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

1634 accumulate in the cell, and the rate-limiting step in
activation appears to be generation of the monophosphate.
Like zidovudine, stavudine is most potent in activated
cells, probably because thymidine kinase is an
S-phase-specific enzyme (Gao et al., 1994). Stavudine and
zidovudine are antagonistic in vitro, and thymidine kinase
has a higher affinity for zidovudine than for stavudine.
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
Stavudine resistance is seen most frequently with mutations
at reverse transcriptase codons 41, 44, 67, 70, 210, 215, and 219
(Gallant et al., 2003), which are the same mutations associated
with zidovudine resistance. Clusters of resistance mutations that
include M41L, K70R, and T215Y are associated with a lower
level of in vitro resistance than seen with zidovudine but are found
in up to 38% of patients who fail to respond to stavudine. TAMs
associated with resistance to zidovudine and stavudine promote
excision of the incorporated triphosphate anabolites through
pyrophosphorolysis (Naeger et al., 2002). As with zidovudine,
resistance mutations for stavudine appear to accumulate slowly.
Cross-resistance to multiple nucleoside analogs has been reported
following prolonged therapy and has been associated with a mutation
cluster involving codons 62, 75, 77, 116, and 151. In addition,
a mutation at codon 69 (typically T69S) followed by a
2-amino acid insertion produces cross-resistance to all current
nucleoside and nucleotide analogs (Gallant et al., 2003).
Absorption, Distribution, and Elimination. Stavudine is well
absorbed and reaches peak plasma concentrations within 1 hour (Hurst
and Noble, 1999). Bioavailability is not affected by food. The drug
undergoes active tubular secretion, and renal elimination accounts for
~40% of parent drug.
Stavudine concentrations are higher in patients with low body
weight, and the dose should be decreased from 40 to 30 mg twice
daily in patients weighing <60 kg, although WHO recommends 30 mg
twice daily in all patients. Dose also should be adjusted in patients
with renal insufficiency (Jayasekara et al., 1999).
Plasma protein binding is <5%. The drug penetrates well into
the CSF, achieving concentrations that are ~40% of those in plasma.
Placental concentrations of stavudine are about half those of zidovudine,
possibly reflecting stavudine’s lower lipid solubility.
Untoward Effects. The most common serious toxicity of stavudine
is peripheral neuropathy.
Neuropathy occurred in up to 71% of patients in initial
monotherapy trials with a dose of 4 mg/kg per day. With the current
recommended dose of 40 mg twice daily, the neuropathy incidence
is ~12% (Hurst and Noble, 1999). Although this is thought to reflect
mitochondrial toxicity, stavudine is a less potent inhibitor of DNA
polymerase-γ than either didanosine or zalcitabine, suggesting that
other mechanisms may be involved. Peripheral neuropathy is more
common with higher doses or concentrations of stavudine and is
more prevalent in patients with underlying HIV-related neuropathy
or in those receiving other neurotoxic drugs. Stavudine is also associated
with a progressive motor neuropathy characterized by weakness
and in some cases respiratory failure, similar to Guillain-Barré
syndrome (HIV Neuromuscular Syndrome Study Group, 2004).
Lactic acidosis and hepatic steatosis have been associated
with stavudine use. This may be more common when stavudine and
didanosine are combined. Elevated serum lactate is more common
with stavudine than with zidovudine or abacavir (Tripuraneni et al.,
2004), but the comparative risk of hepatic steatosis is unknown.
Acute pancreatitis is not highly associated with stavudine but is more
common when stavudine is combined with didanosine than when
didanosine is given alone (Havlir et al., 2001).
Of all nucleoside analogs, stavudine use is associated most
strongly with fat wasting, or lipoatrophy (Calmy et al., 2009).
Whether this is a consequence of the extensive use of this agent combined
with its mitochondrial toxicity or reflects a pathogenetic mechanism
that has yet to be discovered remains to be determined.
Stavudine has fallen out of favor in the developed world largely
because of this toxicity. Other reported adverse effects include elevated
hepatic transaminases, headache, nausea, and rash; however,
these side effects are almost never severe enough to cause discontinuation
of the drug.
Precautions and Interactions. Stavudine is mainly renally cleared
and is not subject to metabolic drug interactions. The incidence and
severity of peripheral neuropathy may be increased when stavudine is
combined with other neuropathic medications, and therefore drugs such
as ethambutol, isoniazid, phenytoin, and vincristine should be avoided.
Combining stavudine with didanosine leads to increased risk
and severity of peripheral neuropathy and potentially fatal pancreatitis;
therefore, these two drugs should not be used together (Havlir et
al., 2001). Stavudine and zidovudine compete for intracellular phosphorylation
and should not be used concomitantly. Three clinical trials
found a significantly worse virologic outcome in patients taking
these two drugs together as compared with either agent used alone
(Havlir et al., 2000).
Therapeutic Use. Stavudine (ZERIT, others) is approved
for use in HIV-infected adults and children, including
neonates.
In early monotherapy trials, stavudine reduced plasma HIV
RNA by 70-90% and delayed disease progression compared with
continued zidovudine therapy. Lamivudine improves the long-term
virologic response to stavudine, possibly reflecting the benefits of the
M184V mutation (Kuritzkes et al., 1999). Many large prospective
clinical trials have demonstrated potent and durable suppression of
viremia and sustained increases in CD4+ cell counts when stavudine
is combined with other nucleoside analogs plus NNRTIs or protease
inhibitors (Hurst and Noble, 1999). Stavudine is no longer a popular
drug in the developed world because of toxicity. However, it continues
to be widely used in resource-poor settings because of its
availability as an inexpensive generic version, often co-formulated
with nevirapine and lamivudine.
Lamivudine
Chemistry and Antiviral Activity. Lamivudine [(–)2′,
3′-dideoxy, 3′-thiacytidine; 3TC] is a cytidine analog
reverse transcriptase inhibitor that is active against
HIV-1, HIV-2, and HBV.
The molecule has two chiral centers and is manufactured as
the pure 2R, cis(−)-enantiomer (Figure 59–2). The racemic mixture
from which lamivudine originates has antiretroviral activity but is