recommended for use with other antiretrovirals. [4] 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. [4] It is sold both by itself and together in combinations such as emtricitabine/tenofovir, efavirenz/emtricitabine/tenofovir, [4] and elvitegravir/cobicistat/emtricitabine/tenofovir. [5] It does not cure HIV/AIDS or hepatitis B. [4] [6] It is available by mouth as a tablet or powder. [4]

Contents

Common side effects include nausea, rash, diarrhea, headache, pain, depression, and weakness. [4] Severe side effects include high blood lactate and an enlarged liver. [4] There are no absolute contraindications. [4] It is often recommended during pregnancy and appears to be safe. [4] It is a nucleotide reverse transcriptase inhibitor and works by decreasing the ability of the viruses to replicate. [4]

Tenofovir was patented in 1996 and approved for use in the United States in 2001. [7] It is on the World Health Organization's List of Essential Medicines. [8] It is available in the United States as a generic medication as of 2017. [9]

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. [10]

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. [11] 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. [12]

Adverse effects

Tenofovir disoproxil is generally well tolerated with low discontinuation rates among the HIV and chronic hepatitis B population. [13] There are no contraindications for use of this drug. [10] The most commonly reported side effects due to use of tenofovir disoproxil were dizziness, nausea, and diarrhea. [13] 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. [14]

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). [15] 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. [13]

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. [10] In addition, since tenofovir is excreted by the kidney, medications that impair renal function can also cause problems. [16]

Pharmacology

Mechanism of action

Tenofovir disoproxil is a nucleotide analog reverse-transcriptase inhibitor (NtRTI). [17] 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. [10] [17] 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. [17] Once incorporated into a growing DNA strand, tenofovir causes premature termination of DNA transcription, preventing viral replication. [17]

Pharmacokinetics

Tenofovir disoproxil is a prodrug that is quickly absorbed from the gut and cleaved to release tenofovir. [10] 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. [16] [17]

In fasting persons, bioavailability is 25%, and highest blood plasma concentrations are reached after one hour. [17] When taken with fatty food, highest plasma concentrations are reached after two hours, and the area under the curve is increased by 40%. [17] It is an inhibitor of cytochrome P450 1A2. [18]

Tenofovir is mainly excreted via the kidneys, both by glomerular filtration and by tubular secretion using the transport proteins OAT1, OAT3 and ABCC4. [16]

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. [19] [20] [21]

Chemistry

Tenofovir is a derivative of adenine and this was the chemical starting point for its first published synthesis [22] which was included in patents to the compound. [23] 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. [24] [25] [26] 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. [24]

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. [23]

In 1985, De Clercq and Holý described the activity of PMPA against HIV in cell culture. [27] 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. [28]

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. [29] [30]

Drug forms

Tenofovir disoproxil can be taken by mouth and is sold under the brand name Viread, among others. [31] Tenofovir disoproxil is a pro-drug form of tenofovir phosphonate, which is liberated intracellularly and converted to tenofovir disphophate. [32] It is marketed by Gilead Sciences (as the fumarate, abbreviated TDF). [33]

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). [31]

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. [13]

Related Research Articles

Reverse-transcriptase inhibitors (RTIs) are a class of antiretroviral drugs used to treat HIV infection or AIDS, and in some cases hepatitis B. RTIs inhibit activity of reverse transcriptase, a viral DNA polymerase that is required for replication of HIV and other retroviruses.

<span class="mw-page-title-main">Lamivudine</span> Chemical compound

Lamivudine, commonly called 3TC, is an antiretroviral medication used to prevent and treat HIV/AIDS. It is also used to treat chronic hepatitis B when other options are not possible. It is effective against both HIV-1 and HIV-2. It is typically used in combination with other antiretrovirals such as zidovudine, dolutegravir, and abacavir. Lamivudine may be included as part of post-exposure prevention in those who have been potentially exposed to HIV. Lamivudine is taken by mouth as a liquid or tablet.

<span class="mw-page-title-main">Emtricitabine</span> Antiretroviral drug used to treat HIV infection

Emtricitabine, with trade name Emtriva, is a nucleoside reverse-transcriptase inhibitor (NRTI) for the prevention and treatment of HIV infection in adults and children. In 2019, it was the 494th most commonly prescribed medication in the United States, with more than 3 thousand prescriptions.

<span class="mw-page-title-main">Gilead Sciences</span> American pharmaceutical company

Gilead Sciences, Inc. is an American biopharmaceutical company headquartered in Foster City, California that focuses on researching and developing antiviral drugs used in the treatment of HIV/AIDS, hepatitis B, hepatitis C, influenza, and COVID-19, including ledipasvir/sofosbuvir and sofosbuvir. Gilead is a member of the NASDAQ Biotechnology Index and the S&P 500.

<span class="mw-page-title-main">Emtricitabine/tenofovir</span> Drug combination for HIV/AIDS prophylaxis and treatment

Emtricitabine/tenofovir, sold under the brand name Truvada among others, is a fixed-dose combination antiretroviral medication used to treat and prevent HIV/AIDS. It contains the antiretroviral medications emtricitabine and tenofovir disoproxil. For treatment, it must be used in combination with other antiretroviral medications. For prevention before exposure, in those who are at high risk, it is recommended along with safer sex practices. It does not cure HIV/AIDS. Emtricitabine/tenofovir is taken by mouth.

<span class="mw-page-title-main">Pre-exposure prophylaxis for HIV prevention</span> HIV prevention strategy using preventative medication for HIV-negative individuals

Pre-exposure prophylaxis for HIV prevention, commonly known as PrEP, is a form of medication used to prevent HIV infection, the cause of HIV/AIDS.

<span class="mw-page-title-main">Efavirenz/emtricitabine/tenofovir</span> Combination drug for HIV

Efavirenz/emtricitabine/tenofovir, sold under the brand name Atripla among others, is a fixed-dose combination antiretroviral medication used to treat HIV/AIDS. It contains efavirenz, emtricitabine, and tenofovir disoproxil. It can be used by itself or together with other antiretroviral medications. It is taken by mouth.

Integrase inhibitors (INIs) are a class of antiretroviral drug designed to block the action of integrase, a viral enzyme that inserts the viral genome into the DNA of the host cell. Since integration is a vital step in retroviral replication, blocking it can halt further spread of the virus. Integrase inhibitors were initially developed for the treatment of HIV infection, but have been applied to other retroviruses. The class of integrase inhibitors called integrase strand transfer inhibitors (INSTIs) are in established medical use. Other classes, such as allosteric integrase inhibitors (ALLINIs) or integrase binding inhibitors (INBIs), are still experimental.

<span class="mw-page-title-main">Rilpivirine</span> HIV treatment

Rilpivirine, sold under the brand names Edurant and Rekambys, is a medication, developed by Tibotec, used for the treatment of HIV/AIDS. It is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) with higher potency, longer half-life and reduced side-effect profile compared with older NNRTIs such as efavirenz.

<span class="mw-page-title-main">Cobicistat</span> Chemical compound

Cobicistat, sold under the brand name Tybost, is a medication for use in the treatment of human immunodeficiency virus infection (HIV/AIDS). Its major mechanism of action is through the inhibition of human CYP3A proteins.

Discovery and development of nucleoside and nucleotide reverse-transcriptase inhibitors began in the 1980s when the AIDS epidemic hit Western societies. NRTIs inhibit the reverse transcriptase (RT), an enzyme that controls the replication of the genetic material of the human immunodeficiency virus (HIV). The first NRTI was zidovudine, approved by the U.S. Food and Drug Administration (FDA) in 1987, which was the first step towards treatment of HIV. Six NRTI agents and one NtRTI have followed. The NRTIs and the NtRTI are analogues of endogenous 2´-deoxy-nucleoside and nucleotide. Drug-resistant viruses are an inevitable consequence of prolonged exposure of HIV-1 to anti-HIV drugs.

iPrEx

iPrEx was a phase III clinical trial to determine whether the antiretroviral medication emtricitabine/tenofovir could safely and effectively prevent HIV acquisition through sex in men who have sex with men and transgender women. iPrEx was the first human study of an HIV prevention strategy known as pre-exposure prophylaxis, or PrEP.

Emtricitabine/rilpivirine/tenofovir is a fixed-dose combination of antiretroviral drugs for the treatment of HIV/AIDS. The drug was co-developed by Gilead Sciences and Johnson & Johnson's Tibotec division and was approved by the Food and Drug Administration in August 2011, and by the European Medicines Agency in November 2011, for patients who have not previously been treated for HIV. It is available as a once-a-day single tablet.

<span class="mw-page-title-main">Tenofovir alafenamide</span> Chemical compound

Tenofovir alafenamide, sold under the brand name Vemlidy, is an antiviral medication used against hepatitis B and HIV. It is used for the treatment of chronic hepatitis B virus (HBV) infection in adults with compensated liver disease and is given in combination with other medications for the prevention and treatment of HIV. It is taken by mouth.

Elvitegravir/cobicistat/emtricitabine/tenofovir, sold under the brand name Stribild, also known as the Quadpill, is a fixed-dose combination antiretroviral medication for the treatment of HIV/AIDS. Elvitegravir, emtricitabine and tenofovir disoproxil directly suppress viral reproduction. Cobicistat increases the effectiveness of the combination by inhibiting the liver and gut wall enzymes that metabolize elvitegravir. It is taken by mouth.

<span class="mw-page-title-main">Cabotegravir</span> Medication for HIV/AIDS

Cabotegravir, sold under the brand name Vocabria among others, is a antiretroviral medication used for the treatment of HIV/AIDS. It is available in the form of tablets and as an intramuscular injection, as well as in an injectable combination with rilpivirine under the brand name Cabenuva.

<span class="mw-page-title-main">Abacavir/dolutegravir/lamivudine</span> Drug combination for HIV

Abacavir/dolutegravir/lamivudine, sold under the brand name Triumeq among others, is a fixed-dose combination antiretroviral medication for the treatment of HIV/AIDS. It is a combination of three medications with different and complementary mechanisms of action: abacavir, dolutegravir and lamivudine.

<span class="mw-page-title-main">Bictegravir</span> Chemical compound

Bictegravir is a second-generation integrase inhibitor (INSTI) class that was structurally derived from an earlier compound dolutegravir by scientists at Gilead Sciences. In vitro and clinical results were presented by Gilead in the summer of 2016. In 2016, bictegravir was in a Phase 3 trial as part of a single tablet regimen in combination with tenofovir alafenamide (TAF) and emtricitabine (FTC) for the treatment of HIV-1 infection.

Efavirenz/lamivudine/tenofovir (EFV/3TC/TDF), sold under the brand name Symfi among others, is a fixed-dose combination antiretroviral medication for the treatment of HIV/AIDS. It combines efavirenz, lamivudine, and tenofovir disoproxil. As of 2019, it is listed by the World Health Organization as an alternative first line option to dolutegravir/lamivudine/tenofovir. It is taken by mouth.

<span class="mw-page-title-main">Bictegravir/emtricitabine/tenofovir alafenamide</span> Fixed dose combination HIV drug

Bictegravir/emtricitabine/tenofovir alafenamide, sold under the brand name Biktarvy, is a fixed-dose combination antiretroviral medication for the treatment of HIV/AIDS. One tablet, taken orally once daily, contains 50 mg bictegravir, 200 mg emtricitabine, and 25 mg tenofovir alafenamide.

References

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  2. 1 2 "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 October 2023.
  3. ↑ "Viread EPAR". European Medicines Agency (EMA). 5 February 2002. Retrieved 25 May 2024.
  4. 1 2 3 4 5 6 7 8 9 10 11 "Tenofovir Disoproxil Fumarate". The American Society of Health-System Pharmacists. Archived from the original on 30 November 2016. Retrieved 29 November 2016.
  5. ↑ "Stribild". PubChem. U.S. National Library of Medicine. Retrieved 6 February 2022.
  6. ↑ Martin P, Lau DT, Nguyen MH, Janssen HL, Dieterich DT, Peters MG, et al. (November 2015). "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. doi:10.1016/j.cgh.2015.07.007. PMID   26188135.
  7. ↑ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 505. ISBN   9783527607495. Archived from the original on 8 September 2017.
  8. ↑ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl: 10665/325771 . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  9. ↑ "Teva Announces Exclusive Launch of a Generic version of Viread in the United States". www.tevapharm.com. Archived from the original on 6 November 2018. Retrieved 6 November 2018.
  10. 1 2 3 4 5 "Tenofovirdisoproxil Prescribing Information" (PDF). Gilead Sciences, Inc. November 2012. Archived from the original (PDF) on 7 February 2013.
  11. ↑ Okwundu CI, Uthman OA, Okoromah CA (July 2012). "Antiretroviral pre-exposure prophylaxis (PrEP) for preventing HIV in high-risk individuals". The Cochrane Database of Systematic Reviews. 7 (7): CD007189. doi:10.1002/14651858.CD007189.pub3. PMID   22786505.
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  13. 1 2 3 4 Ustianowski A, Arends JE (June 2015). "Tenofovir: What We Have Learnt After 7.5 Million Person-Years of Use". Infectious Diseases and Therapy. 4 (2): 145–57. doi:10.1007/s40121-015-0070-1. PMC   4471058 . PMID   26032649.
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  23. 1 2 USpatent 4808716,Holy A, Rosenberg I,"9-(phosponylmethoxyalkyl) adenines, the method of preparation and utilization thereof",published 1989-02-28, assigned to Czech Academy of Sciences
  24. 1 2 Brown Ripin DH, Teager DS, Fortunak J, Basha SM, Bivins N, Boddy CN, et al. (2010). "Process Improvements for the Manufacture of Tenofovir Disoproxil Fumarate at Commercial Scale". Organic Process Research & Development. 14 (5): 1194–1201. doi:10.1021/op1001337.
  25. ↑ Houghton SR, Melton J, Fortunak J, Brown Ripin DH, Boddy CN (2010). "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. doi:10.1016/j.tet.2010.08.037.
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  30. ↑ Shwiff K (11 August 2008). "FDA Clears Viread for Hepatitis B". The Wall Street Journal. Dow Jones & Company, Inc. Archived from the original on 8 September 2017.
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  33. ↑ Emau P, Jiang Y, Agy MB, Tian B, Bekele G, Tsai CC (November 2006). "Post-exposure prophylaxis for SIV revisited: animal model for HIV prevention". AIDS Research and Therapy . 3: 29. doi: 10.1186/1742-6405-3-29 . PMC   1687192 . PMID   17132170.
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