Medical Pharmacology Chapter 36:  Antiviral Drugs

• Antiretroviral Drugs Used in Treating HIV Infection

  • →Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (continued):

    • Abacavir (Ziagen)

      •  

        Structural Comparison Between Guanosine and Abacavir⁶

        • As noted above, abacavir (Ziagen) is an antiretroviral that is classified as a guanosine analogue.¹ 

          • Abacavir is another example of a prodrug, given that it must be phosphorylated to a triphosphate derivative for pharmacological activity.

            • The first step resulting in the monophosphorylated form as catalyzed by adenosine phosphotransferase.

            • The monophosphate is converted to (-)-carbovir 3'-monophosphate which undergoes phosphorylation to the diphosphate and ultimately triphosphate forms, catalyzed by cell kinases.¹ 

      • Mutations and Resistance to Abacavir:

        • Specific mutations in the reverse transcriptase gene can result in resistance to abacavir anti-retroviral activity.¹ 

        • There are four major mutational sites of interest.⁸

          • The first occurs at amino acid position 65 in which the normally occurring lysine is substituted by either arginine, glutamate, or asparagine.⁸

          • The second mutation occurs at amino acid 74, and involves a substitution of the normally occurring leucine by valine.

            The third mutation is located at amino acid 115 and involves a change from the wild type, normally occurring tyrosine to phenylalanine.

            Lastly, the fourth mutation occurs at site 184 involving a transition from the normally occurring methionine to valine.⁸

        • These mutations by themselves may be associated with limited abacavir resistance (2-4-fold).¹ 

          • In combination these substitutions may reduce abacavir susceptibility by up to 10 times, however.

            • Some mutations such as the leucine to valine transition at amino acid 74 result in cross-resistance development to another antiretroviral drug, didanosine.

            • Similarly, the lysine to arginine transition that amino acid 65 is associated with cross-resistance to all nucleoside antiretroviral drugs except zidovudine.¹ 

        • Another set of abacavir resistance mutations sites associated with codons 41, 210 and 215 has also been correlated with reduced pharmacological activity.¹ 

        • Antiretroviral activity of abacavir is also notably decreased by multinucleoside resistance clusters (e.g. glutamate to methionine transition at amino acid 151) along with the 2-amino acid insertion after codon 69.^1,9  

      • Pharmacokinetics:

        • Abacavir is about 80% absorbed following oral administration and the drug's absorption is unaffected by food.⁷

          • Drug half-life is about 1.5 hours. 

          • Abacavir undergoes hepatic metabolism using Phase II systems, supporting glucuronidation and carboxylation.

            • The liver microsomal P450 drug metabolizing system does not participate in abacavir metabolism and abacavir does not act as an inhibitor of CYPP450 isoforms.

          • With respect to CNS penetration, about one-third of the plasma levels are found in the cerebrospinal fluid.⁷

          • Abacavir exhibits about 50% plasma protein binding.¹

      • Adverse Effects:

        • "Pharmacogenetics of Abacavir and Cabamazepine Hypersensitivity"¹⁰

          Attribution:  Larriva M Pharmacogenetics of Abacavir and Carbamazepine Hypersensitivity. https://www.youtube.com/watch?v=UAbieuea3yA (12/2012) HIV/AIDS (CDC) YouTube Channel:  https://www.cdc.gov/hiv/basics/whatishiv.html

         

        • An important adverse effect associated with abacavir administration is a specific, possibly fatal hypersensitivity reaction.

          • Serious Abacavir Adverse Reaction¹

            Presenting symptoms of this reaction is fever, abdominal pain as well as G.I. complaints.1  Furthermore, a "mild maculopapular rash" along with malaise or fatigue may also present. Symptoms occur about 11 days following abacavir were treatment initiation in almost all cases, (93%), occur within a month and a half of beginning the back of your treatment. Should concurrent fever with abdominal pain and rash begin within six weeks present following abacavir, immediate drug discontinuation is required, since these symptoms are diagnostic for abacavir hypersensitivity syndrome.1  Continuing treatment results in a worsening of the condition. Furthermore, abacavir should never be restarted once discontinued for hypersensitivity, since a second exposure to the drug causes severe symptoms recurrence, worsened by hypotension, shock or even death.  Restarting abacavir in this circumstance represents a permanent contraindication. An estimation of mortality rate following restarting abacavir in those individual shown sensitive is about 4%.1,11 "Frequency of symptoms associated with hypersensitivity to abacavir"11 "Symptoms occurring in >10% of patients either on initial presentation or on rechallenge after temporary discontinuation are shown"11 (attribution:  figure above corresponds to Feb. 5, reference 11) Hetherington R Steel H Naderer O et al.  Hypersensitivity reactions during therapy with abacavir:  analysis of 636 cases for clinical presentation and risk factors [abstract and post 60] 7th Conference on Retroviruses and Opportunistic Infections: 2000 Jan 30- Feb. 2; San Francisco

      • Therapeutics:

        • Abacavir (Ziagen) is effective in treating HIV-1 infection especially when administered in combination with other antiretroviral drugs.¹ 

          • Initially, abacavir used as monotherapy reduced the HIV-load marker, HIV plasma RNA levels, by as much as 300 times more than that seen with other antiretroviral nucleosides.¹ 

            • At the same time abacavir administration increased CD4+ T cell lymphocyte counts by 80-200 cells/cc.

          • Abacavir is typically administered in combination with other nucleoside analogues, non-nucleoside reverse transcriptase inhibitors (nnRTIs) and protease inhibitors.¹ 

            • The addition of abacavir to zidovudine and lamivudine further decreases plasma HIV-1 RNA compared to that observed with zidovudine plus lamivudine alone.

            • Coformulated with zidovudine and lamivudine, abacavir (Trizivir) is available for twice-daily administration.

              • Even more effective than this combination appears to be another three drug combination, zidovudine, lamivudine and efavirenz or four drug combination including zidovudine, lamivudine, abacavir and efavirenz.¹  

          • The most common method of abacavir administration is as a coformulation with lamivudine (Epzicom).¹

          • Some clinical studies suggest that abacavir + lamivudine is the preferred "backbone" combination; whereas, other studies suggest this combination as an alternative nucleoside backbone.⁶

            • In comparing tenofovir + emtricitabine with abacavir + lamivudine (in combination with efavirenz or ritonavir-boosted atazanavir) noted decreased serologic responses in patients with viral loads greater than 100,000 and RNA copies/cc, if they were randomized to receive the abacavir + lamivudine combination.

            • For those individuals exhibiting a baseline viral load of <100,000 copies/cc, comparable times to virologic failure for abacavir + lamivudine or for tenofovir + emtricitabine were reported.⁶

          •  

            Abacavir (Ziagen) Formulation Example