DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1636 Carbovir, a related guanine analog, was withdrawn from clinical
development owing to poor oral bioavailability (Hervey and
Perry, 2000). The IC 50
of abacavir for primary clinical HIV-1 isolates
is 0.26 μM, and its IC 50
for laboratory strains ranges from 0.07
to 5.8 μM.
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
Mechanisms of Action and Resistance. Abacavir is the
only approved antiretroviral that is active as a guanosine
analog. It is initially monophosphorylated by
adenosine phosphotransferase. The monophosphate is
then converted to (−)-carbovir 3′-monophosphate,
which is then phosphorylated to the di- and triphosphates
by cellular kinases (Figure 59–3). Carbovir
5′-triphosphate terminates the elongation of proviral
DNA because it is incorporated by reverse transcriptase
into nascent DNA but lacks a 3′-hydroxyl group.
Clinical resistance to abacavir is associated with four specific
codon substitutions: K65R, L74V, Y115F, and M184V (Gallant et al.,
2003). Individually, these substitutions produce only modest (2- to
4-fold) resistance to abacavir, but in combination can reduce susceptibility
by up to 10-fold. The Y115F mutation is seen uniquely with
abacavir and causes low-level resistance. The L74V mutation is associated
with cross-resistance to the purine analog didanosine. K65R
confers cross-resistance to all nucleosides except zidovudine. An
alternate pathway for abacavir resistance involves mutations at
codons 41, 210, and 215, which have been associated with a
reduced likelihood of virologic response. Abacavir sensitivity is
greatly reduced by the multinucleoside resistance clusters, including
that associated with the Q151M, as well as the 2-amino acid
insertion following codon 69 (Gallant et al., 2003).
Absorption, Distribution, and Elimination. Abacavir’s oral
bioavailability is >80% regardless of food intake (Table 59–2).
Abacavir is eliminated by metabolism to the 5′-carboxylic acid
derivative catalyzed by alcohol dehydrogenase, and by glucuronidation
to the 5′-glucuronide (Figure 59–3). These metabolites account
for 30% and 36% of elimination, respectively (Hervey and Perry,
2000). Abacavir is not a substrate or inhibitor of CYPs. Abacavir is
50% bound to plasma proteins, and the CSF/plasma AUC ratio is
~0.3. Although the introduced dose of abacavir was 300 mg twice
daily, carbovir triphosphate accumulates inside the cell and has a
reported elimination t 1/2
of up to 21 hours (Hervey and Perry, 2000);
thus a regimen of 600 mg once daily is approved now.
Untoward Effects. The most important adverse effect of abacavir is
a unique and potentially fatal hypersensitivity syndrome. This syndrome
is characterized by fever, abdominal pain, and other gastrointestinal
(GI) complaints; a mild maculopapular rash; and malaise or
fatigue. Respiratory complaints (cough, pharyngitis, dyspnea), musculoskeletal
complaints, headache, and paresthesias are reported less
commonly. Median time to onset of symptoms is 11 days, and 93% of
cases occur within 6 weeks of initiating therapy (Hetherington et al.,
2002). The presence of concurrent fever, abdominal pain, and rash
within 6 weeks of starting abacavir is diagnostic and necessitates
immediate discontinuation of the drug. Patients having only one of
these symptoms may be observed to see if additional symptoms
appear. Unlike many hypersensitivity syndromes, this condition
worsens with continued treatment. Abacavir can never be restarted
once discontinued for hypersensitivity because reintroduction of the
drug leads to rapid recurrence of severe symptoms, accompanied by
hypotension, a shocklike state, and possibly death. The reported mortality
rate of restarting abacavir in sensitive individuals is 4% (Hervey
and Perry, 2000).
Abacavir hypersensitivity occurs in 2-9% of patients depending
on the population studied. The cause is a genetically mediated
immune response linked to both the HLA-B*5701 locus and the
M493T allele in the heat-shock locus Hsp70-Hom (Mallal et al.,
2008). The latter gene is implicated in antigen presentation, and this
haplotype is associated with aberrant tumor necrosis factor-α
release after exposure of human lymphocytes to abacavir ex vivo.
This is one of the strongest pharmacogenetic associations ever
described. In one white population, the combination of these two
markers occurred in 94.4% of cases and <0.5% of controls for a
positive predictive value of 93.8% and a negative predictive value
of 99.5% (Mallal et al., 2008). Abacavir should not be given to those
with the HLA-B*5701 genotype; in all others, the risk of true
hypersensitivity is essentially zero (Mallal et al., 2008). Aside
from hypersensitivity, abacavir is a well-tolerated drug. Carbovir
5′-triphosphate is a weak inhibitor of human DNA polymerases,
including DNA polymerase-γ (Hervey and Perry, 2000). Abacavir
therefore has not been associated with adverse events thought to be
due to mitochondrial toxicity. Epidemiological associations link
abacavir use and increased risk of myocardial infarction (D:A:D
Study Group et al., 2008).
Precautions and Interactions. Abacavir is not associated with any
clinically significant pharmacokinetic drug interactions. However,
a large dose of ethanol (0.7 g/kg) increased the abacavir plasma
AUC by 41% and prolonged the elimination t 1/2
by 26%
(McDowell et al., 2000) possibly owing to competition for alcohol
dehydrogenase.
Therapeutic Use. Abacavir (ZIAGEN) is approved for the
treatment of HIV-1 infection, in combination with other
antiretroviral agents. In initial monotherapy studies,
abacavir reduced HIV plasma RNA concentrations up
to 300 times more than that seen with other antiretroviral
nucleosides, and it increased CD4+ lymphocyte
counts by 80-200 cells/mm 3 (Hervey and Perry, 2000).
Abacavir is not a more potent inhibitor of HIV replication
than other nucleosides in vitro, and the mechanism
for its more potent in vivo monotherapy activity is
unexplained.
Abacavir is effective in combination with other nucleoside
analogs, NNRTIs, and protease inhibitors. Adding abacavir to
zidovudine and lamivudine resulted in a substantially greater
decrease in plasma HIV-l RNA than seen with the two-drug regimen
of zidovudine plus lamivudine in adults or children (Hervey and
Perry, 2000). Abacavir is available in a co-formulation with zidovudine
and lamivudine (TRIZIVIR) for twice-daily dosing. However, the
combination of abacavir, zidovudine, and lamivudine was less effective
in a randomized, double-blind, placebo-controlled trial in treatment-naive
patients than was the combination of zidovudine,
lamivudine, and efavirenz or the four-drug regimen of zidovudine,