Abacavir

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Abacavir
Abacavir.svg
Abacavir ball-and-stick model.png
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, others[1]
AHFS/Drugs.com Monograph
MedlinePlus a699012
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
Routes of
administration
By mouth (solution or tablets)
Legal status
Legal status
Pharmacokinetic data
Bioavailability 83%
Metabolism Liver
Biological half-life 1.54 ± 0.63 h
Excretion Kidney (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
3D model (Jmol) Interactive image
Physical data
Melting point 165 °C (329 °F)
  (verify)

Abacavir (ABC) is a medication used to prevent and treat HIV/AIDS.[1][2] Similar to other nucleoside reverse transcriptase inhibitors (NRTIs), abacavir is used together with other HIV medications, and is not recommended by itself.[3] It is taken by mouth as a tablet or solution and may be used in children over the age of three months.[1][4]

Abacavir is generally well tolerated.[4] Common side effects include vomiting, trouble sleeping, fever, and feeling tired. More severe side effects include hypersensitivity, liver damage, and lactic acidosis. Genetic testing can indicate whether a person is at higher risk of developing hypersensitivity.[1] Symptoms of hypersensitivity include rash, vomiting, and shortness of breath.[4] Abacavir is in the NRTI class of medications, which work by blocking reverse transcriptase, an enzyme needed for HIV virus duplication.[5] Within the NRTI class, abacavir is a carbocyclic nucleoside.[1]

Abacavir was patented in 1988 and approved for use in the United States in 1998.[6][7] It is on the World Health Organization’s List of Essential Medicines, the most important medication needs in a basic health-care system.[8] It is available as a generic medication.[1] The wholesale cost in the developing world as of 2014 is between 0.36 and 0.83 USD per day.[9] As of 2015 the cost for a typical month of medication in the United States is more than 200 USD.[10] Commonly, abacavir is sold together with other HIV medications, such as abacavir/lamivudine/zidovudine, abacavir/dolutegravir/lamivudine, and abacavir/lamivudine.[4][5]

Medical uses[edit]

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[edit]

Common adverse reactions include nausea, headache, fatigue, vomiting, diarrhea, loss of appetite and trouble sleeping. Rare but serious side effects include hypersensitivity reaction or rash, elevated AST and ALT, depression, anxiety, fever/chills, URI, lactic acidosis, hypertriglyceridemia, and lipodystrophy.[11]

People with liver disease should be cautious about using abacavir because it can aggravate the condition. Signs of liver problems include nausea and vomiting, abdominal pain, dark-colored urine and yellowing of the skin or whites of the eyes. The use of nucleoside drugs such as abacavir can very rarely cause lactic acidosis. Signs of lactic acidosis include fast or irregular heartbeat, unusual muscle pain, fatigue, difficulty breathing and stomach pain with nausea and vomiting.[12] Abacavir can also lead to immune reconstitution inflammatory syndrome, a change in body fat as well as an increased risk of heart attack.

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[edit]

Hypersensitivity to abacavir is strongly associated with a specific allele at the human leukocyte antigen B locus namely HLA-B*57:01.[13][14] 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.[15][16] 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.[17]

Common symptoms of abacavir hypersensitivity syndrome include fever, malaise, nausea, and diarrhea; some patients may also develop a skin rash.[18] 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.[19] The FDA released an alert concerning abacavir and abacavir-containing medications on July 24, 2008,[20] 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.[21] 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.[22][23]

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.[24]

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 [25][26]

Immunopathogenesis[edit]

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.[27]

Interaction[edit]

Abacavir, and in general NRTIs, do not undergo hepatic metabolism and therefore have very limited (to none) interaction with the CYP enzymes and drugs that effect these enzymes. That being said there are still few interactions that can affect the absorption or the availability of abacavir. Below are few of the common established drug and food interaction that can take place during abacavir co-administration:

  • Ethanol may result in increased levels of abacavir through the inhibition of alcohol dehydrogenase. Abacavir is metabolized by both alcohol dehydrogenase and glucuronidation.[30][28]
  • Methadone may diminish the therapeutic effect of Abacavir. Abacavir may decrease the serum concentration of Methadone.[31][32]
  • Orlistat may decrease the serum concentration of Antiretroviral Agents. The mechanism of this interaction is not fully established but it is suspected that it is due to the decrease absorption of abacavirby orlistat.[33]
  • Cabozantinib: Drugs from the MPR2 inhibitor (Multidrug resistance-associated protein 2 inhibitors) family such as abacavir could increase the serum concentration of Cabozantinib.[34]

Mechanism of action[edit]

Abacavir is a nucleoside reverse transcriptase inhibitor that inhibits viral replication. It is a guanosine analogue that is phosphorylated to carbovir triphosphate (CBV-TP). CBV-TP competes with the viral molecules and is incorporated into the viral DNA. Once CBV-TP is integrated into the viral DNA , transcription and HIV reverse transcriptase is inhibited. [35]

Pharmacokinetics[edit]

Abacavir is given orally and is rapidly absorbed with a high bioavailability of 83%. Solution and tablet have comparable concentrations and bioavailability. Abacavir can be taken with or without food.

Abacavir can cross the blood-brain barrier. Abacavir is metabolized primarily through the enzymes alcohol dehydrogenase and glucuronyl transferase to an inactive carboxylate and glucuronide metabolites. It has a half life of approximately 1.5-2.0 hours. If a person has liver failure, abacavir’s half life is increased by 58%.

Abacavir is eliminated via excretion in the urine (83%) and feces (16%). It is unclear whether abacavir can be removed by hemodialysis or peritoneal dialysis. [35]

History[edit]

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 and Susan Daluge in the '80s along with a visiting scientist from China, Mei Hua, developed the medication.[36][37][38]

Synthesis[edit]

Abacavir synthesis:[39]

References[edit]

  1. ^ a b c d e f "Abacavir Sulfate". The American Society of Health-System Pharmacists. Retrieved 31 July 2015. 
  2. ^ "Drug Name Abbreviations Adult and Adolescent ARV Guidelines". AIDSinfo. Retrieved 2016-11-08. 
  3. ^ "What Not to Use Adult and Adolescent ARV Guidelines". AIDSinfo. Retrieved 2016-11-08. 
  4. ^ a b c d Yuen, GJ; Weller, S; Pakes, GE (2008). "A review of the pharmacokinetics of abacavir.". Clinical pharmacokinetics. 47 (6): 351–71. doi:10.2165/00003088-200847060-00001. PMID 18479171. 
  5. ^ a b "Nucleoside reverse transcriptase inhibitors (NRTIs or 'nukes') - HIV/AIDS". www.hiv.va.gov. Retrieved 2016-11-08. 
  6. ^ Fischer, Janos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 505. ISBN 9783527607495. 
  7. ^ Kane, Brigid M. (2008). HIV/AIDS Treatment Drugs. Infobase Publishing. p. 56. ISBN 9781438102078. 
  8. ^ "WHO Model Lists of Essential Medicines". World Health Organization. Retrieved 2016-11-08. 
  9. ^ "International Drug Price Indicator Guide". ERC. Retrieved 20 November 2016. 
  10. ^ Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 64. ISBN 9781284057560. 
  11. ^ https://online.epocrates.com/noFrame/showPage.do?method=drugs&MonographId=2043&ActiveSectionId=5
  12. ^ "Abacavir | Dosage, Side Effects | AIDSinfo". AIDSinfo. Retrieved 2016-11-08. 
  13. ^ 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. 
  14. ^ 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. 
  15. ^ 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. 
  16. ^ 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. 
  17. ^ 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. 
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  20. ^ http://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm123927.htm Accessed November 29, 2013.
  21. ^ http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=ca73b519-015a-436d-aa3c-af53492825a1
  22. ^ 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. 
  23. ^ 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 3994233Freely accessible. PMID 24561393. 
  24. ^ 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. 
  25. ^ http://www.drugs.com/fda/abacavir-ongoing-safety-review-possible-increased-risk-heart-attack-12914.html Accessed November 29, 2013.
  26. ^ 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. 
  27. ^ Illing, PT; et al. (2012). "Immune self-reactivity triggered by drug-modified HLA-peptide repertoire". Nature. doi:10.1038/nature11147. 
  28. ^ a b Prescribing information. Ziagen (abacavir). Research Triangle Park, NC: GlaxoSmithKline, July 2002
  29. ^ Vourvahis M,Kashuba AD, “Mechanisms of Pharmacokinetic and Pharmacodynamic Drug Interactions Associated with Ritonavir-Enhanced Tipranavir,”Pharmacotherapy, 2007, 27:888-909. [PubMed 17542771]
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  31. ^ Berenguer J, Perez-Elias MJ, Bellon JM, et al. Effectiveness and safety of abacavir, lamivudine, and zidovudine in antiretroviral therapy-naive HIV-infected patients: results from a large multicenter observational cohort.J Acquir Immune Defic Syndr. 2006;41(2):154-159. [PubMed 16394846]
  32. ^ Dolophine(methadone) [prescribing information]. Columbus, OH: Roxane Laboratories, Inc.; March 2015.
  33. ^ Gervasoni C, Cattaneo D, Di Cristo V, et al. Orlistat: weight lost at cost of HIV rebound.J Antimicrob Chemother. 2016;71(6):1739-1741. [PubMed 26945709]
  34. ^ Cometriq (cabozantinib) [prescribing information]. South San Francisco, CA: Exelixis, Inc.; May 2016.
  35. ^ a b Product Information: ZIAGEN(R) oral tablets, oral solution, abacavir sulfate oral tablets, oral solution. ViiV Healthcare (per Manufacturer), Research Triangle Park, NC, 2015.
  36. ^ "Dr. Robert Vince - 2010 Inductee". Minnesota Inventors Hall of Fame. Minnesota Inventors Hall of Fame. Retrieved 10 February 2016. 
  37. ^ Vince, R. University of Minnesota. University of Minnesota http://drugdesign.umn.edu/bio/cdd-faculty-staff/robert-vince.  Missing or empty |title= (help)
  38. ^ Daluge SM, Good SS, Faletto MB, Miller WH, St Clair MH, Boone LR, Tisdale M, Parry NR, Reardon JE, Dornsife RE, Averett DR (May 1997). "1592U89, a novel carbocyclic nucleoside analog with potent, selective anti-human immunodeficiency virus activity". Antimicrobial agents and chemotherapy. 41 (5): 1082–1093. PMC 163855Freely accessible. PMID 9145874. 
  39. ^ 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[edit]

Cetegory:RTT