Entecavir

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Entecavir
Entecavir structure.svg
Systematic (IUPAC) name
2-Amino-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylidenecyclopentyl]-6,9-dihydro-3H-purin-6-one
Clinical data
Trade names Baraclude
AHFS/Drugs.com monograph
MedlinePlus a605028
Licence data EMA:Link, US FDA:link
Pregnancy cat.
Legal status
Routes Oral
Pharmacokinetic data
Bioavailability n/a (≥70)[1]
Protein binding 13% (in vitro)
Metabolism negligible/nil
Half-life 128–149 hours
Excretion Renal 62–73%
Identifiers
CAS number 142217-69-4 YesY
ATC code J05AF10
PubChem CID 153941
DrugBank DB00442
ChemSpider 135679 N
UNII NNU2O4609D YesY
KEGG D04008 YesY
ChEBI CHEBI:59902 YesY
ChEMBL CHEMBL713 N
Chemical data
Formula C12H15N5O3 
Mol. mass 277.279 g/mol
 N (what is this?)  (verify)

Entecavir INN /ɛnˈtɛkəvɪər/ en-TEK-a-vir or en-te-ka-veer, 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.[2]

Mechanism of Action[edit]

Entecavir is a nucleoside analog[3] (more specifically, a deoxyguanosine analogue) that inhibits reverse transcription, DNA replication and transcription in the viral replication process.

Uses[edit]

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.[2] It is also used to prevent HBV reinfection after liver transplant[4] and to treat HIV patients infected with HBV. However, entecavir is not active against HIV.

Dosage forms and strengths[2][edit]

Tablet: 0.5 mg and 1 mg

Oral solution: 0.05 mg/mL

Administration[edit]

Entecavir should be taken on an empty stomach, at least 2 hours before a meal and 2 hours after a meal.[2]

Adverse Effects[edit]

The most common adverse effects from entecavir include headache, fatigue, dizziness, and nausea.[2] Others adverse effects include diarrhea, dyspepsia, vomitting, somnolence and insomnia.[2] Laboratory abnormalities resulting from treatment include elevated alanine transaminase (ALT) and hematuria. Periodic monitoring of hepatic function and hematology are recommended.[2]

Patent Information[edit]

Bristol-Myers Squibb is currently the drug patent holder for Baraclude®, the brand name of entecavir in the US and Canada. The drug patent expiration date for both Baraclude® 0.5 mg and 1 mg tablets is set for February 21, 2015.[5] On August 26, 2014, TEVA Pharms USA gained FDA approval for generic equivalents of Baraclude® 0.5 mg and 1 mg tablets.[5]

Clinical Trials[edit]

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.[6]

History[edit]

  • 1992: SQ-34676 at Squibb as part of anti-herpes virus program[7]
  • 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[8]
  • Superior activity observed against HBV pushed research towards BMS 200475, its base analogues and its enantiomer against HBV in HepG2.2.15 cell line[8]
  • Comparison to other NAs, proven more selective potent inhibitor of HBV by virtue of being Guanine NA[9]
  • 1998: Inhibition of hepadnaviral polymerases was demonstrated in vitro in comparison to a number of NAs-TP[10]
  • Metabolic studies showed more efficient phosphorylation to triphosphate active form[11]
  • 3 year treatment of woodchuck model of CHB à sustained antiviral efficacy and prolonged life spans without detectable emergence of resistance[12]
  • Efficacy # LVD resistant HBV replication in vitro[13]
  • Superior activity compared to LVD in vivo for both HBeAg+ & HBeAg− patients[14][15]
  • Efficacy in LVD refractory CHB patients[16]
  • Entecavir was approved by the U.S. FDA in March 2005.

References[edit]

  1. ^ BARACLUDE® (entecavir) Tablets for Oral Use & Oral Solution. U.S. Full Prescribing Information.” Bristol-Myers Squibb Company, 2005. Revised December 2013. [1]
  2. ^ a b c d e f g "Baraclude Full Prescribing Information". www.baraclude.com. Bristol-Myers Squibb. Retrieved 31 October 2014. 
  3. ^ Sims KA, Woodland AM (December 2006). "Entecavir: a new nucleoside analog for the treatment of chronic hepatitis B infection". Pharmacotherapy 26 (12): 1745–57. doi:10.1592/phco.26.12.1745. PMID 17125436. 
  4. ^ Fung J, Cheung C, Chan SC, et al, "Entecavir Monotherapy is Effective in Suppressing Hepatitis B Virus After Liver Transplantation," Gastroenterology, 2011, 141(4):1212-9.
  5. ^ a b "Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations". www.FDA.gov. FDA. Retrieved 30 October 2014. 
  6. ^ Scott LJ, Keating GM.[2].Drugs 2009;69(8):1003-1033. doi:10.2165/00003495-200969080-00005.
  7. ^ 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
  8. ^ a b 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
  9. ^ 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
  10. ^ 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
  11. ^ 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
  12. ^ 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
  13. ^ 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
  14. ^ Chang, T. T. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N. Engl. J. Med. 2006. 354:1001–1010
  15. ^ Lai, C. L. et al. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N. Engl. J.Med. 2006. 354:1011–1020.
  16. ^ 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.

External links[edit]