Chemistry:Entecavir

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Short description: Chemical compound

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Entecavir
Entecavir structure.svg
Entecavir ball-and-stick model.png
Clinical data
Pronunciation/ɛnˈtɛkəvɪər/ en-TEK-ə-veer
Trade namesBaraclude, others
Other namesBMS-200475-01
AHFS/Drugs.comMonograph
MedlinePlusa605028
License data
Pregnancy
category
Routes of
administration		By mouth
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • CA: ℞-only
  • UK: POM (Prescription only)
  • US: ℞-only [2]
  • EU: Rx-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailabilityn/a (≥70)[2]
Protein binding13% (in vitro)
Metabolismnegligible/nil
Elimination half-life128–149 hours
ExcretionKidney 62–73%
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC12H15N5O3
Molar mass277.284 g·mol−1
3D model (JSmol)
Melting point220 °C (428 °F) value applies to entecavir monohydrate and is a minimum value[3]
 ☒N☑Y (what is this?)  (verify)

Entecavir (ETV), sold under the brand name Baraclude, is an antiviral medication used in the treatment of hepatitis B virus (HBV) infection.[4] In those with both HIV/AIDS and HBV antiretroviral medication should also be used.[4] Entecavir is taken by mouth as a tablet or solution.[4]

Common side effects include headache, nausea, high blood sugar, and decreased kidney function.[4] Severe side effects include enlargement of the liver, high blood lactate levels, and liver inflammation if the medication is stopped.[4] While there appears to be no harm from use during pregnancy, this use has not been well studied.[1] Entecavir is in the nucleoside reverse transcriptase inhibitors (NRTIs) family of medications.[4][5] It prevents the hepatitis B virus from multiplying by blocking reverse transcriptase.[4]

Entecavir was approved for medical use in 2005.[4] It is on the World Health Organization's List of Essential Medicines.[6] Available as a generic medication in the United States.

Medical uses

Entecavir is mainly used to treat chronic hepatitis B infection in adults and children two years and older with active viral replication and evidence of active disease with elevations in liver enzymes.[2] It is also used to prevent HBV reinfection after liver transplant[7] and to treat HIV patients infected with HBV. Entecavir is weakly active against HIV, but is not recommended for use in HIV-HBV co-infected patients without a fully suppressive anti-HIV regimen[8] as it may select for resistance to lamivudine and emtricitabine in HIV.[9]

The efficacy of entecavir has been studied in several randomized, double-blind, multicentre trials. Entecavir by mouth is effective and generally well tolerated treatment.[10]

Pregnancy and breastfeeding

No adequate and well-controlled studies exist in pregnant women.[1]

Side effects

The majority of people who use entecavir have little to no side effects.[11] The most common side effects include headache, fatigue, dizziness, and nausea.[2] Less common effects include trouble sleeping and gastrointestinal symptoms such as sour stomach, diarrhea, and vomiting.[12]

Serious side effects from entecavir include lactic acidosis, liver problems, liver enlargement, and fat in the liver.[2]

Laboratory tests may show an increase in alanine transaminase (ALT), hematuria, glycosuria, and an increase in lipase.[2] Periodic monitoring of hepatic function and hematology are recommended.[2]

Mechanism of action

Entecavir is a nucleoside analog,[13] or more specifically, a deoxyguanosine analogue that belongs to a class of carbocyclic nucleosides and inhibits reverse transcription, DNA replication and transcription in the viral replication process. Other nucleoside and nucleotide analogues include lamivudine, telbivudine, adefovir dipivoxil, and tenofovir.

Entecavir reduces the amount of HBV in the blood by reducing its ability to multiply and infect new cells.[14]

Administration

Entecavir is taken by mouth as a tablet or solution. Doses are based on a person's weight.[2] The solution is recommended for children more than 2 years old who weigh up to 30 kg. Entecavir is recommended on an empty stomach at least 2 hours before or after a meal, generally at the same time every day. It is not used in children less than 2 years old. Dose adjustments are also recommended for people with decreased kidney function.[2]

History

  • 1992: SQ-34676 at Squibb as part of anti-herpes virus program[15]
  • 1997: BMS 200475 developed at BMS pharmaceutical research institute as antiviral nucleoside analogue à Activity demonstrated against HBV, HSV-1, HCMV, VZV in cell lines & no or little activity against HIV or influenza[16]
  • Superior activity observed against HBV pushed research towards BMS 200475, its base analogues and its enantiomer against HBV in HepG2.2.15 cell line[16]
  • Comparison to other NAs, proven more selective potent inhibitor of HBV by virtue of being Guanine NA[17]
  • 1998: Inhibition of hepadnaviral polymerases was demonstrated in vitro in comparison to a number of NAs-TP[18]
  • Metabolic studies showed more efficient phosphorylation to triphosphate active form[19]
  • 3-year treatment of woodchuck model of CHB à sustained antiviral efficacy and prolonged life spans without detectable emergence of resistance[20]
  • Efficacy # LVD resistant HBV replication in vitro[21]
  • Superior activity compared to LVD in vivo for both HBeAg+ & HBeAg− patients[22][23]
  • Efficacy in LVD refractory CHB patients[24]
  • Entecavir was approved by the U.S. Food and Drug Administration (FDA) in March 2005.[25]

Patent information

Bristol-Myers Squibb was the original patent holder for Baraclude, the brand name of entecavir in the US and Canada. The drug patent expiration for Baraclude was in 2015.[26][27] Entecavir patents were a subject of litigation in the US between Bristol Myers Squibb (the patent owner) and Teva Pharmaceuticals USA (a generic manufacturer). The lawsuit resulted in a relatively rare in the pharmaceutical field patent invalidation for obviousness, which was affirmed on 12 June 2014, by the US Court of Appeals for the Federal Circuit (752 F.32d 967).

On August 26, 2014, Teva Pharmaceuticals USA gained FDA approval for generic equivalents of Baraclude 0.5 mg and 1 mg tablets;[28] Hetero Labs received such approval on August 21, 2015;[29] and Aurobindo Pharma on August 26, 2015.[30]

References

  1. ↑ 1.0 1.1 1.2 "Entecavir (Baraclude) Use During Pregnancy". 3 December 2019. https://www.drugs.com/pregnancy/entecavir.html. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 "Baraclude- entecavir tablet, film coated Baraclude- entecavir solution". https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=046e61c9-9298-4b2e-b76e-b26b81fecd20. 
  3. ↑ "The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals". The Merck Index (14th ed.). 2006. p. 613. ISBN 978-0-911910-00-1. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 "Entecavir". The American Society of Health-System Pharmacists. https://www.drugs.com/monograph/entecavir.html. 
  5. ↑ (in en) Chronic Viral Hepatitis: Diagnosis and Therapeutics. Springer Science & Business Media. 2009. p. 34. ISBN 9781597455657. https://books.google.com/books?id=o67J8smzgHEC&pg=PA34. 
  6. ↑ 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. 
  7. ↑ "Entecavir monotherapy is effective in suppressing hepatitis B virus after liver transplantation". Gastroenterology 141 (4): 1212–1219. October 2011. doi:10.1053/j.gastro.2011.06.083. PMID 21762659. 
  8. ↑ "Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents". Panel on Antiretroviral Guidelines for Adults and Adolescents. http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf. 
  9. ↑ "The HBV drug entecavir - effects on HIV-1 replication and resistance". The New England Journal of Medicine 356 (25): 2614–2621. June 2007. doi:10.1056/NEJMoa067710. PMID 17582071. 
  10. ↑ "Entecavir: a review of its use in chronic hepatitis B". Drugs 69 (8): 1003–1033. May 2009. doi:10.2165/00003495-200969080-00005. PMID 19496629. http://adisonline.com/drugs/abstract/2009/69080/Entecavir__A_Review_of_its_Use_in_Chronic.5.aspx. Retrieved 2010-03-29. 
  11. ↑ "Entecavir: Indications, Side Effects, Warnings - Drugs.com". https://www.drugs.com/cdi/entecavir.html. 
  12. ↑ "Entecavir Side Effects in Detail - Drugs.com". https://www.drugs.com/sfx/entecavir-side-effects.html. 
  13. ↑ "Entecavir: a new nucleoside analog for the treatment of chronic hepatitis B infection". Pharmacotherapy 26 (12): 1745–1757. December 2006. doi:10.1592/phco.26.12.1745. PMID 17125436. 
  14. ↑ "Entecavir: Indications, Side Effects, Warnings - Drugs.com". https://www.drugs.com/cdi/entecavir.html. 
  15. ↑ "4-Hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl purines and pyrimidines, a new class of anti-herpesvirus agents". Antiviral Research 17: 98. 1992. doi:10.1016/0166-3542(92)90200-o. 
  16. ↑ 16.0 16.1 "BMS-200475, a novel carbocyclic 29-deoxyguanosine analog with potent and selective antihepatitis B virus activity in vitro". Bioorganic & Medicinal Chemistry Letters 7 (2): 127–132. 1997. doi:10.1016/s0960-894x(96)00594-x. 
  17. ↑ "Identification of BMS-200475 as a potent and selective inhibitor of hepatitis B virus". Antimicrobial Agents and Chemotherapy 41 (7): 1444–1448. July 1997. doi:10.1128/AAC.41.7.1444. PMID 9210663. 
  18. ↑ "In vitro inhibition of hepadnavirus polymerases by the triphosphates of BMS-200475 and lobucavir". Antimicrobial Agents and Chemotherapy 42 (12): 3200–3208. December 1998. doi:10.1128/AAC.42.12.3200. PMID 9835515. 
  19. ↑ "Metabolic studies on BMS-200475, a new antiviral compound active against hepatitis B virus". Antimicrobial Agents and Chemotherapy 43 (1): 190–193. January 1999. doi:10.1128/AAC.43.1.190. PMID 9869593. 
  20. ↑ "Long-term entecavir treatment results in sustained antiviral efficacy and prolonged life span in the woodchuck model of chronic hepatitis infection". The Journal of Infectious Diseases 184 (10): 1236–1245. November 2001. doi:10.1086/324003. PMID 11679911. 
  21. ↑ "Efficacies of entecavir against lamivudine-resistant hepatitis B virus replication and recombinant polymerases in vitro". Antimicrobial Agents and Chemotherapy 46 (8): 2525–2532. August 2002. doi:10.1128/aac.46.8.2525-2532.2002. PMID 12121928. 
  22. ↑ "A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B". The New England Journal of Medicine 354 (10): 1001–1010. March 2006. doi:10.1056/nejmoa051285. PMID 16525137. 
  23. ↑ "Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B". The New England Journal of Medicine 354 (10): 1011–1020. March 2006. doi:10.1056/NEJMoa051287. PMID 16525138. 
  24. ↑ "Entecavir for treatment of lamivudine-refractory, HBeAg-positive chronic hepatitis B". Gastroenterology 130 (7): 2039–2049. June 2006. doi:10.1053/j.gastro.2006.04.007. PMID 16762627. 
  25. ↑ "Drug Approval Package: Baraclude (Entecavir) NDA #021797 & 021798". 28 December 2011. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/21797_21798_BaracludeTOC.cfm. 
  26. ↑ "Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations". http://www.accessdata.fda.gov/scripts/cder/ob/docs/patexclnew.cfm?Appl_No=021797&Product_No=001&table1=OB_Rx. 
  27. ↑ "Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations". http://www.accessdata.fda.gov/scripts/cder/ob/patent_info.cfm?Product_No=001&Appl_No=021798&Appl_type=N. 
  28. ↑ "Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations". Search results from the "OB_Rx" table for query on "202122.". http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=202122&TABLE1=OB_Rx. 
  29. ↑ "Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations". Search results from the "OB_Rx" table for query on "205740.". http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=205740&TABLE1=OB_Rx. 
  30. ↑ "Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations". Search results from the "OB_Rx" table for query on "206217.". http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=206217&TABLE1=OB_Rx. 

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