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

1650 the low doses used for this purpose are not known to
induce ritonavir resistance mutations.
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
The primary ritonavir resistance mutation is usually at protease
codon 82 (several possible substitutions for valine) or codon 84
(isoleucine-to-valine substitution). Additional mutations associated
with increasing resistance occur at codons 20, 32, 46, 54, 63, 71, 84,
and 90. High-level resistance requires accumulation of multiple
mutations.
Absorption, Distribution, and Elimination. Absorption of ritonavir
is rapid and is only slightly affected by food, depending on the
formulation. The overall absorption of ritonavir from the capsule formulation
increases by 13% when the capsule is taken with meals, but
the bioavailability of the oral solution decreases by 7% (Flexner,
1998). A heat-stable 100-mg tablet formulation is now available.
Interindividual variability in pharmacokinetics is high, with a variability
exceeding 6-fold in trough concentrations among patients
given 600 mg ritonavir every 12 hours as capsules (Hsu et al., 1998).
Ritonavir is metabolized primarily by CYP3A4 and to a lesser
extent by CYP2D6. Ritonavir and its metabolites are mainly eliminated
in feces (86% of parent drug and metabolites), with only 3% of
drug eliminated unchanged in the urine. Ritonavir induces its own
metabolism; steady-state concentrations are reached within 2 weeks.
Ritonavir is 98-99% bound to plasma proteins, mainly to α 1
-acid glycoprotein.
Physiological concentrations of α 1
-acid glycoprotein
increase the in vitro IC 50
by a factor of 10, whereas albumin increases
the IC 50
by a factor of 4 (Molla et al., 1998).
Untoward Effects. The major side effects of ritonavir are GI and
include dose-dependent nausea, vomiting, diarrhea, anorexia,
abdominal pain, and taste perversion. GI toxicity may be reduced if
the drug is taken with meals. Peripheral and perioral paresthesias
can occur at the therapeutic dose of 600 mg twice daily. These side
effects generally abate within a few weeks of starting therapy.
Ritonavir also causes dose-dependent elevations in serum total cholesterol
and triglycerides, as well as other signs of lipodystrophy,
and it could increase the long-term risk of atherosclerosis in some
patients.
Precautions and Interactions. Ritonavir is one of the most potent
known inhibitors of CYP3A4, markedly increasing the plasma concentrations
and prolonging the elimination of many drugs. Ritonavir
should be used with caution in combination with any CYP3A4 substrate
and should not be combined with drugs that have a narrow
therapeutic index such as midazolam, triazolam, fentanyl, and ergot
derivatives (Flexner, 1998). Ritonavir is a mixed competitive and
irreversible inhibitor of CYP 3A4 and its effects can persist for 2-3
days after the drug is discontinued (Washington et al., 2003).
Ritonavir is also a weak inhibitor of CYP2D6. Potent inducers of
CYP3A4 activity such as rifampin may lower ritonavir concentrations
and should be avoided or dosage adjustments considered. The
capsule and solution formulations of ritonavir contain alcohol and
should not be administered with disulfiram or metronidazole
(Chapter 23).
Ritonavir is also a moderate inducer of CYP3A4, glucuronosyl
S-transferase, and possibly other hepatic enzymes and
drug transport proteins. The concentrations of some drugs therefore
will be decreased in the presence of ritonavir. Ritonavir reduces the
ethinyl estradiol AUC by 40%, and alternative forms of contraception
should be used (Piscitelli and Gallicano, 2001).
Therapeutic Use. Among patients with susceptible
strains of HIV-1, ritonavir (NORVIR) as a sole agent lowered
plasma HIV-1 RNA concentrations by 100- to
1000-fold (Ho et al., 1995). In a trial in patients with
advanced HIV disease, the addition of ritonavir to current
therapy reduced HIV-related mortality and disease
progression by ~50% over a median of 6 months of follow-up
(Flexner, 1998). Ritonavir is used infrequently
as the sole protease inhibitor in combination regimens
because of GI toxicity. However, numerous clinical trials
have shown benefit of ritonavir as a pharmacokinetic
enhancer in various dual protease inhibitor
combinations (Flexner, 2000).
Use of Ritonavir as a CYP3A4 Inhibitor. Ritonavir
inhibits the metabolism of all current HIV protease
inhibitors and is frequently used in combination with
most of these drugs, with the exception of nelfinavir, to
enhance their pharmacokinetic profile and allow a
reduction in dose and dosing frequency of the coadministered
drug (Flexner, 2000). Ritonavir also overcomes
the deleterious effect of food on indinavir
bioavailability. Under most circumstances, low doses
of ritonavir (100 or 200 mg once or twice daily) are just
as effective at inhibiting CYP3A4 and are much better
tolerated than the 600 mg twice-daily treatment dose.
Fosamprenavir
Chemistry and Antiviral Activity. Fosamprenavir is a
phosphonooxy prodrug of amprenavir that has the
advantage of greatly increased water solubility and
improved oral bioavailability (Arvieux and Tribut,
2005). This allowed reduction in the pill burden from
16 capsules to 4 tablets per day. Fosamprenavir is as
effective, more convenient, and generally better tolerated
than amprenavir, and as a result, amprenavir is no
longer marketed.
Amprenavir is an N,N-disubstituted (hydroxyethyl) amino
sulfonamide nonpeptide HIV protease inhibitor. Although developed
using a sophisticated structure-based drug-design program, the same
compound was identified previously using a more traditional highthroughput
screen of an available chemical library (Werth, 1994).
Amprenavir contains a sulfonamide moiety, which may play a role
in its dermatologic side effects. The drug is active against both HIV-
1 and HIV-2, with an IC 90
for wild-type HIV-1 of ~80 nM.
Mechanisms of Resistance. Amprenavir’s primary
resistance mutation occurs at HIV protease codon 50;
this isoleucine-to-valine substitution confers only 2-fold
decreased susceptibility in vitro. Primary resistance