"Entry Inhibitors (including Fusion Inhibitors) and CCR5 Co-receptor Antagonist
Entry inhibitors block HIV entry into CD4+ cells.
The only drug in this class "...
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.
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, (L10l/V/R, K20l/M/R, L24l, M46l/L, l54A/V, L63P, l64V, A71T/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/ p1 and p1/ 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 13 patients who experienced virologic rebounds during indinavir monotherapy. Pre-treatment isolates from five patients exhibited indinavir IC95 values of 50-100 nM. At or following viral RNA rebound (after 12-76 weeks of therapy), IC95 values ranged from 25 to > 3000 nM, and the viruses carried 2 to 10 mutations in the protease gene relative to baseline.
Cross-Resistance to Other Antiviral Agents
Varying degrees of HIV-1 cross-resistance have been observed between indinavir and other HIV-1 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. W ithin 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.
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 AUC, Cmax or trough concentration.
Indinavir was approximately 60% bound to human plasma proteins over a concentration range of 81 nM to 16,300 nM.
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.
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.
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).
The pharmacokinetics of indinavir have not been studied in patients with renal insufficiency.
The effect of gender on the pharmacokinetics of indinavir was evaluated in 10 HIV seropositive women who received CRIXIVAN 800 mg every 8 hours with zidovudine 200 mg every 8 hours and lamivudine 150 mg twice a day for one week. Indinavir pharmacokinetic parameters in these women were compared to those in HIV seropositive men (pooled historical control data). Differences in indinavir exposure, peak concentrations, and trough concentrations between males and females are shown in Table 1 below:
|PK Parameter||% change in PK parameter for females relative to males||90% Confidence Interval|
|AUC0-8h (nM•hr)||↓13%||(↓32%, ↑12%)|
|Cmax (nM)||↓13%||(↓32%, ↑10%)|
|C8h (nM)||↓22%||(↓47%, ↑15%)|
|↓Indicates a decrease in the PK parameter; ↑indicates an increase in the PK parameter.|
The clinical significance of these gender differences in the pharmacokinetics of indinavir is not known.
Pharmacokinetics of indinavir appear to be comparable in Caucasians and Blacks based on pharmacokinetic studies including 42 Caucasians (26 HIV-positive) and 16 Blacks (4 HIV-positive).
The optimal dosing regimen for use of indinavir in pediatric patients has not been established. In HIV-infected pediatric patients (age 4-15 years), a dosage regimen of indinavir capsules, 500 mg/m² every 8 hours, produced AUC0-8hr of 38,742 ± 24,098 nM•hour (n=34), Cmax of 17,181 ± 9809 nM (n=34), and trough concentrations of 134 ± 91 nM (n=28). The pharmacokinetic profiles of indinavir in pediatric patients were not comparable to profiles previously observed in HIV-infected adults receiving the recommended dose of 800 mg every 8 hours. The AUC and Cmax values were slightly higher and the trough concentrations were considerably lower in pediatric patients. Approximately 50% of the pediatric patients had trough values below 100 nM; whereas, approximately 10% of adult patients had trough levels below 100 nM. The relationship between specific trough values and inhibition of HIV replication has not been established.
The optimal dosing regimen for use of indinavir in pregnant patients has not been established. A CRIXIVAN dose of 800 mg every 8 hours (with zidovudine 200 mg every 8 hours and lamivudine 150 mg twice a day) has been studied in 16 HIV-infected pregnant patients at 14 to 28 weeks of gestation at enrollment (study PACTG 358). The mean indinavir plasma AUC0-8hr at weeks 30-32 of gestation (n=11) was 9231 nM•hr, which is 74% (95% CI: 50%, 86%) lower than that observed 6 weeks postpartum. Six of these 11 (55%) patients had mean indinavir plasma concentrations 8 hours post-dose (Cmin) below assay threshold of reliable quantification. The pharmacokinetics of indinavir in these 11 patients at 6 weeks postpartum were generally similar to those observed in non-pregnant patients in another study (see PRECAUTIONS, Pregnancy).
(also see CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, DRUG INTERACTIONS) Indinavir is an inhibitor of the cytochrome P450 isoform CYP3A4. Coadministration of CRIXIVAN and drugs primarily metabolized by CYP3A4 may result in increased plasma concentrations of the other drug, which could increase or prolong its therapeutic and adverse effects (see CONTRAINDICATIONS and WARNINGS). Based on in vitro data in human liver microsomes, indinavir does not inhibit CYP1A2, CYP2C9, CYP2E1 and CYP2B6. However, indinavir may be a weak inhibitor of CYP2D6.
Indinavir is metabolized by CYP3A4. Drugs that induce CYP3A4 activity would be expected to increase the clearance of indinavir, resulting in lowered plasma concentrations of indinavir. Coadministration of CRIXIVAN and other drugs that inhibit CYP3A4 may decrease the clearance of indinavir and may result in increased plasma concentrations of indinavir.
Drug interaction studies were performed with CRIXIVAN and other drugs likely to be coadministered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of coadministration of CRIXIVAN on the AUC, Cmax and Cmin are summarized in Table 2 (effect of other drugs on indinavir) and Table 3 (effect of indinavir on other drugs). For information regarding clinical recommendations, see Table 9 in PRECAUTIONS.
Table 2: Drug Interactions: Pharmacokinetic Parameters
for Indinavir in the Presence of the Coadministered Drug (See PRECAUTIONS,
Table 9 for Recommended Alterations in Dose or Regimen)
|Coadministered drug||Dose of Coadministered drug (mg)||Dose of CRIXIVAN (mg)||n||Ratio (with/without coadministered drug) of Indinavir Pharmacokinetic Parameters (90% CI); No Effect = 1.00|
|Cimetidine||600 twice daily, 6 days||400 single dose||12||1.07
|Clarithromycin||500 q12h, 7 days||800 three times daily, 7 days||10||1.08
|Delavirdine||400 three times daily||400 three times daily, 7 days||28||0.64
|No significant change||2.18
|Delavirdine||400 three times daily||600 three times daily, 7 days||28||No significant change||1.53
|Efavirenz†||600 once daily, 10 days||1000 three times daily, 10 days||20|
|After morning dose||No significant change*||0.67*
|After afternoon dose||No significant change*||0.63*
|After evening dose||0.71*
|Fluconazole†||400 once daily, 8 days||1000 three times daily, 7 days||11||0.87
|Grapefruit Juice||8 oz.||400 single dose||10||0.65
|Isoniazid||300 once daily in the morning, 8 days||800 three times daily, 7 days||11||0.95
|Itraconazole||200 twice daily, 7 days||600 three times daily, 7 days||12||0.78
|Ketoconazole||400 once daily, 7 days||600 three times daily, 7 days||12||0.69
|400 once daily, 7 days||400 three times daily, 7 days||12||0.42*
|Methadone||20-60 once daily in the morning, 8 days||800 three times daily, 8 days||10||See text below for discussion of interaction.|
|Quinidine||200 single dose||400 single dose||10||0.96
|Rifabutin||150 once daily in the morning, 10 days||800 three times daily, 10 days||14||0.80
|Rifabutin||300 once daily in the morning, 10 days||800 three times daily, 10 days||10||0.75
|Rifampin||600 once daily in the morning, 8 days||800 three times daily, 7 days||12||0.13
|Ritonavir||100 twice daily, 14 days||800 twice daily, 14 days||10, 16‡||See text below for discussion of interaction.|
|Ritonavir||200 twice daily, 14 days||800 twice daily, 14 days||9, 16‡||See text below for discussion of interaction.|
|Sildenafil||25 single dose||800 three times daily||6||See text below for discussion of interaction.|
|St. John’s wort Hypericum perforatum, standardized to 0.3 % hypericin)||300 three times daily with meals, 14 days||800 three times daily||8||Not Available||0.46 §
|T Stavudine (d4T)†||40 twice daily, 7 days||800 three times daily, 7 days||11||0.95
|Trimethoprim/ Sulfamethoxazole||800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days||400 four times daily, 7 days||12||1.12
|Zidovudine†||200 three times daily, 7 days||1000 three times daily, 7 days||12||1.06
|Zidovudine/ Lamivudine (3TC)†||200/150 three times daily, 7 days||800 three times daily, 7 days||6, 9¶||1.05
|All interaction studies
conducted in healthy, HIV-negative adult subjects, unless otherwise indicated.
* Relative to indinavir 800 mg three times daily alone.
† Study conducted in HIV-positive subjects.
‡ Comparison to historical data on 16 subjects receiving indinavir alone.
¶Parallel group design; n for indinavir + coadministered drug, n for indinavir alone.
Table 3: Drug Interactions:
Pharmacokinetic Parameters for Coadministered Drug in the Presence of Indinavir
(See PRECAUTIONS, Table 9 for Recommended Alterations in Dose or Regimen)
|Coadministered drug||Dose of Coadministered drug (mg)||Dose of CRIXIVAN (mg)||n||Ratio (with/without CRIXIVAN) of Coadministered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00|
|Clarithromycin||500 twice daily, 7 days||800 three times daily, 7 days||12||1.19
(1.58, 2.46) n=11
|Efavirenz||200 once daily, 14 days||800 three times daily, 14 days||20||No significant change||No significant change||--|
|35 mcg, 8 days||800 three times daily, 8 days||18||1.02
|Isoniazid||300 once daily in the morning, 8 days||800 three times daily, 8 days||11||1.34
|Methadone†||20-60 once daily in the morning, 8 days||800 three times daily, 8 days||12||0.93
|1 mcg, 8 days||800 three times daily, 8 days||18||1.05
|Rifabutin 150 mg once daily in the morning, 11 days + indinavir compared to 300 mg once daily in the morning, 11 days alone||150 once daily in the morning, 10 days 300 once daily in the morning, 10 days||800 three times daily, 10 days 800 three times daily, 10 days||14 10||1.29
(1.05, 1.59) 2.34
(1.33, 1.79) 2.73
(1.71, 2.31) n=13 3.44
(2.65, 4.46) n=9
|Ritonavir||100 twice daily, 14 days||800 twice daily, 14 days||10, 4‡||1.61
|200 twice daily, 14 days||800 twice daily, 14 days||9, 5‡||1.19
(2.66, 8.33) n=9, 4
|Hard gel formulation||600 single dose||800 three times daily, 2 days||6||4.7
|Soft gel formulation||800 single dose||800 three times daily, 2 days||6||6.5
(2.2, 14.1) §
|Soft gel formulation||1200 single dose||800 three times daily, 2 days||6|| 4.0
|Sildenafil||25 single dose||800 three times daily||6||See text below for discussion of interaction.|
|Stavudine¶||40 twice daily, 7 days||800 three times daily, 7 days||13||0.86
|Theophylline||250 single dose
(on Days 1 and 7)
|800 three times daily, 6 days
(Days 2 to 7)
(0.86, 1.49) n=7, 3
|Trimethoprim||800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days||400 q6h, 7 days||12||1.18
|Sulfamethoxazole||800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days||400 q6h, 7 days||12||1.01
|Vardenafil||10 single dose||800 three times daily||18||See text below for discussion of interaction.|
|Zidovudine¶||200 three times daily, 7 days||1000 three times daily, 7 days||12||0.89
(0.71, 3.20) n=4
|Zidovudine||200/150 three times daily, 7 days||800 three times daily, 7 days||6, 7‡||1.23
(0.77, 1.50) n=5, 5
|Lamivudine||200/150 three times daily, 7 days||800 three times daily, 7 days||6, 7‡||0.73
|All interaction studies
conducted in healthy, HIV-negative adult subjects, unless otherwise indicated.
* Registered trademark of Ortho Pharmaceutical Corporation.
† Study conducted in subjects on methadone maintenance.
‡ Parallel group design; n for coadministered drug + indinavir, n for coadministered drug alone.
¶Study conducted in HIV-positive subjects.
Delavirdine: Delavirdine inhibits the metabolism of indinavir such that coadministration of 400-mg or 600-mg indinavir three times daily with 400-mg delavirdine three times daily alters indinavir AUC, Cmax and Cmin (see Table 2). Indinavir had no effect on delavirdine pharmacokinetics (see DOSAGE AND ADMINISTRATION, Concomitant Therapy, Delavirdine), based on a comparison to historical delavirdine pharmacokinetic data.
Methadone: Administration of indinavir (800 mg every 8 hours) with methadone (20 mg to 60 mg daily) for one week in subjects on methadone maintenance resulted in no change in methadone AUC. Based on a comparison to historical data, there was little or no change in indinavir AUC.
Ritonavir: Compared to historical data in patients who received indinavir 800 mg every 8 hours alone, twice-daily coadministration to volunteers of indinavir 800 mg and ritonavir with food for two weeks resulted in a 2.7-fold increase of indinavir AUC24h, a 1.6-fold increase in indinavir Cmax, and an 11-fold increase in indinavir Cmin for a 100-mg ritonavir dose and a 3.6-fold increase of indinavir AUC24h, a 1.8fold increase in indinavir Cmax, and a 24-fold increase in indinavir Cmin for a 200-mg ritonavir dose. In the same study, twice-daily coadministration of indinavir (800 mg) and ritonavir (100 or 200 mg) resulted in ritonavir AUC24h increases versus the same doses of ritonavir alone (see Table 3).
Sildenafil: The results of one published study in HIV-infected men (n=6) indicated that coadministration of indinavir (800 mg every 8 hours chronically) with a single 25-mg dose of sildenafil resulted in an 11% increase in average AUC0-8hr of indinavir and a 48% increase in average indinavir peak concentration (Cmax) compared to 800 mg every 8 hours alone. Average sildenafil AUC was increased by 340% following coadministration of sildenafil and indinavir compared to historical data following administration of sildenafil alone (see CONTRAINDICATIONS, WARNINGS, Drug Interactions and PRECAUTIONS: DRUG INTERACTIONS).
Vardenafil: Indinavir (800 mg every 8 hours) coadministered with a single 10-mg dose of vardenafil resulted in a 16-fold increase in vardenafil AUC, a 7-fold increase in vardenafil Cmax, and a 2-fold increase in vardenafil half-life (see WARNINGS: Drug Interactions and PRECAUTIONS: DRUG INTERACTIONS).
Description of Studies
In all clinical studies, with the exception of ACTG 320, the AMPLICOR HIV MONITOR assay was used to determine the level of circulating HIV RNA in serum. This is an experimental use of the assay. HIV RNA results should not be directly compared to results from other trials using different HIV RNA assays or using other sample sources.
Study ACTG 320 was a multicenter, randomized, double-blind clinical endpoint trial to compare the effect of CRIXIVAN in combination with zidovudine and lamivudine with that of zidovudine plus lamivudine on the progression to an AIDS-defining illness (ADI) or death. Patients were protease inhibitor and lamivudine naive and zidovudine experienced, with CD4 cell counts of ≤ 200 cells/mm³. The study enrolled 1156 HIV-infected patients (17% female, 28% Black, 18% Hispanic, mean age 39 years). The mean baseline CD4 cell count was 87 cells/mm³. The mean baseline HIV RNA was 4.95 log10 copies/mL (89,035 copies/mL). The study was terminated after a planned interim analysis, resulting in a median follow-up of 38 weeks and a maximum follow-up of 52 weeks. Results are shown in Table 4 and Figures 1 & 2.
Table 4: ACTG 320
|Endpoint||Number (%) of Patients with IDV+ZDV+L
|AIDS-defining Illness or Death ZDV+L
|HIV Progression or Death||35 (6.1)||63 (10.9)|
|Death*||10 (1.7)||19 (3.3)|
|* The number of deaths is inadequate to assess the impact of Indinavir on survival. IDV = Indinavir, ZDV = Zidovudine, L = Lamivudine|
Study 028, a double-blind, multicenter, randomized, clinical endpoint trial conducted in Brazil, compared the effects of CRIXIVAN plus zidovudine with those of CRIXIVAN alone or zidovudine alone on the progression to an ADI or death, and on surrogate marker responses. All patients were antiretroviral naive with CD4 cell counts of 50 to 250 cells/mm³. The study enrolled 996 HIV-1 seropositive patients [28% female, 11% Black, 1% Asian/Other, median age 33 years, mean baseline CD4 cell count of 152 cells/mm³, mean serum viral RNA of 4.44 log10 copies/mL (27,824 copies/mL)]. Treatment regimens containing zidovudine were modified in a blinded manner with the optional addition of lamivudine (median time: week 40). The median length of follow-up was 56 weeks with a maximum of 97 weeks. The study was terminated after a planned interim analysis, resulting in a median follow-up of 56 weeks and a maximum follow-up of 97 weeks. Results are shown in Table 5 and Figures 3 and 4.
Table 5: Protocol 028
|Endpoint||Number (%) of Patients with AIDS-defining Illness or Death|
|HIV Progression or Death||21 (6.3)||27 (8.1)||62 (18.7)|
|Death*||8 (2.4)||5 (1.5)||11 (3.3)|
|* The number of deaths is inadequate to assess the impact of Indinavir on survival.|
Study 035 was a multicenter, randomized trial in 97 HIV-1 seropositive patients who were zidovudine experienced (median exposure 30 months), protease-inhibitor-and lamivudine-naive, with mean baseline CD4 count 175 cells/mm³ and mean baseline serum viral RNA 4.62 log10 copies/mL (41,230 copies/mL). Comparisons included CRIXIVAN plus zidovudine plus lamivudine vs. CRIXIVAN alone vs. zidovudine plus lamivudine. After at least 24 weeks of randomized, double-blind therapy, patients were switched to open-label CRIXIVAN plus lamivudine plus zidovudine. Mean changes in log10 viral RNA in serum, the proportions of patients with viral RNA below 500 copies/mL in serum, and mean changes in CD4 cell counts, during 24 weeks of randomized, double-blinded therapy are summarized in Figures 5, 6, and 7, respectively. A limited number of patients remained on randomized, double-blind treatment for longer periods; based on this extended treatment experience, it appears that a greater number of subjects randomized to CRIXIVAN plus zidovudine plus lamivudine demonstrated HIV RNA levels below 500 copies/mL during one year of therapy as compared to those in other treatment groups.
Genotypic Resistance in Clinical Studies
Study 006 (10/15/93-10/12/94) was a dose-ranging study in which patients were initially treated with CRIXIVAN at a dose of < 2.4 g/day followed by 2.4 g/day. Study 019 (6/23/94-4/10/95) was a randomized comparison of CRIXIVAN 600 mg every 6 hours, CRIXIVAN plus zidovudine, and zidovudine alone. Table 6 shows the incidence of genotypic resistance at 24 weeks in these studies.
Table 6: Genotypic
Resistance at 24 Weeks
|Treatment Group||Resistance to IDV
|Resistance to ZDV
|< 2.4 g/day||31/37 (84%)||—|
|2.4 g/day||9/21 (43%)||1/17 (6%)|
|IDV/ZDV||4/22 (18%)||1/22 (5%)|
|ZDV||1/18 (6%)||11/17 (65%)|
|*N -includes patients with non-amplifiable virus at 24 weeks who had amplifiable virus at week 0.|
Last reviewed on RxList: 8/7/2014
This monograph has been modified to include the generic and brand name in many instances.
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