Abacavir

Abacavir

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 i/ʌ.bæk.ʌ.vɪər/
Trade names Ziagen
AHFS/Drugs.com monograph
MedlinePlus a699012
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
Routes of
administration		 Oral (solution or tablets)
Legal status
Legal status
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
Molar mass 286.332 g/mol
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 in the combination formulations abacavir/lamivudine/zidovudine, abacavir/dolutegravir/lamivudine, and abacavir/lamivudine. As of 2015 the cost for a typical month of medication in the United States is more than 200 USD.[3]

Medical uses

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.[4]

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.[5][6] 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.[7][8] 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.[9]

Common symptoms of abacavir hypersensitivity syndrome include fever, malaise, nausea, and diarrhea; some patients may also develop a skin rash.[10] 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.[11] The FDA released an alert concerning abacavir and abacavir-containing medications on July 24, 2008,[12] 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.[13] 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.[14][15]

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.[16]

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 [17][18]

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.[19]

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.[20]

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.


Robert Vince in the '80s along with a visiting scientist from China, Mei Hua, developed the medication.[21][22]

Synthesis

Abacavir synthesis:[23]

References

  1. ↑ "Abacavir Sulfate". The American Society of Health-System Pharmacists. Retrieved 31 July 2015.
  2. ↑ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
  3. ↑ Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 64. ISBN 9781284057560.
  4. ↑ https://online.epocrates.com/noFrame/showPage.do?method=drugs&MonographId=2043&ActiveSectionId=5
  5. ↑ Mallal, S., Phillips, E., Carosi, G.; et al. (2008). "HLA-B*5701 screening for hypersensitivity to abacavir". New England Journal of Medicine 358 (6): 568–579. doi:10.1056/nejmoa0706135. PMID 18256392.
  6. ↑ Rauch, A., Nolan, D., Martin, A.; et al. (2006). "Prospective genetic screening decreases the incidence of abacavir hypersensitivity reactions in the Western Australian HIV cohort study". Clinical Infectious Diseases 43 (1): 99–102. doi:10.1086/504874. PMID 16758424.
  7. ↑ Heatherington; et al. (2002). "Genetic variations in HLA-B region and hypersensitivity reactions to abacavir". Lancet 359 (9312): 1121–1122. doi:10.1016/s0140-6736(02)08158-8. PMID 11943262.
  8. ↑ Mallal; et al. (2002). "Association between presence of HLA*B5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir". Lancet 359 (9308): 727–732. doi:10.1016/s0140-6736(02)07873-x. PMID 11888582.
  9. ↑ Rotimi, C.N.; Jorde, L.B. (2010). "Ancestry and disease in the age of genomic medicine". New England Journal of Medicine 363 (16): 1551–1558. doi:10.1056/nejmra0911564. PMID 20942671.
  10. ↑ Phillips, E., Mallal, S. (2009). "Successful translation of pharmacogenetics into the clinic". Molecular Diagnosis & Therapy 13: 1–9. doi:10.1007/bf03256308.
  11. ↑ Phillips, E., Mallal S. (2007). "Drug hypersensitivity in HIV". Current Opinion in Allergy and Clinical Immunology 7 (4): 324–330. doi:10.1097/aci.0b013e32825ea68a. PMID 17620824.
  12. ↑ http://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm123927.htm Accessed November 29, 2013.
  13. ↑ http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=ca73b519-015a-436d-aa3c-af53492825a1
  14. ↑ Swen JJ, Nijenhuis M, de Boer A; et al. (May 2011). "Pharmacogenetics: from bench to byte--an update of guidelines". Clin Pharmacol Ther. 89 (5): 662–73. doi:10.1038/clpt.2011.34. PMID 21412232.
  15. ↑ Martin MA, Hoffman JM, Freimuth RR; et al. (May 2014). "Clinical Pharmacogenetics Implementation Consortium Guidelines for HLA-B Genotype and Abacavir Dosing: 2014 update". Clin Pharmacol Ther. 95 (5): 499–500. doi:10.1038/clpt.2014.38. PMC 3994233. PMID 24561393.
  16. ↑ Shear, N.H., Milpied, B., Bruynzeel, D.P.; et al. (2008). "A review of drug patch testing and implications for HIV clinicians". AIDS 22 (9): 999–1007. doi:10.1097/qad.0b013e3282f7cb60. PMID 18520343.
  17. ↑ http://www.drugs.com/fda/abacavir-ongoing-safety-review-possible-increased-risk-heart-attack-12914.html Accessed November 29, 2013.
  18. ↑ Ding X, Andraca-Carrera E, Cooper C; et al. (December 2012). "No association of abacavir use with myocardial infarction: findings of an FDA meta-analysis". J Acquir Immune Defic Syndr. 61 (4): 441–7. doi:10.1097/QAI.0b013e31826f993c. PMID 22932321.
  19. ↑ Illing, PT; et al. (2012). "Immune self-reactivity triggered by drug-modified HLA-peptide repertoire". Nature. doi:10.1038/nature11147.
  20. ↑ The Pharmacological Basics of Therapeutics, 12th Ed. Goodman and Gilman
  21. ↑ "Dr. Robert Vince - 2010 Inductee". Minnesota Inventors Hall of Fame. Minnesota Inventors Hall of Fame. Retrieved 10 February 2016.
  22. ↑ Vince, R. University of Minnesota. University of Minnesota http://drugdesign.umn.edu/bio/cdd-faculty-staff/robert-vince. Missing or empty |title= (help)
  23. ↑ Crimmins, M. T.; King, B. W. (1996). "An Efficient Asymmetric Approach to Carbocyclic Nucleosides: Asymmetric Synthesis of 1592U89, a Potent Inhibitor of HIV Reverse Transcriptase". The Journal of Organic Chemistry 61 (13): 4192–4193. doi:10.1021/jo960708p. PMID 11667311.

External links

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