Chemical formula: C₃₆H₄₇N₅O₄ Molecular mass: 613.79 g/mol PubChem compound: 5362440
Indinavir inhibits recombinant HIV-1 and HIV-2 protease with an approximate tenfold selectivity for HIV-1 over HIV-2 proteinase. Indinavir binds reversibly to the protease active site and inhibits competitively the enzyme, thereby preventing cleavage of the viral precursor polyproteins that occurs during maturation of the newly formed viral particle.
The resulting immature particles are non-infectious and are incapable of establishing new cycles of infection. Indinavir did not significantly inhibit the eukaryotic proteases human renin, human cathepsin D, human elastase, and human factor Xa.
Indinavir at concentrations of 50 to 100 nM mediated 95% inhibition (IC95) of viral spread (relative to an untreated virus-infected control) in human T-lymphoid cell cultures and primary human monocytes/macrophages infected with HIV1 variants LAI, MN, RF, and a macrophage-tropic variant SF-162, respectively. Indinavir at concentrations of 25 to 100 nM mediated 95% inhibition of viral spread in cultures of mitogen-activated human peripheral blood mononuclear cells infected with diverse, primary clinical isolates of HIV1, including isolates resistant to zidovudine and non- nucleoside reverse transcriptase inhibitors (NNRTIs). Synergistic antiretroviral activity was observed when human T-lymphoid cells infected with the LAI variant of HIV-1 were incubated with indinavir and either zidovudine, didanosine, or NNRTIs.
Loss of suppression of viral RNA levels occurred in some patients; however, CD4 cell counts were often sustained above pre-treatment levels. When loss of viral RNA suppression occurred, it was typically associated with replacement of circulating susceptible virus with resistant viral variants. Resistance was correlated with the accumulation of mutations in the viral genome that resulted in the expression of amino acid substitutions in the viral protease.
At least eleven amino acid sites in the protease have been associated with indinavir resistance: L10, K20, L24, M46, I54, L63, I64, A71, V82, I84, and L90. The basis for their contributions to resistance, however, is complex. None of these substitutions was either necessary or sufficient for resistance. For example, no single substitution or pair of substitutions was capable of engendering measurable (four-fold) resistance to indinavir, and the level of resistance was dependent on the ways in which multiple substitutions were combined. In general, however, higher levels of resistance resulted from the co-expression of greater numbers of substitutions at the eleven identified positions. Among patients experiencing viral RNA rebound during indinavir monotherapy at 800 mg q8h, substitutions at only three of these sites were observed in the majority of patients: V82 (to A or F), M46 (to I or L), and L10 (to I or R). Other substitutions were observed less frequently. The observed amino acid substitutions appeared to accumulate sequentially and in no consistent order, probably as a result of ongoing viral replication.
It should be noted that the decrease in suppression of viral RNA levels was seen more frequently when therapy with indinavir was initiated at doses lower than the recommended oral dose of 2.4 g/day. Therefore, therapy with indinavir should be initiated at the recommended dose to increase suppression of viral replication and therefore inhibit the emergence of resistant virus.
The concomitant use of indinavir with nucleoside analogues (to which the patient is naive) may lessen the risk of the development of resistance to both indinavir and the nucleoside analogues. In one comparative trial, combination therapy with nucleoside analogues (triple therapy with zidovudine plus didanosine) conferred protection against the selection of virus expressing at least one resistance- associated amino acid substitution to both indinavir (from 13/24 to 2/20 at therapy week 24) and to the nucleoside analogues (from 10/16 to 0/20 at therapy week 24).
HIV1 patient isolates with reduced susceptibility to indinavir expressed varying patterns and degrees of cross-resistance to a series of diverse HIV PIs, including ritonavir and saquinavir. Complete crossresistance was noted between indinavir and ritonavir; however, crossresistance to saquinavir varied among isolates. Many of the protease amino acid substitutions reported to be associated with resistance to ritonavir and saquinavir were also associated with resistance to indinavir.
Indinavir is rapidly absorbed in the fasted state with a time to peak plasma concentration of 0.8 hours ± 0.3 hours (mean ± S.D.). A greater than dose-proportional increase in indinavir plasma concentrations was observed over the 200-800 mg dose range. Between 800-mg and 1,000-mg dose levels, the deviation from dose-proportionality is less pronounced. As a result of the short half-life, 1.8 ± 0.4 hours, only a minimal increase in plasma concentrations occurred after multiple dosing. The bioavailability of a single 800-mg dose of indinavir was approximately 65% (90% CI, 58-72%).
Data from a steady state study in healthy volunteers indicate that there is a diurnal variation in the pharmacokinetics of indinavir. Following a dose regimen of 800 mg every 8 hours, measured peak plasma concentrations (Cmax) after morning, afternoon and evening doses were 15,550 nM, 8,720 nM and 8,880 nM, respectively. Corresponding plasma concentrations at 8 hours post dose were 220 nM, 210 nM and 370 nM, respectively. The relevance of these findings for ritonavir boosted indinavir is unknown. At steady state following a dose regimen of 800 mg every 8 hours, HIV-seropositive adult patients in one study achieved geometric means of: AUC0-8h of 27,813 nM*h (90% confidence interval = 22,185, 34,869), peak plasma concentrations 11,144 nM (90% confidence interval = 9,192, 13,512) and plasma concentrations at 8 hours post dose 211 nM (90% confidence interval = 163,274).
At steady state following a dose regimen of 800 mg/100 mg of indinavir/ritonavir every 12 hours with a low-fat meal, healthy volunteers in one study achieved geometric means: AUC0-12h 116,067 nM*h (90% confidence interval = 101,680, 132,490), peak plasma concentrations 19,001 nM (90% confidence interval = 17,538, 20,588), and plasma concentrations at 12 hours post dose 2,274 nM (90% confidence interval = 1,701, 3,042). No significant difference in exposure was seen when the regimen was given with a high-fat meal.
Indinavir boosted regimen. Limited data are available on the pharmacokinetics of indinavir in association with low dose ritonavir. The pharmacokinetics of indinavir (400 mg) with ritonavir (100 mg) dosed twice daily was examined in two studies. Pharmacokinetic analysis in one study was performed on nineteen of the patients, with a median (range) indinavir AUC0-12hr, Cmax, and Cmin 48 of 25,421 nM*h (21,489-36,236 nM*h), 5,758 nM (5,056-6,742 nM) and 239 (169-421 nM), respectively. The pharmacokinetic parameters in the second study were comparable.
In HIV-infected paediatric patients, a dose regimen of indinavir hard capsules, 500 mg/m² every 8 hours, produced AUC0-8hr values of 27,412 nM*h, peak plasma concentrations of 12,182 nM, and plasma concentrations at 8 hours post dose of 122 nM. The AUC and peak plasma concentrations were generally similar to those previously observed in HIV-infected adults receiving the recommended dose of 800 mg every 8 hours; it should be observed that the plasma concentrations 8 hours post dose were lower.
During pregnancy, it has been demonstrated that the systemic exposure of indinavir is relevantly decreased (PACTG 358. indinavir, 800 mg every 8 hours + zidovudine 200 mg every 8 hours and lamivudine 150 mg twice a day). The mean indinavir plasma AUC0-8hr at week 30-32 of gestation (n=11) was 9,231 nMhr, 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 postdose (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.
Administration of indinavir with a meal high in calories, fat, and protein resulted in a blunted and reduced absorption with an approximate 80% reduction in AUC and an 86% reduction in Cmax. Administration with light meals (e.g., dry toast with jam or fruit conserve, apple juice, and coffee with skimmed or fat-free milk and sugar or corn flakes, skimmed or fat-free milk and sugar) resulted in plasma concentrations comparable to the corresponding fasted values.
The pharmacokinetics of indinavir taken as indinavir sulphate salt (from opened hard capsules) mixed in apple sauce were generally comparable to the pharmacokinetics of indinavir taken as hard capsules, under fasting conditions. In HIV-infected paediatric patients, the pharmacokinetic parameters of indinavir in apple sauce were: AUC0-8hr of 26,980 nM*h; peak plasma concentration of 13,711 nM; and plasma concentration at 8 hours post dose of 146 nM.
Indinavir was not highly bound to human plasma proteins (39% unbound).
There are no data concerning the penetration of indinavir into the central nervous system in humans.
Seven major metabolites were identified and the metabolic pathways were identified as glucuronidation at the pyridine nitrogen, pyridine-N-oxidation with and without 3'-hydroxylation on the indane ring, 3'-hydroxylation of indane, p-hydroxylation of phenylmethyl moiety, and N-depyridomethylation with and without the 3'-hydroxylation. In vitro studies with human liver microsomes indicated that CYP3A4 is the only P450 isozyme that plays a major role in the oxidative metabolism of indinavir. Analysis of plasma and urine samples from subjects who received indinavir indicated that indinavir metabolites had little proteinase inhibitory activity.
Over the 200-1,000-mg dose range administered in both volunteers and HIV infected patients, there was a slightly greater than dose-proportional increase in urinary recovery of indinavir. Renal clearance (116 mL/min) of indinavir is concentration-independent over the clinical dose range. Less than 20% of indinavir is excreted renally. Mean urinary excretion of unchanged medicinal product following single dose administration in the fasted state was 10.4% following a 700 mg dose, and 12.0% following a 1,000 mg dose. Indinavir was rapidly eliminated with a half-life of 1.8 hours.
Pharmacokinetics of indinavir do not appear to be affected by race.
There are no clinically significant differences in the pharmacokinetics of indinavir in HIV seropositive women compared to HIV seropositive men.
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 400 mg dose. The mean half-life of indinavir increased to approximately 2.8 hours.
Crystals have been seen in the urine of rats, one monkey, and one dog. The crystals have not been associated with medicinal product-induced renal injury. An increase in thyroidal weight and thyroidal follicular cell hyperplasia, due to an increase in thyroxine clearance, was seen in rats treated with indinavir at doses ≥160 mg/kg/day. An increase in hepatic weight occurred in rats treated with indinavir at doses 40 mg/kg/day and was accompanied by hepatocellular hypertrophy at doses ≥320 mg/kg/day.
The maximum non-lethal oral dose of indinavir was at least 5,000 mg/kg in rats and mice, the highest dose tested in acute toxicity studies.
Studies in rats indicated that uptake into brain tissue was limited, distribution into and out of the lymphatic system was rapid, and excretion into the milk of lactating rats was extensive. Distribution of indinavir across the placental barrier was significant in rats, but limited in rabbits.
Indinavir did not have any mutagenic or genotoxic activity in studies with or without metabolic activation.
No carcinogenicity was noted in mice at the maximum tolerated dose, which corresponded to a systemic exposure approximately 2 to 3 times higher than the clinical exposure. In rats, at similar exposure levels, an increased incidence of thyroid adenomas was seen, probably related to an increase in release of thyroid stimulating hormone secondary to an increase in thyroxine clearance. The relevance of the findings to humans is likely limited.
Developmental toxicity studies were performed in rats, rabbits and dogs (at doses which produced systemic exposures comparable to or slightly greater than human exposure) and revealed no evidence of teratogenicity. No external or visceral changes were observed in rats, however, increases in the incidence of supernumerary ribs and of cervical ribs were seen. No external, visceral, or skeletal changes were observed in rabbits or dogs. In rats and rabbits, no effects on embryonic/foetal survival or foetal weights were observed. In dogs, a slight increase in resorptions was seen; however, all foetuses in medication-treated animals were viable, and the incidence of live foetuses in medication-treated animals was comparable to that in controls.
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