CLINICAL PHARMACOLOGY
Mechanism of Action: HIV-1 protease is
an enzyme required for the proteolytic cleavage of the
viral polyprotein precursors into the individual functional
proteins found in infectious HIV-1. Indinavir binds to
the protease active site and inhibits the activity of
the enzyme. This inhibition prevents cleavage of the viral
polyproteins resulting in the formation of immature non-infectious
viral particles.
Antiretroviral Activity In Vitro: The
in vitro activity of indinavir was assessed in cell
lines of lymphoblastic and monocytic origin and in peripheral
blood lymphocytes. HIV-1 variants used to infect the different
cell types include laboratory-adapted variants, primary
clinical isolates and clinical isolates resistant to nucleoside
analogue and nonnucleoside inhibitors of the HIV-1 reverse
transcriptase. The IC95 (95% inhibitory concentration)
of indinavir in these test systems was in the range of 25
to 100 nM. In drug combination studies with the nucleoside
analogues zidovudine and didanosine, indinavir showed synergistic
activity in cell culture. The relationship between in vitro
susceptibility of HIV-1 to indinavir and inhibition of HIV-1
replication in humans has not been established.
Drug Resistance: Isolates of HIV-1 with
reduced susceptibility to the drug have been recovered
from some patients treated with indinavir. Viral resistance
was correlated with the accumulation of mutations that
resulted in the expression of amino acid substitutions
in the viral protease. Eleven amino acid residue positions,
(L 1 0l/V/R, K20l/M/R, L24l, M46l/L, l54A/V, L63P, l64V,
A7 1 T/V, V82A/F/T, l84V, and L90M), at which substitutions
are associated with resistance, have been identified.
Resistance was mediated by the co-expression of multiple
and variable substitutions at these positions. No single
substitution was either necessary or sufficient for measurable
resistance (= 4-fold increase in IC95). In general, higher
levels of resistance were associated with the co-expression
of greater numbers of substitutions, although their individual
effects varied and were not additive. At least 3 amino
acid substitutions must be present for phenotypic resistance
to indinavir to reach measurable levels. In addition,
mutations in the p7/ p 1 and p 1 / p6 gag cleavage sites
were observed in some indinavir resistant HIV-1 isolates.
In vitro phenotypic susceptibilities to indinavir were
determined for 38 viral isolates from 1 3 patients who
experienced virologic rebounds during indinavir monotherapy.
Pre-treatment isolates from five patients exhibited indinavir
IC95 values of 50-1 00 nM. At or following viral RNA rebound
(after 1 2-76 weeks of therapy), IC95 values ranged from
25 to >3000 nM, and the viruses carried 2 to 1 0 mutations
in the protease gene relative to baseline.
Cross-Resistance to Other Antiviral Agents:
Varying degrees of cross-resistance have been observed
between indinavir and other HIV-protease inhibitors. In
studies with ritonavir, saquinavir, and amprenavir, the
extent and spectrum of cross-resistance varied with the
specific mutational patterns observed. In general, the
degree of cross-resistance increased with the accumulation
of resistance-associated amino acid substitutions. Within
a panel of 29 viral isolates from indinavir-treated patients
that exhibited measurable (= 4-fold) phenotypic resistance
to indinavir, all were resistant to ritonavir. Of the
indinavir resistant HIV-1 isolates, 63% showed resistance
to saquinavir and 81 % to amprenavir.
Pharmacokinetics
Absorption: Indinavir was rapidly absorbed
in the fasted state with a time to peak plasma concentration
(Tmax) of 0.8 ± 0.3 hours (mean ±
S.D.) (n=11). A greater than dose-proportional increase
in indinavir plasma concentrations was observed over the
200-1000 mg dose range. At a dosing regimen of 800 mg
every 8 hours, steady-state area under the plasma concentration
time curve (AUC) was 30,691 ± 11,407 nM•hour
(n=16), peak plasma concentration (Cmax) was
12,617 ± 4037 nM (n=16), and plasma concentration
eight hours post dose (trough) was 251 ± 178 nM
(n=16).
Effect of Food on Oral Absorption: Administration
of indinavir with a meal high in calories, fat, and protein
(784 kcal, 48.6 g fat, 31.3 g protein) resulted in a 77%
± 8% reduction in AUC and an 84% ± 7% reduction
in Cmax (n=10). Administration with lighter
meals (e.g., a meal of dry toast with jelly, apple juice,
and coffee with skim milk and sugar or a meal of corn
flakes, skim milk and sugar) resulted in little or no
change in A.C. Cmax or trough concentration.
Distribution: Indinavir was approximately
60% bound to human plasma proteins over a concentration
range of 81 nM to 16,300 nM.
Metabolism: Following a 400-mg dose of
14C-indinavir, 83 ± 1% (n=4) and 19
± 3% (n=6) of the total radioactivity was recovered
in feces and urine, respectively; radioactivity due to
parent drug in feces and urine was 19.1% and 9.4%, respectively.
Seven metabolites have been identified, one glucuronide
conjugate and six oxidative metabolites. In vitro studies
indicate that cytochrome P-450 3A4 (CYP3A4) is the major
enzyme responsible for formation of the oxidative metabolites.
Elimination: Less than 20% of indinavir
is excreted unchanged in the urine. Mean urinary excretion
of unchanged drug was 10.4 ± 4.9% (n=10) and 12.0
± 4.9% (n=10) following a single 700-mg and 1000-mg
dose, respectively. Indinavir was rapidly eliminated with
a half-life of 1.8 ± 0.4 hours (n=10). Significant
accumulation was not observed after multiple dosing at
800 mg every 8 hours.
Special Populations
Hepatic Insufficiency: Patients with mild
to moderate hepatic insufficiency and clinical evidence
of cirrhosis had evidence of decreased metabolism of indinavir
resulting in approximately 60% higher mean AUC following
a single 400-mg dose (n=12). The half-life of indinavir
increased to 2.8 ± 0.5 hours. Indinavir pharmacokinetics
have not been studied in patients with severe hepatic
insufficiency (see DOSAGE AND ADMINISTRATION, Hepatic
Insufficiency).
Renal Insufficiency: The pharmacokinetics
of indinavir have not been studied in patients with renal
insufficiency.
Gender: Pharmacokinetics of indinavir appear
to be comparable in men and women based on pharmacokinetic
studies including 32 women (15 HIV-1-positive).
Race: Pharmacokinetics of indinavir appear
to be comparable in Caucasians and Blacks based on pharmacokinetic
studies including 42 Caucasians (26 HIV-1-positive) and
16 Blacks (4 HIV-1-positive).
Drug Interactions (also see DRUG INTERACTIONS).
Specific drug interaction studies were performed with
indinavir and a number of drugs.
Drugs That Should Not Be Coadministered With CRIXIVAN
Administration of indinavir (800 mg every 8 hours) with
rifampin (600 mg once daily) for one week resulted in
an 89% ± 9% decrease in indinavir AUC.
Drugs Requiring Dose Modification Rifabutin:
The coadministration of indinavir 800 mg every 8 hours
with rifabutin either 300 mg once daily or 150 mg once
daily was evaluated in two separate clinical studies.
The results of these studies showed a decrease in indinavir
AUC (32% ± 19% and 31% ± 15%, respectively)
vs. indinavir 800 mg every 8 hours alone and an increase
in rifabutin AUC (204% ± 142% and 60% ±
47%, respectively) vs. rifabutin 300 mg once daily alone.
(See DOSAGE AND ADMINISTRATION, Concomitant
Therapy, Rifabutin.) Ketoconazole:
Administration of a 400-mg dose of ketoconazole with a
400-mg dose of indinavir resulted in a 68% ± 48%
increase in indinavir AUC (see DOSAGE AND ADMINISTRATION,
Concomitant Therapy, Ketoconazole).
The effects of administering a 400- or 800-mg dose of
ketoconazole with an 800-mg dose of indinavir are not
known.
Drugs Not Requiring Dose Modification
Nucleoside analogue antiretroviral agents: Administration
of indinavir (1000 mg every 8 hours) with zidovudine (200
mg every 8 hours) for one week resulted in a 13% ±
48% increase in indinavir AUC and a 17% ± 23% increase
in zidovudine A.C. In another study, administration of
indinavir (800 mg every 8 hours) with zidovudine (200
mg every 8 hours) in combination with lamivudine (150
mg twice daily) for one week resulted in no change in
indinavir A.C. a 36% increase in zidovudine A.C. and a
6% decrease in lamivudine A.C. Administration of indinavir
(800 mg every 8 hours) in combination with stavudine (40
mg every 12 hours) for one week resulted in no change
in indinavir AUC and a 25% ± 26% increase in stavudine
A.C.
ORTHO-NOVUM 1/35**: Administration of indinavir
(800 mg every 8 hours) with ORTHO-NOVUM 1/35 for one week
resulted in a 24% ± 17% increase in ethinyl estradiol
AUC and a 26% ± 14% increase in norethindrone A.C.
Cimetidine, Quinidine, Grapefruit Juice:
Administration of a single 400-mg dose of indinavir following
six days of cimetidine (600 mg every 12 hours) did not
affect indinavir A.C. Administration of a single 400-mg
dose of indinavir with 8 oz. of grapefruit juice resulted
in a decrease in indinavir AUC (26% ± 18%). Administration
of a single 400-mg dose of indinavir with 200 mg of guinidine
sulfate resulted in a 10% ± 26% increase in indinavir
A.C.
Trimethoprim/Sulfamethoxazole, Fluconazole, Isoniazid,
Clarithromycin: Administration of indinavir (400
mg every 6 hours) with trimethoprim/sulfamethoxazole (one
double strength tablet every 12 hours) for one week resulted
in no change in indinavir A.C. a 19% ± 31% increase
in trimethoprim AUC, and no change in sulfamethoxazole
A.C. Administration of indinavir (1000 mg every 8 hours)
with fluconazole (400 mg once daily) for one week resulted
in a 19% ± 33% decrease in indinavir AUC and no
change in fluconazole AUC. Administration of indinavir
(800 mg every 8 hours) with isoniazid (300 mg once daily)
for one week resulted in no change in indinavir AUC and
a 13% ± 15% increase in isoniazid A.C. Administration
of indinavir (800 mg every 8 hours) with clarithromycin
(500 mg every 12 hours) for one week resulted in a 29%
± 42% increase in indinavir AUC and a 53% ±
36% increase in clarithromycin A.C.
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