Entecavir

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Entecavir
240px
240px
Systematic (IUPAC) name
2-Amino-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylidenecyclopentyl]-6,9-dihydro-3H-purin-6-one
Clinical data
Pronunciation /ɛnˈtɛkəvɪər/ en-TEK-a-vir or en-te-ka-veer
Trade names Baraclude
AHFS/Drugs.com monograph
MedlinePlus a605028
Licence data EMA:Link, US FDA:link
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
Legal status
Routes of
administration		 Oral
Pharmacokinetic data
Bioavailability n/a (≥70)[1]
Protein binding 13% (in vitro)
Metabolism negligible/nil
Biological half-life 128–149 hours
Excretion Renal 62–73%
Identifiers
CAS Number 142217-69-4 YesY
ATC code J05AF10 (WHO)
PubChem CID: 153941
DrugBank DB00442 YesY
ChemSpider 135679 N
UNII NNU2O4609D YesY
KEGG D04008 YesY
ChEBI CHEBI:59902 YesY
ChEMBL CHEMBL713 N
Chemical data
Formula C12H15N5O3
Molecular mass 277.279 g/mol
  • O=C2/N=C(\Nc1n(cnc12)[C@@H]3C(=C)/[C@H](CO)[C@@H](O)C3)N
  • InChI=1S/C12H15N5O3/c1-5-6(3-18)8(19)2-7(5)17-4-14-9-10(17)15-12(13)16-11(9)20/h4,6-8,18-19H,1-3H2,(H3,13,15,16,20)/t6-,7-,8-/m0/s1 N
  • Key:
    • YXPVEXCTPGULBZ-WQYNNSOESA-N
    • QDGZDCVAUDNJFG-FXQIFTODSA-N
     YesY
Physical data
Melting point 220 °C (428 °F) value applies to entecavir monohydrate and is a minimum value[2]
 NYesY (what is this?)  (verify)

Entecavir INN, abbreviated ETV, is an oral antiviral drug used in the treatment of hepatitis B virus (HBV) infection. Entecavir is a reverse transcriptase inhibitor. It prevents the hepatitis B virus from multiplying and reduces the amount of virus in the body.[3] More specifically, it is a deoxyguanosine analogue, that inhibits reverse transcription, DNA replication and transcription in the viral replication process.

Uses

Entecavir is mainly used to treat chronic hepatitis B infection in adults and children 2 years and older with active viral replication and evidence of active disease.[1] It is also used to prevent HBV reinfection after liver transplant[4] and to treat HIV patients infected with HBV. Entecavir is weakly active against HIV, however it is not recommended for use in HIV-HBV co-infected patients without a fully suppressive anti-HIV regimen[5] as it may select for resistance to lamivudine and emtricitabine in HIV.[6]

Administration

Entecavir should be taken on an empty stomach: at least 2 hours before a meal or 2 hours after a meal.[1]

Adverse Effects

The most common adverse effects from entecavir include headache, fatigue, dizziness, and nausea.[1] Others adverse effects include diarrhea, dyspepsia, vomiting, somnolence and insomnia.[1] Laboratory abnormalities resulting from treatment include elevated alanine transaminase (ALT) and hematuria. Periodic monitoring of hepatic function and hematology are recommended.[1]

Clinical Trials

The clinical efficacy of entecavir has been studied in several randomized, double-blind, multicentre trials. Oral entecavir was an effective and generally well tolerated treatment.[7]

History

  • 1992: SQ-34676 at Squibb as part of anti-herpes virus program[8]
  • 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[9]
  • Superior activity observed against HBV pushed research towards BMS 200475, its base analogues and its enantiomer against HBV in HepG2.2.15 cell line[9]
  • Comparison to other NAs, proven more selective potent inhibitor of HBV by virtue of being Guanine NA[10]
  • 1998: Inhibition of hepadnaviral polymerases was demonstrated in vitro in comparison to a number of NAs-TP[11]
  • Metabolic studies showed more efficient phosphorylation to triphosphate active form[12]
  • 3-year treatment of woodchuck model of CHB à sustained antiviral efficacy and prolonged life spans without detectable emergence of resistance[13]
  • Efficacy # LVD resistant HBV replication in vitro[14]
  • Superior activity compared to LVD in vivo for both HBeAg+ & HBeAg− patients[15][16]
  • Efficacy in LVD refractory CHB patients[17]
  • Entecavir was approved by the U.S. FDA in March 2005.

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.[18] On August 26, 2014, Teva Pharmaceuticals USA gained FDA approval for generic equivalents of Baraclude® 0.5 mg and 1 mg tablets;[19] Hetero Labs received such approval on August 21, 2015;[20] and Aurobindo Pharma on August 26, 2015.[21]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 "BARACLUDE® (entecavir) Tablets for Oral Use & Oral Solution. U.S. Full Prescribing Information." Bristol-Myers Squibb Company, 2005. Revised December 2013.
  2. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  3. ↑ Lua error in package.lua at line 80: module 'strict' not found.Closed access
  4. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  5. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  6. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  7. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  8. ↑ Slusarchyk, W. A., A. K. Field, J. A. Greytok, P. Taunk, A. V. Tooumari, M. G. Young, and R. Zahler. 4-Hydroxy-3-(hydroxymethyl)-2-methylcyclopentyl purines and pyrimidines, a novel class of anti-herpesvirus agents. Abstract from the Fifth International Conference on Antiviral Research. Antivir Res 1992.17(Suppl. 1):98
  9. ↑ 9.0 9.1 Bisacchi, G. S., S. T. Chao, C. Bachard, J. P. Daris, S. F. Innaimo, J. A. Jacobs, O. Kocy, P. Lapointe, A. Martel, Z. Merchant, W. A. Slusarchyk, J. E. Sundeen, M. G. Young, R. Colonno, and R. Zahler. BMS-200475, a novel carbocyclic 29-deoxyguanosine analog with potent and selective antihepatitis B virus activity in vitro. Bioorg. Med. Chem. Lett. 1997. 7:127–132
  10. ↑ Innaimo S F, Seifer M, Bisacchi G S, Standring D N, Zahler R, Colonno R J. Identification of BMS-200475 as a Potent and Selective Inhibitor of Hepatitis B Virus. Antimicrob. Agents Chemother. 1997. 41(7): 1444–1448
  11. ↑ Seifer, M., R. K. Hamatake, R. J. Colonno, and D. N. Standring. In vitro inhibition of hepadnavirus polymerases by the triphosphates of BMS-200475 and lobucavir. Antimicrob. Agents Chemother. 1998. 42:3200–3208
  12. ↑ Yamanaka, G., T. Wilson, S. Innaimo, G. S. Bisacchi, P. Egli, J. K. Rinehart, R. Zahler, and R. J. Colonno. Metabolic studies on BMS-200475, a new antiviral compound active against hepatitis B virus. Antimicrob. Agents Chemother. 1999. 43:190–193
  13. ↑ Colonno, R. J., E. V. Genovesi, I. Medina, L. Lamb, S. K. Durham, M. L. Huang, L. Corey, M. Littlejohn, S. Locarnini, B. C. Tennant, B. Rose, and J. M. Clark. Long-term entecavir treatment results in sustained antiviral efficacy and prolonged life span in the woodchuck model of chronic hepatitis infection. J. Infect. Dis. 2001.184:1236–1245
  14. ↑ Levine, S., D. Hernandez, G. Yamanaka, S. Zhang, R. Rose, S. Weinheimer, and R. J. Colonno. Efficacies of entecavir against lamivudine-resistant hepatitis B virus replication and recombinant polymerases in vitro. Antimicrob. Agents Chemother. 2002.46:2525–2532
  15. ↑ Chang, T. T. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N. Engl. J. Med. 2006. 354:1001–1010
  16. ↑ Lai, C. L. et al. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N. Engl. J.Med. 2006. 354:1011–1020.
  17. ↑ Sherman, M., C. Yurdaydin, J. Sollano, M. Silva, Y. F. Liaw, J. Cianciara, A. Boron-Kaczmarska, P. Martin, Z. Goodman, R. J. Colonno, A. Cross, G. Denisky, B. Kreter, R. Hindes, and the AI463026 Behold Study Group. Entecavir for the treatment of lamivudine-refractory, HBeAg-positive chronic hepatitis B. Gastroenterology 2006. 130:2039–2049.
  18. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  19. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  20. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  21. ↑ Lua error in package.lua at line 80: module 'strict' not found.

External links

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