Abacavir

Abacavir
Chemical structure of abacavir
Names
Pronunciation/əˈbækəvɪər/ (About this soundlisten)
Trade namesZiagen, others[1]
IUPAC name
  • {(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]cyclopent-2-en-1-yl}methanol
Clinical data
Drug classNucleoside analog reverse-transcriptase inhibitors (NRTIs)[1]
Main usesHIV/AIDS[2]
Side effectsVomiting, trouble sleeping, fever, feeling tired[1]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
    Routes of
    use
    By mouth (solution or tablets)
    Defined daily dose0.6 gram[3]
    External links
    AHFS/Drugs.comMonograph
    WHO Essential Medicines611
    MedlinePlusa699012
    Legal
    License data
    Legal status
    Pharmacokinetics
    Bioavailability83%
    MetabolismLiver
    Elimination half-life1.54 ± 0.63 h
    ExcretionKidney (1.2% abacavir, 30% 5'-carboxylic acid metabolite, 36% 5'-glucuronide metabolite, 15% unidentified minor metabolites). Fecal (16%)
    Chemical and physical data
    FormulaC14H18N6O
    Molar mass286.339 g·mol−1
    3D model (JSmol)
    Melting point165 °C (329 °F)
    SMILES
    • n3c1c(ncn1[C@H]2/C=C\[C@@H](CO)C2)c(nc3N)NC4CC4
    InChI
    • 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 checkY
    • Key:MCGSCOLBFJQGHM-SCZZXKLOSA-N checkY

    Abacavir, sold under the brand name Ziagen, is a medication used to prevent and treat HIV/AIDS.[1][4] Similar to other nucleoside analog reverse-transcriptase inhibitors (NRTIs), abacavir is used together with other HIV medications, and is not recommended by itself.[5] It is taken by mouth as a tablet or solution and may be used in children over the age of three months.[1][6]

    Abacavir is generally well tolerated.[6] Common side effects include vomiting, trouble sleeping, fever, and feeling tired.[1] More severe side effects include hypersensitivity, liver damage, and lactic acidosis.[1] 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.[6] Abacavir is in the NRTI class of medications, which work by blocking reverse transcriptase, an enzyme needed for HIV virus replication.[7] 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.[8][9] It is on the World Health Organization's List of Essential Medicines.[10] It is available as a generic medication.[1] The wholesale cost in the developing world as of 2014 is between US$0.36 and US$0.83 per day.[11] As of 2016 the wholesale cost for a typical month of medication in the United States is US$70.50.[12] Commonly, abacavir is sold together with other HIV medications, such as abacavir/lamivudine/zidovudine, abacavir/dolutegravir/lamivudine, and abacavir/lamivudine.[6][7] The combination abacavir/lamivudine is also an essential medicine.[10]

    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 and 2 infection.[2]

    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.

    Dosage

    The defined daily dose is 600 mg (by mouth).[3] The dose in people over 25 kg is 300 mg twice per day by mouth while that in children under 25 kg is 8 mg/kg.[2]

    Side effects

    Common adverse reactions include nausea, headache, fatigue, vomiting, diarrhea, loss of appetite, and trouble sleeping. Rare but serious side effects include hypersensitivity reaction such as rash, elevated AST and ALT, depression, anxiety, fever/chills, URI, lactic acidosis, hypertriglyceridemia, and lipodystrophy.[13][14]

    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, yellowing of the skin, and yellowing of the 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.[15] 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 three 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*5701.[16][17][18] 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 percent on average in populations of European ancestry, 17.6 percent in Indian Americans, 3.0 percent in Hispanic Americans, and 1.2 percent in Chinese Americans.[19][20] 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 percent on average, 0 percent in the Yoruba from Nigeria, 3.3 percent in the Luhya from Kenya, and 13.6 percent in the Masai from Kenya, although the average values are derived from highly variable frequencies within sample groups.[21]

    Common symptoms of abacavir hypersensitivity syndrome include fever, malaise, nausea, and diarrhea. Some patients may also develop a skin rash.[22] Symptoms of AHS typically manifest within six weeks of treatment using abacavir, although they may be confused with symptoms of HIV, immune reconstitution syndrome, hypersensitivity syndromes associated with other drugs, or infection.[23] The U.S. Food and Drug Administration (FDA) released an alert concerning abacavir and abacavir-containing medications on 24 July 2008,[24] 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.[25] Additionally, both the Clinical Pharmacogenetics Implementation Consortium and the Dutch Pharmacogenetics Working Group recommend use of an alternative therapy in individuals with the HLA-B*5701 allele.[26][27]

    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.[28]

    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 1 March 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.[29] A meta-analysis of 26 studies conducted by the FDA, however, did not find any association between abacavir use and heart attack [30][31]

    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.[32]

    Interaction

    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:

    • Protease inhibitors such as tipranavir or ritonovir may decrease the serum concentration of abacavir through induction of glucuronidation. Abacavir is metabolized by both alcohol dehydrogenase and glucuronidation.[33][34]
    • Ethanol may result in increased levels of abacavir through the inhibition of alcohol dehydrogenase. Abacavir is metabolized by both alcohol dehydrogenase and glucuronidation.[33][35]
    • Methadone may diminish the therapeutic effect of Abacavir. Abacavir may decrease the serum concentration of Methadone.[36][37]
    • Orlistat may decrease the serum concentration of antiretroviral drugs. The mechanism of this interaction is not fully established but it is suspected that it is due to the decreased absorption of abacavir by orlistat.[38]
    • Cabozantinib: Drugs from the MPR2 inhibitor (Multidrug resistance-associated protein 2 inhibitors) family such as abacavir could increase the serum concentration of Cabozantinib.[39]

    Mechanism of action

    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.[40]

    Pharmacokinetics

    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.[40]

    History

    Robert Vince and Susan Daluge along with Mei Hua, a visiting scientist from China, developed the medication in the '80s.[41][42][43]

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

    Synthesis

    Abacavir synthesis:[44]

    References

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