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

less potent and substantially more toxic than the pure (−)-enantiomer.
Compared with the (+)-enantiomer, the phosphorylated (−)-
enantiomer is more resistant to cleavage from nascent RNA/DNA
duplexes by cellular 3′-5′ exonucleases, which may contribute to its
greater potency. The IC 50
of lamivudine against laboratory strains of
HIV-1 ranges from 2 to 670 nM, although the IC 50
in primary human
peripheral blood mononuclear cells is as high as 15 μM (Perry and
Faulds, 1997).
Mechanisms of Action and Resistance. Lamivudine
enters cells by passive diffusion, is converted to the
monophosphate by deoxycytidine kinase, and undergoes
further phosphorylation by deoxycytidine monophosphate
kinase and nucleoside diphosphate kinase to yield
lamivudine 5′-triphosphate, which is the active anabolite
(Perry and Faulds, 1997) (Figure 59–3). Lamivudine is
phosphorylated more efficiently in resting cells, which
may explain its reduced potency in primary peripheral
blood mononuclear cells as compared with cell lines
(Gao et al., 1994). Lamivudine has low affinity for
human DNA polymerases, explaining its low toxicity to
the host.
High-level resistance to lamivudine occurs with single-aminoacid
substitutions, M184V or M184I. These mutations can reduce in
vitro sensitivity to lamivudine by up to 1000-fold (Perry and Faulds,
1997). The same mutations confer high-level cross-resistance to
emtricitabine and a lesser degree of resistance to abacavir (Gallant et
al., 2003). The M184V mutation restores zidovudine susceptibility in
zidovudine-resistant HIV (Larder et al., 1995) and also partially
restores tenofovir susceptibility in tenofovir-resistant HIV harboring
the K65R mutation (Wainberg et al., 1999). The same K65R mutation
confers resistance to lamivudine, emtricitabine, didanosine, stavudine,
and abacavir.
HIV-1 isolates harboring the M184V mutation have increased
transcriptional fidelity in vitro (Wainberg et al., 1996) and decreased
replication capacity (Miller et al., 1999). Variants with the M184I
mutation are even more impaired with regard to in vitro replication
(Larder et al., 1995) and usually are replaced in lamivudine-treated
patients by the M184V mutation. The reduced fitness of lamivudineresistant
viruses harboring these mutations, and their ability to prevent
or partially reverse the effect of thymidine analog mutations,
may contribute to the sustained virologic benefits of zidovudine and
lamivudine combination therapy (Eron et al., 1995).
Lamivudine is used to treat HBV infection (Chapter 58), and
some parallels in drug resistance are worth noting. High-level resistance
to lamivudine occurs with a single mutation in the HBV DNA
polymerase gene; as with HIV, this consists of a methionine-tovaline
substitution (M2041V) in the enzyme active site. Resistance
to lamivudine occurs in up to 90% of HIV/HBV co-infected patients
after 4 years of treatment. However, virologic benefits persist in
some treated patients harboring lamivudine-resistant HBV possibly
because the mutated virus has substantially reduced replicative
capacity (Leung et al., 2001).
Absorption, Distribution, and Elimination. The oral bioavailability
of lamivudine is >80% and is not affected by food. Although
lamivudine was marketed originally with a recommended dose of
150 mg twice daily based on the short plasma t 1/2
of the parent compound,
the intracellular t 1/2
of lamivudine 5′-triphosphate is 12-18
hours, and the drug is now approved for use once daily at 300 mg
(Moore et al., 1999).
Lamivudine is excreted primarily unchanged in the urine, and
dose adjustment is recommended for patients with a creatinine clearance
<50 mL/minute (Jayasekara et al., 1999). Lamivudine does not
bind significantly to plasma proteins and freely crosses the placenta
into the fetal circulation. Like zidovudine, lamivudine concentrations
are higher in the male genital tract than in the peripheral circulation,
suggesting active transport or trapping. Penetration to the
CNS appears to be moderate, with a CSF-to-plasma concentration
ratio of ≤0.15 (Perry and Faulds, 1997). The clinical significance of
the low CSF penetration is unknown.
Untoward Effects. Lamivudine is one of the least toxic antiretroviral
drugs and has few significant adverse effects.
Neutropenia, headache, and nausea have been reported at higher
than recommended doses. Pancreatitis has been reported in pediatric
patients, but this has not been confirmed in controlled trials of adults or
children. Because lamivudine also has activity against HBV and substantially
lowers plasma HBV DNA concentrations, caution is warranted
in using this drug in patients co-infected with HBV or in
HBV-endemic areas; discontinuation of lamivudine may be associated
with a rebound of HBV replication and exacerbation of hepatitis.
Precautions and Interactions. Because lamivudine and emtricitabine
have nearly identical resistance and activity patterns, there is no
rationale for their combined use. Lamivudine is synergistic with
most other nucleoside analogs in vitro (Perry and Faulds, 1997).
Therapeutic Use. Lamivudine (EPIVIR) is approved for
HIV in adults and children ≥3 months of age.
In early monotherapy studies, initial declines in plasma HIV-1
RNA concentrations of up to 90% occurred within 14 days but
rebounded rapidly with emergence of lamivudine-resistant HIV
(Perry and Faulds, 1997). Patients randomized to the combination
of lamivudine plus zidovudine had substantially better mean
decreases in plasma HIV-1 RNA at 52 weeks (97% vs. 70% decrease
in copies/mL) and increases in CD4+ lymphocyte counts (+61 versus
–53 cells/mm 3 ) compared with those receiving zidovudine alone
(Eron et al., 1995). In a large randomized double-blind trial, combining
lamivudine with zidovudine or stavudine caused ~12-fold further
decline in viral load at 24 weeks compared with zidovudine or
stavudine monotherapy (Kuritzkes et al., 1999); in the same trial,
combining lamivudine with didanosine conferred no additional benefits.
Lamivudine has been effective in combination with other antiretroviral
drugs in both treatment-naive and experienced patients
(Perry and Faulds, 1997) and is a common component of therapy,
given its safety, convenience, and efficacy.
Lamivudine (EPIVIR-HBV) also is approved for treatment of
chronic hepatitis B.
Abacavir
Chemistry and Antiviral Activity. Abacavir is a synthetic
carbocyclic purine analog (Figure 59–2).
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CHAPTER 59
ANTIRETROVIRAL AGENTS AND TREATMENT OF HIV INFECTION