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

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SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
GI side effects including nausea, vomiting, and
diarrhea are common, although symptoms generally
resolve within 4 weeks of starting treatment.
The speed with which HIV develops resistance to
unboosted protease inhibitors is intermediate between
that of nucleoside analogs and NNRTIs. In initial
monotherapy studies, the median time to rebound in
HIV plasma RNA concentrations of one log or greater
was 3-4 months (Flexner, 1998). In contrast to NNRTIs,
high-level resistance to these drugs generally requires
accumulation of a minimum of four to five codon substitutions,
which may take many months.
Initial (primary) resistance mutations in the enzymatic active
site confer only a 3- to 5-fold drop in sensitivity to most drugs; these
are followed by secondary mutations often distant from the active
site that compensate for the reduction in proteolytic efficiency.
Accumulation of secondary resistance mutations increases the likelihood
of cross-resistance to other PIs (Flexner, 1998; Kuritzkes,
2004). Patients failing boosted PI-based combination regimens are
more likely to have resistance mutations to the other drugs in the
regimen, especially NRTIs (Kuritzkes, 2004), suggesting a high
genetic barrier to resistance.
With potent activity and favorable resistance profiles,
these drugs are a common component of regimens
for treatment-experienced patients. However, the virologic
benefits of these drugs must be balanced against
short- and long-term toxicities, including the risk of
insulin resistance and lipodystrophy (Garg, 2004).
Improvements in pill burden, convenience, and tolerability
have greatly improved adherence to drugs in this
class (Gardner et al., 2009).
Saquinavir
Chemistry and Antiviral Activity. Saquinavir, the first
approved HIV protease inhibitor, is a peptidomimetic
hydroxyethylamine (Figure 59–6). It is a transitionstate
analog of a phenylalanine-proline cleavage site in
one of the native substrate sequences for the HIV
aspartyl protease and was the product of a rational drugdesign
program (Roberts et al., 1990). Saquinavir
inhibits both HIV-1 and HIV-2 replication and has an
in vitro IC 50
in peripheral blood lymphocytes that
ranges from 3.5 to 10 nM (Noble and Faulds, 1996).
Mechanisms of Resistance. As is typical of HIV protease
inhibitors, high-level resistance requires accumulation
of multiple resistance mutations.
The primary saquinavir resistance mutation occurs at HIV
protease codon 90 (a leucine-to-methionine substitution), although
primary resistance also has been reported with a glycine-to-valine
substitution at codon 48. Secondary resistance mutations occur at
codons 36, 46, 82, 84, and others, and these are associated with clinical
saquinavir resistance as well as cross-resistance to most other
HIV protease inhibitors (Noble and Faulds, 1996).
Absorption, Distribution, and Elimination. Fractional oral
bioavailability is low (~4%) owing mainly to extensive first-pass
metabolism (Flexner, 1998), and so this drug should always be given
in combination with ritonavir. Low doses of ritonavir increase the
saquinavir steady-state AUC by 20- to 30-fold (Flexner, 2000),
allowing administration once or twice daily.
Substances that inhibit intestinal but not hepatic CYP3A4,
such as grapefruit juice, increase the saquinavir AUC by 3-fold at
most (Flexner, 2000). Saquinavir is metabolized primarily by intestinal
and hepatic CYP3A4 (Fitzsimmons and Collins, 1997); its
metabolites are not known to be active against HIV-1. The parent
drug and its metabolites are eliminated through the biliary system
and feces (>95% of drug), with minimal urinary excretion (<3%).
Untoward Effects. The most frequent side effects of saquinavir are
GI: nausea, vomiting, diarrhea, and abdominal discomfort. Most side
effects of saquinavir are mild and short lived, although long-term
use is associated with lipodystrophy.
Precautions and Interactions. Saquinavir clearance is increased
with CYP3A4 induction; thus, co-administration of inducers of
CYP3A4 such as rifampin, phenytoin, or carbamazepine lowers
saquinavir concentrations and should be avoided (Flexner, 1998).
The effect of nevirapine or efavirenz on saquinavir may be partially
or completely reversed with ritonavir. Most drug interactions seen
with saquinavir/ritonavir reflect the effect of the boosting agent.
Therapeutic Use. Saquinavir is available as a hardgelatin
capsule (INVIRASE). In initial clinical trials,
unboosted saquinavir at the approved dose (600 mg
three times daily) produced only modest virologic benefit
because of its poor oral bioavailability. When combined
with ritonavir and nucleoside analogs, saquinavir
produces viral load reductions comparable with those
of other HIV protease inhibitor regimens (Flexner,
2000). Saquinavir is no longer widely prescribed in the
developed world because of its relatively high pill burden,
but the drug remains popular as a generic combined
with ritonavir in resource-limited settings
because of its favorable toxicity and efficacy profile.
Ritonavir
Chemistry and Antiviral Activity. Ritonavir is a peptidomimetic
HIV protease inhibitor designed to complement
the C 2
axis of symmetry of the enzyme active
site (Flexner, 1998) (Figure 59–5). Ritonavir is active
against both HIV-1 and HIV-2, although it may be
slightly less active against the latter. Its IC 50
for wildtype
HIV-1 variants in the absence of human serum
ranges from 4 to 150 nM.
Mechanisms of Resistance. Ritonavir is mostly used as
a pharmacokinetic enhancer (CYP 3A4 inhibitor), and