Tenofovir

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Structural formula
Tenofovir structural formula
General
Non-proprietary name Tenofovir
other names

( R ) - [2- (6-Amino-9 H -purin-9-yl) -1-methylethoxy] methylphosphonic acid ( IUPAC )

Molecular formula C 9 H 14 N 5 O 4 P
Brief description

Crystals

External identifiers / databases
CAS number
  • 147127-20-6 (tenofovir)
  • 206184-49-8 (hydrate)
EC number 604-571-2
ECHA InfoCard 100.129.993
PubChem 464205
ChemSpider 408154
DrugBank DB14126
Wikidata Q155954
Drug information
ATC code

J05 AF07 , J05 AF13

Drug class

Antivirals

Mechanism of action

Nucleosidic Reverse Transcriptase Inhibitors

properties
Molar mass 287.21 g · mol -1
Physical state

firmly

Melting point

279 ° C

safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS hazard labeling
no classification available
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Tenofovir is an antiviral agent , which as a drug in the treatment of HIV -1 infections and hepatitis B is used. Tenofovir belongs to the group of nucleotide reverse transcriptase inhibitors (NtRTIs), which are used clinically like nucleoside reverse transcriptase inhibitors (NRTIs). Chemically it is a nucleotide - analogue , which with the natural due to its structural similarity substrate in its place in the viral DNA is incorporated and subsequently inhibits the multiplication of viruses. The ending -fovir characterizes the substance as an antiviral derivative of phosphonic acid . The discoverer of the active ingredient was Antonín Holý .

Use as a medicine

Tenofovir prodrugs

Tenofovir comes in the form of prodrugs such as tenofovir disoproxil [bis (isopropoxycarbonyloxy) methoxy ester of tenofovir] or tenofovir alafenamide [( S ) -P - [(2 S ) -1-oxo-1- (propan-2-yloxy) propane-2- yl] amide and P-phenyl ester of tenofovir] for use. Another form of prodrug is tenofovirexalidex .

  • Tenofovir disoproxil

  • Tenofovir alafenamide

Water-soluble salts, for example of fumaric acid, such as tenofovir disoproxil fumarate , tenofovir alafenamide fumarate or tenofovir alafenamide hemifumarate , are used pharmaceutically .

As a single substance

Tenofovir was approved in the US in 2001 and in the EU in 2002 in the form of tenofovir disoproxil fumarate as a film-coated tablet for the treatment of human immunodeficiency virus (HIV) infections in adults, always in combination with other anti- retroviral drugs. In 2008, the indication was expanded to include the treatment of chronic hepatitis B in adults with compensated liver disease if this is accompanied by certain findings, such as increased serum alanine aminotransferase values, active liver inflammation or liver fibrosis and proven active virus replication .

In 2010, a study became known in which the effectiveness of tenofovir in the prophylaxis of HIV in women was investigated. The administration of the active ingredient as a vaginal cream could consequently reduce the risk of HIV infection during sexual intercourse by 39%. However, a later study by the US National Institutes of Health showed that the preparation was ineffective as a vaginal cream.

A 2013 study showed that prophylactic use of tenofovir can prevent 49% (if regularly observed ingestion) to 74% (if blood levels are appropriate) of HIV infections in drug addicts. A total of 2413 participants took part in the placebo-controlled study.

Another study in 2013 showed that vaginal rings coated with tenofovir stopped infections with HIV-like viruses 100% in animal experiments. Further tests must follow. The system would have the advantage of significantly increasing compliance .

Combination with emtricitabine

In 2012, the Food and Drug Administration approved a combination of the active ingredients tenofovir and emtricitabine in tablet form for HIV prevention. Studies by Family Health International (FHI) indicate, however, that this dosage form only lowers the risk of infection in men, but not in women.

On August 22, 2016, the European Commission granted conditional approval for tenofovir in combination with emtricitabine under the brand name Truvada for pre-exposure prophylaxis ( PrEP ).

Mechanism of action

After absorption, tenofovir disoproxil forms the nucleotide analogue structurally related to adenosine monophosphate, tenofovir, which is phosphorylated to the active tenofovir diphosphate in virus-infected cells. In nucleic acid synthesis, this competes with the natural substrate deoxyadenosine triphosphate and inactivates viral enzymes that are important for reproduction, such as reverse transcriptase of the HI virus or the DNA polymerase of the hepatitis B virus ( "suicide inhibition" ). Nucleotides built into the DNA also prevent the attachment of further nucleotides due to their chemical structure and the chain is broken.

Tenofovir alafenamide is more stable in plasma than tenofovir disoproxil and is mainly hydrolyzed to tenofovir in the virus-infected cells via an intermediate tenofovir- alanine stage, as described above. This increases the selectivity of the active ingredient and consequently the intracellular concentrations. Adverse effects on the kidneys and bones ( proteinuria , bone mineralization) occur less.

Pharmacokinetics

The oral bioavailability of tenofovir is approximately 25% after fasting and increases to 40% with food. The plasma protein binding is low. The potential for cytochrome P450 -mediated interactions between tenofovir and other medicinal products is considered to be low. Tenofovir is largely excreted unchanged by the renal route by both glomerular filtration and active tubular secretion. The terminal plasma half-life is 12–18 hours.

Side effects and restrictions on use

No data are available on its use in people under 18 years of age or in patients over 65 years of age. Caution is advised when treating patients with kidney failure . Due to insufficient data, the risk-benefit assessment in pregnancy should be carried out accordingly. As it is not known whether tenofovir disoproxil is excreted in breast milk, patients taking tenofovir disoproxil should refrain from breastfeeding. Mainly gastrointestinal complaints and headaches can occur, less often nephrotoxic side effects.

Early benefit assessment

In Germany, since 2011, newly approved drugs with new active ingredients must be subjected to an " early benefit assessment " by the Federal Joint Committee (G-BA) in accordance with Section 35a SGB ​​V if the pharmaceutical manufacturer wants to achieve a higher sales price than just the fixed amount . Only if there is an additional benefit can the pharmaceutical manufacturer negotiate a price with the umbrella association of statutory health insurance companies. The dossier evaluations, on the basis of which the G-BA makes its decisions, are created by the Institute for Quality and Efficiency in Health Care (IQWiG) .

Since 2012, tenofovir has undergone numerous early benefit assessments in various combinations and as a single preparation, mainly for the indication of HIV infection, but also for the treatment of chronic hepatitis B. The appropriate comparator therapy often depended on the age of those affected (children, adolescents, adults) as well as possible antiretroviral pretreatment. According to a G-BA decision of 2012, there is proof of a minor added benefit for the combination emtricitabine / rilpivirine / tenofovir disoproxil (trade name Eviplera) for the treatment of adults who have not been previously treated with antiretroviral agents with a viral load of ≤ 100,000 HIV-1 RNA copies / ml versus efavirenz in combination with two nucleoside / nucleotide analogues (tenofovir plus emtricitabine or abacavir plus lamivudine). For all other combinations, indication areas and comparisons, an added benefit in the early benefit assessments up to and including 2019 is not proven.

Trade names

Monopreparations
  • Tenofovir disoproxil: Viread (D, A, CH), generics
  • Tenofovir alafenamide : Vemlidy (EU, CH)
Combination preparations
  • Tenofovir disoproxil + emtricitabine : Truvada (EU, CH), generics
  • Tenofovir disoproxil + emtricitabine + efavirenz : Atripla (EU, CH), generics
  • Tenofovir disoproxil + emtricitabine + rilpivirine : Eviplera (EU, CH)
  • Tenofovir disoproxil + emtricitabine + elvitegravir + cobicistat : Stribild (EU, CH)
  • Tenofovir disoproxil + doravirine + lamivudine : Delstrigo
  • Tenofovir alafenamide + emtricitabine + elvitegravir + cobicistat: Genvoya (EU, CH)
  • Tenofovir alafenamide + emtricitabine: Descovy (EU, CH)
  • Tenofovir alafenamide + emtricitabine + rilpirivine: Odefsey (EU)
  • Tenofovir alafenamide + emtricitabine + cobicistat + darunavir : Symtuza
  • Tenofovir alafenamide + bictegravir + emtricitabine: Biktarvy (EU, CH)

Web links

Individual evidence

  1. ^ A b The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals, 14th Edition (Merck & Co., Inc.), Whitehouse Station, NJ, USA, 2006; ISBN 978-0-911910-00-1
  2. ↑ This substance has either not yet been classified with regard to its hazardousness or a reliable and citable source has not yet been found.
  3. ↑ The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances (“Stem Book” of the WHO; PDF; 802 kB), 2011.
  4. ↑ External identifiers or database links for tenofovir disoproxil: CAS number: 201341-05-1, EC number: 606-442-6, ECHA InfoCard: 100.114.051 , PubChem : 5481350 , ChemSpider : 4587262 , DrugBank : DB00300 , Wikidata : Q27132753 .
  5. ↑ External identifiers or database links for tenofovir alafenamide: CAS number: 379270-37-8, PubChem : 9574768 , ChemSpider : 7849225 , DrugBank : DB09299 , Wikidata : Q22075912 .
  6. ↑ External identifiers or database links for Tenofovirexalidex : CAS number: 911208-73-6, PubChem : 23628250 , ChemSpider : 23336649 , Wikidata : Q27282054 .
  7. ↑ External identifiers or database links for tenofovir disoproxil fumarate: CAS number: 202138-50-9, EC number: 687-766-5, ECHA InfoCard: 100.213.968 , PubChem : 6398764 , ChemSpider : 4911265 , DrugBank : DBSALT000172 , Wikidata : Q27132754 .
  8. ↑ External identifiers or database links for tenofovir alafenamide fumarate: CAS number: 379270-38-9, EC number: 695-673-6, ECHA InfoCard: 100.224.335 , PubChem : 68516365 , ChemSpider : 8005737 , Wikidata : Q90688469 .
  9. ↑ External identifiers or database links for tenofovir alafenamide hemifumarate: CAS number: 1392275-56-7, EC number: 805-448-8, ECHA InfoCard: 100.232.257 , PubChem : 71492247 , ChemSpider : 29398961 , DrugBank : DBSALT002533 , Wikidata : Q27162911 .
  10. ↑ Q. Abdool Karim, SS Abdool Karim u. a .: Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. In: Science. Volume 329, number 5996, September 2010, pp. 1168–1174, doi: 10.1126 / science.1193748 . PMID 20643915 . PMC 3001187 (free full text).
  11. ↑ NIH Discontinues Tenofovir Vaginal Gel in 'VOICE' HIV Prevention Study . NIH News, Nov. 25, 2011.
  12. ↑ K. Choopanya, M. Martin et al. a .: Antiretroviral prophylaxis for HIV infection in injecting drug users in Bangkok, Thailand (the Bangkok Tenofovir Study): a randomized, double-blind, placebo-controlled phase 3 trial. In: Lancet. Volume 381, Number 9883, June 2013, pp. 2083-2090, doi: 10.1016 / S0140-6736 (13) 61127-7 . PMID 23769234 .
  13. ↑ JM Smith, R. Rastogi et al. a .: Intravaginal ring eluting tenofovir disoproxil fumarate completely protects macaques from multiple vaginal simian-HIV challenges. In: Proceedings of the National Academy of Sciences . Volume 110, number 40, October 2013, pp. 16145–16150, doi: 10.1073 / pnas.1311355110 . PMID 24043812 . PMC 3791780 (free full text).
  14. ↑ US experts recommend the approval of anti-AIDS pills . Stern, May 11, 2012.
  15. ↑ Truvada: HIV prevention study stopped. In: Deutsches Ärzteblatt . April 19, 2011, archived from the original on March 4, 2016 ; accessed on October 10, 2019 .
  16. ↑ http://www.hivandmore.de/aktuell/2016-08/truvada-zur-prep-zugelassen-aber.shtml
  17. ^ A b Ernst Mutschler, Gerd Geisslinger, Heyo K. Kroemer, Peter Ruth, Monika Schäfer-Korting: drug effects. Textbook of pharmacology and toxicology. 9th edition. Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart 2008, ISBN 3-8047-1952-X .
  18. ↑ a b c d EMA: Summary of Product Characteristics Viread
  19. ↑ PJ Ruane et al .: Antiviral activity, safety, and pharmacokinetics / pharmacodynamics of tenofovir alafenamide as 10-day monotherapy in HIV-1-positive adults. J Acquir Immune Defic Syndr. 2013 Aug 1; 63 (4): 449-55. doi : 10.1097 / QAI.0b013e3182965d45 .
  20. ↑ Search for tenofovir on the IQWiG website → Projects (17); Accessed March 25, 2020.
  21. ↑ Drugs Directive / Annex XII: Emtricitabine, Rilpivirine, Tenofovir Disoproxil; Accessed March 25, 2020.
  22. ↑ Benefit assessment procedure for the active ingredient elvitegravir / cobicistat / emtricitabine / tenofovir alafenamide (HIV infection); Accessed March 25, 2020.
  23. ↑ Benefit assessment procedure for the active ingredient elvitegravir / cobicistat / emtricitabine / tenofovir alafenamide (HIV infection); Accessed March 25, 2020.
  24. ↑ Benefit assessment procedure for the active ingredient emtricitabine / tenofovir alafenamide (HIV infection); Accessed March 25, 2020.
  25. ↑ Benefit assessment procedure for the active ingredient emtricitabine / tenofovir alafenamide (HIV infection); Accessed March 25, 2020.
  26. ↑ Benefit assessment procedure for the active ingredient emtricitabine / rilpivirine / tenofovir alafenamide (HIV infection); Accessed March 25, 2020.
  27. ↑ Benefit assessment procedure for the active ingredient tenofovir alafenamide - replaced by a new decision in 2018; Accessed March 25, 2020.
  28. ↑ Benefit assessment procedure for the active ingredient darunavir / cobicistat / emtricitabine / tenofovir alafenamide (HIV infection); Accessed March 25, 2020.
  29. ↑ Benefit assessment procedure for the active ingredient elvitegravir / cobicistat / emtricitabine / tenofovir alafenamide (new indication: HIV infection, 6 to <12 years); Accessed March 25, 2020.
  30. ↑ Benefit assessment procedure for the active ingredient bictegravir / emtricitabine / tenofovir alafenamide (HIV infection); Accessed March 25, 2020.
  31. ↑ Benefit assessment procedure for the active ingredient tenofovir alafenamide (reassessment after the deadline: chronic hepatitis B, ≥ 12 years); Accessed March 25, 2020.
  32. ↑ Benefit assessment procedure for the active ingredient bictegravir / emtricitabine / tenofovir alafenamide (HIV infection); Accessed March 25, 2020.
  33. ↑ Drugs Directive / Annex XII: Elvitegravir / Cobicistat / Emtricitabine / Tenofovir disoproxil; Accessed March 25, 2020.
  34. ↑ Drugs Directive / Annex XII: Emtricitabine / Rilpivirine / Tenofovir disoproxil (new area of ​​application); Accessed March 25, 2020.
  35. ↑ Benefit assessment procedure for the active ingredient elvitegravir / cobicistat / emtricitabine / tenofovir disoproxil (new indication: HIV infection, 12 to <18 years of age); Accessed March 25, 2020.
  36. ↑ Benefit assessment procedure for the active ingredient doravirine / lamivudine / tenofovir disoproxil (HIV infection); Accessed March 25, 2020.