Abacavir

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Abacavir
Abacavir.svg
200px
Chemical structure of abacavir
Systematic (IUPAC) name
{(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]cyclopent-2-en-1-yl}methanol
Clinical data
Pronunciation Listeni/ʌ.bæk.ʌ.vɪər/
Trade names Ziagen
AHFS/Drugs.com monograph
MedlinePlus a699012
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
Legal status
Routes of
administration		 Oral (solution or tablets)
Pharmacokinetic data
Bioavailability 83%
Metabolism Hepatic
Biological half-life 1.54 ± 0.63 h
Excretion Renal (1.2% abacavir, 30% 5'-carboxylic acid metabolite, 36% 5'-glucuronide metabolite, 15% unidentified minor metabolites). Fecal (16%)
Identifiers
CAS Number 136470-78-5 YesY
ATC code J05AF06 (WHO)
PubChem CID: 441300
DrugBank DB01048 YesY
ChemSpider 390063 YesY
UNII WR2TIP26VS YesY
KEGG D07057 YesY
ChEBI CHEBI:421707 YesY
ChEMBL CHEMBL1380 YesY
NIAID ChemDB 028596
Chemical data
Formula C14H18N6O
Molecular mass 286.332 g/mol
  • n3c1c(ncn1[C@H]2/C=C\[C@@H](CO)C2)c(nc3N)NC4CC4
  • InChI=1S/C14H18N6O/c15-14-18-12(17-9-2-3-9)11-13(19-14)20(7-16-11)10-4-1-8(5-10)6-21/h1,4,7-10,21H,2-3,5-6H2,(H3,15,17,18,19)/t8-,10+/m1/s1 YesY
  • Key:MCGSCOLBFJQGHM-SCZZXKLOSA-N YesY
Physical data
Melting point 165 °C (329 °F)
  (verify)

Abacavir (ABC) is an antiretroviral medication used to prevent and treat HIV/AIDS.[1] It is of the nucleoside analog reverse transcriptase inhibitor (NRTI) type. Viral strains that are resistant to zidovudine (AZT) or lamivudine (3TC) are generally, but not always, sensitive to abacavir.

It is well tolerated: the main side effect is hypersensitivity, which can be severe, and in rare cases, fatal. Genetic testing can indicate whether an individual is likely to be hypersensitive; over 90% of people can safely take abacavir.

It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.[2] It is available under the trade name Ziagen and in the combination formulations abacavir/lamivudine/zidovudine, abacavir/dolutegravir/lamivudine, abacavir/lamivudine.

Medical uses

File:Abacavir (Ziagen) 300mg.jpg
Two Abacavir 300mg tablets

Abacavir tablets and oral solution, in combination with other antiretroviral agents, are indicated for the treatment of HIV-1 infection.

Abacavir should always be used in combination with other antiretroviral agents. Abacavir should not be added as a single agent when antiretroviral regimens are changed due to loss of virologic response.

Side effects

Common reactions include nausea, headache, fatigue, vomiting, hypersensitivity reaction, diarrhea, fever/chills, depression, rash, anxiety, URI, ALT, AST elevated, hypertriglyceridemia, and lipodystrophy.[3]

Patients with liver disease should be cautious about using abacavir because of the possibility that it can aggravate the condition. The use of nucleoside drugs such as abacavir can very rarely cause lactic acidosis. Resistance to abacavir has developed in laboratory versions of HIV which are also resistant to other HIV-specific antiretrovirals such as lamivudine, didanosine and zalcitabine. HIV strains that are resistant to protease inhibitors are not likely to be resistant to abacavir.

Abacavir is contraindicated for use in infants under 3 months of age.

Little is known about the effects of Abacavir overdose. Overdose victims should be taken to a hospital emergency room for treatment.

Hypersensitivity syndrome

Hypersensitivity to abacavir is strongly associated with a specific allele at the human leukocyte antigen B locus namely HLA-B*57:01.[4][5] There is an association between the prevalence of HLA-B*5701 and ancestry. The prevalence of the allele is estimated to be 3.4 to 5.8% on average in populations of European ancestry, 17.6% in Indian Americans, 3.0% in Hispanic Americans, and 1.2% in Chinese Americans.[6][7] There is significant variability in the prevalence of HLA-B*5701 among African populations. In African Americans, the prevalence is estimated to be 1.0% on average, 0% in the Yoruba from Nigeria, 3.3% in the Luhya from Kenya, and 13.6% in the Masai from Kenya, although the average values are derived from highly variable frequencies within sample groups.[8]

Common symptoms of abacavir hypersensitivity syndrome include fever, malaise, nausea, and diarrhea; some patients may also develop a skin rash.[9] Symptoms of AHS typically manifest within six weeks of treatment using abacavir, although they may be confused with symptoms of HIV, immune restoration disease, hypersensitivity syndromes associated with other drugs, or infection.[10] The FDA released an alert concerning abacavir and abacavir-containing medications on July 24, 2008,[11] and the FDA-approved drug label for abacavir recommends pre-therapy screening for the HLA-B*5701 allele, and the use of alternative therapy in subjects with this allele.[12] Additionally, both the Clinical Pharmacogenetics Implementation Consortium (CPIC) and Dutch Pharmacogenetics Working Group (DPWG) recommend use of an alternative therapy in individuals with the HLA-B*5701 allele.[13][14]

Patch test

Skin-patch testing may also be used to determine whether an individual will experience a hypersensitivity reaction to abacavir, although some patients susceptible to developing AHS may not react to the patch test.[15]

The development of suspected hypersensitivity reactions to abacavir requires immediate and permanent discontinuation of abacavir therapy in all patients, including patients who do not possess the HLA-B*5701 allele. On March 1, 2011, the FDA informed the public about an ongoing safety review of abacavir and a possible increased risk of heart attack associated with the drug. However, a meta-analysis of 26 studies conducted by the FDA did not find any association between abacavir use and heart attack [16][17]

Immunopathogenesis

The mechanism underlying abacavir hypersensitivity syndrome is related to the change in the HLA-B*5701 protein product. Abacavir binds with high specificity to the HLA-B*5701 protein, changing the shape and chemistry of the antigen-binding cleft. This results in a change in immunological tolerance and the subsequent activation of abacavir-specific cytotoxic T cells, which produce a systemic reaction known as abacavir hypersensitivity syndrome.[18]

Mechanism of action

ABC is an analog of guanosine (a purine). Its target is the viral reverse transcriptase enzyme. After ABC is completely phosphorylated (having a three phosphate groups), it competes with guanosine for incorporation into the DNA strand. When reverse transcriptase incorporates the ABC product, transcription is terminated because there is no 3' hydroxyl group on the molecule to make a phosphodiester bond to the next nucleotide in the DNA sequence.[19]

Pharmacokinetics

Abacavir is given orally and has a high bioavailability (83%). It is metabolised primarily through alcohol dehydrogenase or glucuronyl transferase. It is capable of crossing the blood–brain barrier.

History

Abacavir was approved by the Food and Drug Administration (FDA) on December 18, 1998 and is thus the fifteenth approved antiretroviral drug in the United States. Its patent expired in the United States on 2009-12-26.

Synthesis

File:Abacavir synthesis.png
Abacavir synthesis:[20]

References

  1. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  2. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  3. ↑ https://online.epocrates.com/noFrame/showPage.do?method=drugs&MonographId=2043&ActiveSectionId=5
  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. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  9. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  10. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  11. ↑ http://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm123927.htm Accessed November 29, 2013.
  12. ↑ http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=ca73b519-015a-436d-aa3c-af53492825a1
  13. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  14. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  15. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  16. ↑ http://www.drugs.com/fda/abacavir-ongoing-safety-review-possible-increased-risk-heart-attack-12914.html Accessed November 29, 2013.
  17. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  18. ↑ Illing PT et al. 2012, Nature, doi:10.1038/nature11147
  19. ↑ The Pharmacological Basics of Therapeutics, 12th Ed. Goodman and Gilman
  20. ↑ Lua error in package.lua at line 80: module 'strict' not found.

External links

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