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

1654 In treatment-naive patients receiving tenofovir plus emtricitabine
randomized to darunavir/ritonavir 800/100 mg once daily,
virologic outcomes after 48 weeks were comparable to those seen
with lopinavir/ritonavir 800/200 mg once daily (84% vs. 78%,
respectively, achieved plasma HIV RNA <50 copies/mL). In protease
inhibitor–experienced patients receiving an optimized background
regimen and randomized to darunavir/ritonavir 600/100 mg
twice daily, virologic outcomes after 48 weeks were better than those
seen with lopinavir/ritonavir 400/100 mg twice daily (71% vs. 60%,
respectively, achieving plasma HIV RNA <50 copies/mL) (McKeage
et al., 2009).
Darunavir/ritonavir can be used as a once-daily (800/100 mg)
or twice-daily (600/100 mg) regimen with nucleosides in treatmentnaive
adults and as a twice-daily regimen in treatment-experienced
adults, taken with food. Darunavir/ritonavir twice daily is approved for
use in pediatric patients >6 years of age, with dosing based on weight.
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
Indinavir
Chemistry and Antiviral Activity. Indinavir is a peptidomimetic
hydroxyethylene HIV protease inhibitor (Figure 59–6) whose structure
was based on a renin inhibitor with some similarity to the phenylalanine-proline
cleavage site in the HIV gag polyprotein (Plosker
and Noble, 1999), although indinavir is not itself a renin inhibitor.
Indinavir is 10-fold more potent against the HIV-1 protease than that
of HIV-2, and its 95% inhibitory concentration (IC 95
) for wild-type
HIV-1 ranges from 25 to 100 nM.
Mechanisms of Resistance. The primary indinavir resistance mutations
occur at HIV protease codons 46 (a methionine-to-isoleucine
or leucine), 82, and 84. However, secondary resistance mutations can
accumulate at codons 10, 20, 24, 46, 54, 63, 71, 82, 84, and 90, and
these are associated with clinical indinavir resistance as well as crossresistance
to other HIV protease inhibitors (Plosker and Noble, 1999).
Absorption, Distribution, and Elimination. Indinavir is absorbed
rapidly after oral administration, with peak concentrations achieved
in ~1 hour. Unlike other drugs in this class, food can adversely affect
indinavir bioavailability; a high-calorie, high-fat meal reduces plasma
concentrations by 75% (Plosker and Noble, 1999). Therefore, indinavir
must be taken with ritonavir or while fasting or with a light lowfat
meal.
Indinavir has the lowest protein binding of the HIV protease
inhibitors, with only 60% of drug bound to plasma proteins (Plosker
and Noble, 1999). As a consequence, indinavir has higher fractional
CSF penetration than other drugs in this class, although the clinical
significance of this is unknown.
The short t 1/2
of indinavir makes thrice-daily (every 8 hours)
dosing necessary unless the drug is combined with ritonavir.
Indinavir clearance is greatly reduced by low doses of ritonavir,
which also overcome the deleterious effects of food on bioavailability
(Flexner, 2000). This allows indinavir to be dosed twice daily
regardless of meals.
Untoward Effects. A unique and common adverse effect of indinavir
is crystalluria and nephrolithiasis. This stems from the poor
solubility of the drug, which is lower at pH 7.4 than at pH 3.5
(Plosker and Noble, 1999). Precipitation of indinavir and its metabolites
in urine can cause renal colic, and nephrolithiasis occurs in ~3%
of patients. Patients must drink sufficient fluids to maintain dilute
urine and prevent renal complications. Risk of nephrolithiasis is
related to higher plasma drug concentrations, which presumably produce
higher urine concentrations, regardless of whether or not the
drug is combined with ritonavir (Dieleman et al., 1999).
Like atazanavir, indinavir frequently causes unconjugated
hyperbilirubinemia, and 10% of patients develop an indirect serum
bilirubin concentration >2.5 mg/dL (Plosker and Noble, 1999). This
is generally asymptomatic and not associated with serious long-term
sequelae. As with other HIV protease inhibitors, prolonged administration
of indinavir is associated with the HIV lipodystrophy syndrome,
especially fat accumulation. Indinavir has been associated with
hyperglycemia and can induce a relative state of insulin resistance in
healthy HIV-seronegative volunteers following a single 800-mg dose
(Noor et al., 2002). Dermatologic complications have been reported,
including hair loss, dry skin, dry and cracked lips, and ingrown toenails
(Plosker and Noble, 1999).
Precautions and Interactions. Patients taking indinavir should
drink at least 2 L of water daily to prevent renal complications. This
is especially problematic for those who live in warm climates.
Because indinavir solubility decreases at higher pH, antacids or other
buffering agents should not be taken at the same time. Didanosine
formulations containing an antacid buffer should not be taken within
2 hours before or 1 hour after indinavir. Like most other HIV protease
inhibitors, indinavir is metabolized by CYP3A4 and is a moderately
potent CYP3A4 inhibitor. Indinavir should not be
co-administered with other CYP3A4 substrates that have a narrow
therapeutic index. Drugs that induce CYP3A4 may lower indinavir
concentrations and should be avoided.
Therapeutic Use. Indinavir (CRIXIVAN) is no longer widely prescribed
because of problems with nephrolithiasis and other nephrotoxicities,
and it lacks significant advantages over other available
HIV protease inhibitors. When combined with ritonavir and nucleoside
analogs, twice-daily indinavir produces viral load reductions
comparable with those of other HIV protease inhibitor regimens
(Flexner, 2000).
Nelfinavir
Chemistry and Antiviral Activity. Nelfinavir is a nonpeptidic protease
inhibitor that is active against both HIV-1 and HIV-2 (Bardsley-
Elliot and Plosker, 2000) (Figure 59–6). The mean IC 95
for HIV-1 in
various in vitro assays is 59 nM.
Mechanisms of Action and Resistance. The primary nelfinavir
resistance mutation is unique to this drug and occurs at HIV protease
codon 30 (aspartic acid-to-asparagine substitution); this mutation
results in a 7-fold decrease in susceptibility. Isolates with only
this mutation retain full sensitivity to other HIV protease inhibitors
(Bardsley-Elliot and Plosker, 2000). Less commonly, a primary
resistance mutation occurs at position 90, which can confer crossresistance.
In addition, secondary resistance mutations can accumulate
at codons 35, 36, 46, 71, 77, 88, and 90, and these are associated
with further resistance to nelfinavir, as well as cross-resistance to
other HIV protease inhibitors.
Absorption, Distribution, and Elimination. Nelfinavir absorption
is very sensitive to food effects; a moderate-fat meal increases the
AUC 2- to 3-fold, and higher concentrations are achieved with