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PubMed2003

Effect of indinavir on the intestinal exsorption of amprenavir, saquinavir and nelfinavir after intravenous administration in rats.

To elucidate drug interaction between human immunodeficiency virus (HIV) protease inhibitors (PIs), the effect of indinavir (IDV) on the intestinal exsorption of other HIV PIs, amprenavir (APV), saquinavir (SQV) and nelfinavir (NFV) was investigated in rats using an in situ single perfusion method. IDV in the intestinal perfusate inhibited the exsorption of rhodamine 123 (Rho123), a known P-glycoprotein (P-gp) substrate, from blood into intestinal lumen in a concentration-dependent manner, and the inhibitory potency of 10 micro M IDV in the perfusate was close to that of 10 micro M cyclosporin A (CsA) in the perfusate. Ten micro M of IDV in the intestinal perfusate also decreased significantly the exsorption clearance of Rho123 after intravenous administration. The IDV concentration in this system was not likely to cause hepatic interaction between HIV PIs, because the plasma IDV concentration was far below its inhibition constants for other HIV PIs in the liver microsomes. Thus, 10 micro M of IDV was chosen to investigate the effect of this inhibition on the exsorption of APV, SQV and NFV. IDV in the intestinal perfusate markedly increased the exsorbed amounts of SQV and NFV but not APV after intravenous administrations. Their exsorption clearances, however, showed only a slight increasing tendency or remained unchanged. These findings suggest that in addition to P-gp inhibition, other factors such as CYP3A inhibition might be important in the drug interaction of IDV with APV, SQV and NFV after intravenous administration in rat small intestine. The results obtained in this study will provide useful information to discuss the interactions among PIs when a double protease therapy is used for in HIV-infected patients.

Animals↗
PubMed2000

Indinavir use: associated reversible hair loss and mood disturbance.

We present the case of a 55-year-old heterosexual man who had a generalized alopecia and mood changes associated with the antiretroviral protease inhibitor; indinavir within 6 months of use. This was reversed within 3 months of change of therapy to the protease inhibitor, nelfinavir with demonstrable changes in his Hospital Anxiety and Depression (HAD) scale scores.

Alopecia↗
PubMedDate not supplied

A clinical study of the combination of 100 mg ritonavir plus 800 mg indinavir as salvage therapy: influence of increased plasma drug levels in the rate of response.

PURPOSE: The purpose of our study was to evaluate the efficacy of indinavir (IDV) in a twice daily dosing regimen with coadministration of 100 mg ritonavir (RTV) and to explore the influence of plasma drug levels in the rate of virologic response. METHOD: We performed a prospective study of 59 patients who switched to a salvage regimen with two nucleoside analogs plus the combination of 100 mg RTV plus 800 mg IDV twice daily. Pharmacokinetics of IDV and RTV were assessed in 11 patients. RESULTS: Previous antiretroviral exposure was 44 months, and 78% and 39% of patients had previously failed regimens with either IDV or RTV. Median CD4 count was 248 x 10(6)/L and HIV load was 3.9 log(10) copies/mL. The median number of mutations in the protease gene was 9 (3-14), predominantly at residues 82 (53%), 90 (42%), and 46 (32%). After 24 weeks, 61% of patients had a viral load decrease greater than 1 log(10), and 38% had a viral load below 50 copies/mL. Nephrolitiasis, hematuria, or flank pain was observed in 13 patients (22%), leading to withdrawal in six cases (10%). IDV trough levels were well above the IC(95) (median 1.75 mg/L, interquartile range 1.07-2.57), but RTV trough levels were below the IC(95) in 88% of patients. There was a close correlation between higher peak levels of IDV, virological response, and renal toxicity. CONCLUSION: RTV/IDV 100/800 mg in a twice daily dosing regimen is associated with a significant virological response in patients with antiretroviral treatment failure. The correlation between plasma drug levels, toxicity, and response suggests the usefulness of individualized drug monitoring.

Anti-HIV Agents↗
PubMedDate not supplied

Combination therapy with indinavir, ritonavir, and delavirdine and nucleoside reverse transcriptase inhibitors in patients with HIV/AIDS who have failed multiple antiretroviral combinations.

PURPOSE: Ritonavir (RTV) and delavirdine (DLV) are inhibitors of cytochrome P450 (CYP) 3A4, the specific CYP that metabolizes indinavir (IDV). We hypothesized that patients who have failed multiple therapies containing protease inhibitors would still respond to IDV if high plasma concentrations were achieved. We retrospectively examined the antiviral efficacy of the combination of RTV, DLV, and IDV in heavily antiretroviral-experienced patients. METHOD: A chart review of patients treated with IDV/RTV/DLV and two nucleoside reverse transcriptase inhibitor (NRTI) drugs was performed. Only patients who failed at least three highly active antiretroviral therapy (HAART) regimens and remained on IDV/RTV/DLV therapy for at least 2 months were included. Plasma concentrations for IDV and RTV were obtained if patients were still on therapy. RESULTS: Ten participants were identified who qualified for this study. The median plasma HIV RNA prior to initiating IDV/RTV/DLV was 359,300 copies/mL. Nine of the 10 patients had failed nonnucleoside reverse transcriptase inhibitor (NNRTI)-containing regimens in the past. Eight out of 10 patients had at reduction in HIV RNA. Four of eight patients maintained the 1 log(10) reduction in HIV RNA past 6 months. Mean CD4 cell count increased from 142+/-99 to 273+/-126 cells/mm(3). Genotypic data available on six patients showed multiple protease gene mutations. Plasma concentration of IDV in three patients (two troughs and one 7 hours postdose) were >1,000 ng/mL. CONCLUSION: Our data suggests that in heavily antiretroviral drug-treated patients, partial antiretroviral response to RTV/IDV/DLV can still be achieved. The use of IDV/RTV/DLV and two NRTIs as salvage therapy has merit in patients who have no viable treatment options. A prospective trial utilizing this drug combination is warranted.

Adult↗
PubMed2006

Urinary NO3 excretion and renal failure in indinavir-treated patients.

Treatment with indinavir (IDV), a protease inhibitor, is frequently associated with renal abnormalities. We determined the incidence of renal failure (creatinine clearance <80 mL min-1 1.73 (m(2))-1) in HIV patients treated with highly active antiretroviral therapy, including IDV, and investigated the possible mechanisms and risk factors of IDV nephrotoxicity. Thirty-six patients receiving IDV were followed for 3 years. All were assessed for age, body weight, duration of infection, duration of IDV treatment, sulfur-derivative use, total cholesterol, triglycerides, magnesium, sodium, potassium, creatinine, and urinalysis. We also determined renal function in terms of creatinine clearance, urine osmolality and fractional excretion of sodium, potassium, and water. Urinary nitrate (NO3) excretion was measured in 18 IDV-treated patients and compared with that of 8 patients treated with efavirenz, a drug without renal side effects. Sterile leukocyturia occurred in 80.5% of the IDV-treated patients. Creatinine clearance <80 mL min-1 1.73 (m(2))-1 was observed in 22 patients (61%) and was associated with low body weight and the use of sulfur-derivatives. These patients also had lower osmolality, lower urine volume and a higher fractional excretion of water compared to the normal renal function group. Urinary NO3 excretion was significantly lower in IDV-treated patients (809 +/- 181 microM NO3-/mg creatinine) than in efavirenz-treated patients (2247 +/- 648 microM NO3-/mg creatinine, P < 0.01). The lower NO3 excretion suggests that IDV decreases nitric oxide production.

Adult↗
PubMed1999

["Buffalo hump" related to indinavir treatment].

BACKGROUND: Since 1997, new side effects like lipodystrophia have been described in HIV-1-infected patients treated with protease inhibitors. The evolution is not specified in the most reported cases. CASE REPORT: A 44-year-old man treated for HIV 1 infection developed a Buffalo hump 12 months after initiating a new treatment including indinavir-protease inhibitor (Crixivan). Ten months later, we observe neither other fat accumulation nor fat loss and significant metabolic disorders. DISCUSSION: Many publications emphasized the relationship that would exist between protease inhibitors therapy and the occurrence of lipodystrophia. Clinical features of this syndrome appear like an accumulation of fatty tissue anywhere on the trunk, or a fat loss on the limbs, the buttocks and the face. It is sometimes associated with metabolic disorders. The pathogenesis of these lipodystrophia is unclear. Larger studies have to be led to highlight the incidence of these lipodystrophia and their subsequent effects on the HIV-1 infection.

Adipose Tissue↗
PubMed2000

AVANTI 2. Randomized, double-blind trial to evaluate the efficacy and safety of zidovudine plus lamivudine versus zidovudine plus lamivudine plus indinavir in HIV-infected antiretroviral-naive patients.

OBJECTIVES: To investigate the effect of combination antiretroviral therapy on plasma HIV-1 RNA as measured by HIV RNA PCR and to assess their safety and tolerability. DESIGN: A randomized, multicentre, double-blind, placebo-controlled trial. SETTING: Multicentre study in eight European countries, Australia and Canada. PATIENTS: Antiretroviral naive patients (n = 103) with CD4 cell counts between 150 and 500 x 10(6)/l. INTERVENTION: Patients were randomly assigned to zidovudine (ZDV; 200 mg three times per day) plus lamivudine (3TC; 150 mg twice per day) or to ZDV + 3TC + indinavir (IND; 800 mg q8h) for 52 weeks. MAIN OUTCOME MEASURES: Degree and duration of reduction of plasma HIV-1 RNA as measured by RNA PCR; Development of drug-related toxicities sufficiently severe to warrant dose modification, interruption or permanent discontinuation. RESULTS: ZDV + 3TC + IND reduced plasma HIV-1 RNA (P < 0.001) and increased CD4 cell count significantly (P = 0.01) more than ZDV + 3TC. The addition of IND to ZDV + 3TC as initial therapy markedly increased the proportion of patients with plasma HIV-1 RNA values < 500 copies/ml (31/52, 60%) or 20 copies/ml (24/52, 46%) as compared with ZDV + 3TC (9/50, 18% or 2/50, 4% respectively) at week 52 in an intention-to-treat, missing = failure analysis. Assessment of time to virological rebound (> 0.5 log10 copies/ml above nadir) showed that patients who attained a minimum plasma HIV-1 RNA of < or = 20 copies/ml were less likely to rebound than those who did not reach this threshold. The addition of IND to ZDV + 3TC did not result in any significant increase in adverse experiences. CONCLUSION: ZDV + 3TC + IND resulted in a considerable improvement compared with the double combination, in reduction in plasma HIV-1 RNA, increase in CD4 cell count and proportion of patients with HIV RNA below the limit of detection. Despite an average 3 log10 decrease in plasma HIV-1 RNA on triple therapy, however, maximal suppression (< or = 20 copies/ml) was only attained in about one-half of the patients in an intent-to-treat analysis.

Adult↗
PubMedDate not supplied

Efficacy and safety of didanosine and lamivudine both once daily plus indinavir in human immunodeficiency virus-infected patients.

BACKGROUND: The combination of didanosine (DDI) and lamivudine (3TC) has been not recommended in guidelines for the first-line treatment of human immunodeficiency virus (HIV) infection because two major considerations might reduce its efficacy. First, both drugs are non-thymidine nucleosides and might exert less antiviral activity on activated T cells. Second, the codon 184 mutation emerging under 3TC failure could confer cross-resistance to DDI. However, because the intracellular half-life of their active metabolites allows administration once daily, the resulting improvement in patient compliance should favor this combination over others. PATIENTS AND METHODS: We analyzed the virologic and immunologic outcome at 6 months in 46 naive HIV-infected patients (41% were intravenous drug users) who began a treatment of a triple combination of DDI, 3TC, and indinavir (IDV) with the schedule optimized to improve adherence. Both DDI and 3TC were administered once daily (450 mg and 300 mg, respectively) and IDV was taken twice daily (1,200 mg). Patients chose schedules at their convenience, according to their job timings and preferences. All had a plasma viral load (PVL) of more than 500 HIV-RNA copies/mL at the time they entered the study, and overall the mean PVL value was 54,201 copies/mL. RESULTS: Overall, nine patients did not complete the study period: two died of non-acquired immunodeficiency syndrome (AIDS)-related causes, three described severe gastrointestinal symptoms, one discontinued therapy voluntarily, and three were lost to follow-up. Among the remaining 37 patients, a PVL value of less than 500 copies/mL was reached by 31 (83.7%) patients, and values below 40 copies/mL were recorded in 71% (22/31) of them. Overall, a clinically significant increase in the CD4 cell count (more than 60 cells/microL) was seen in 70.2% (26/37) of patients. Treatment adherence, assessed using both self-reporting and the pill count method, was considered good (more than 90% of pills prescribed were taken) in all but four patients; three of them were among those six who did not reach undetectable PVL values at the sixth month. Mutations at codons 184, 74, 65, and 151, which confer resistance to 3TC and DDI, could be examined in 12 of the 15 patients having PVL values above 40 copies/mL at the sixth month. The codon 184 mutation emerged in 25%, meanwhile the codon 74 mutation only appeared in one patient; none carried the codon 151 mutant genotype. Nine months after beginning treatment, 29 (93.5%) of the 31 patients who reached less than 500 copies/mL at the sixth month still sustained PVL values below this threshold, and 25 (80.6%) had less than 40 copies/mL. CONCLUSION: The combination of DDI and 3TC both once daily plus IDV twice daily is well tolerated, seems to favor a good adherence, and shows significant antiviral activity.

Anti-HIV Agents↗
PubMed2001

The absence of hyperbilirubinaemia is highly predictive of treatment failure in advanced HIV-infected patients treated with indinavir.

In order to determine prognostic factors associated with treatment failure (TF) in advanced HIV-infected patients treated with a regimen including indinavir, a prospective cohort study of 80 patients was set up between 1 March and 31 December 1996. TF time was calculated using the Kaplan-Meier method, from treatment induction to the first of the following events: treatment modification for adverse event or lack of significant virological and/or immunological response, AIDS-defining diagnosis or death. Date of point was 31 December 1998. Multivariate analysis was performed using a Cox model. At baseline, 60% of the patients were AIDS-free, median viral load and CD4+ count were respectively 4.8 log/ml and 79/microl. After a median follow-up of 26 months, 70% of the patients experienced a TF in a median time of 8 months. Seventy-two per cent presented an hyperbilirubinaemia (>2 mg/dl). In multivariate analysis, initial AIDS stage (hazard ratios [HR]=1.94, P=0.04) and digestive intolerance (HR=2.32, P=0.003) were predictive of TF. Conversely, hyperbilirubinaemia was associated with a better outcome (HR=0.35, P<0.0001). These 2 latter parameters very likely reflected patients' treatment compliance.

Adult↗
PubMed2001

[Indinavir-ritonavir combination: pharmacologic results and tolerance in patients infected by HIV].

OBJECTIVES: Ritonavir (RTV) is a powerful inhibitor of P450 3A4 cytochorme. When given in combination with indinavir (IDV) it increases the IDV trough concentrations (Cmin) allowing a lower IDV dosage in a twice a day regimen, independently of meals. We report tolerance data and IDV Cmin levels observed in plasma and cerebrospinal fluid (CSF) in a cohort of HIV-infected patients treated with the IDV-RTV combination at different dosages of IDV and RTV. PATIENTS AND METHODS: IDV Cmin was assayed 56 times in 40 patients (few patients had received different dosages of the IDV-RTV combination). Tolerance was recorded. RESULTS: For patients given the IDV-RTV combination at the doses of 800/100 mg b.i.d., 800/200 mg b.i.d. or 400/400 mg b.i.d., the IDV Cmin was 12 times the median IDV IC95. If the Cmin/IC95 ratio was greater than 10 with the 800/100 mg b.i.d. regimen and virological success was achieved, the IDV dosage was reduced to 400 mg b.i.d. For these patients, the 400/100 mg b.i.d. IDV-RTV regimen always gave a Cmin above the IDV IC95. Median Cmin for IDV in CSF was 146 ng/ml (range 71-881 ng/ml), above the IDV IC95. It was possible to control most of the adverse effects by reducing dosage after obtaining the IDV pharmacological levels. Definitive interruption of treatment was required in only 2 cases at mean follow-up of 7.9 months. DISCUSSION: The IDV-RTV combination should be used to improve observance of antiretroviral treatments and reduce the risk of virological failure related to low plasma levels. The IDV-RTV combination at 800/100 mg b.i.d. is a useful protocol when IDV efficacy alone is the goal. The 400/400 mg b.i.d. IDV-RTV regimen is an interesting alternative when efficacy of both inhibitors is the goal. Drug assays should be systematic to adapt individual dosages and limit the risk of adverse effects.

Drug Therapy, Combination↗
PubMed2001

Simultaneous determination of the new HIV protease inhibitor lopinavir (ABT 378) and of indinavir(1), amprenavir, saquinavir, ritonavir (ABT 538)(2) and nelfinavir(3) in human plasma by gradient HPLC.

Protease inhibitors are known by their inhibition of a viral protease that leads to production of immature and non-infectious virus particles. The novel protease inhibitor KALETRA is a co-formulation of lopinavir and ritonavir. Ritonavir reduces the metabolization of lopinavir by the cytochrome P450 3A4 isoenzyme which leads to markedly increased plasma levels of lopinavir(4). A new rapid and sensitive HPLC method for the simultaneous determination of lopinavir, indinavir, amprenavir, saquinavir, ritonavir and nelfinavir in human plasma has been developed. An aliquot of 500 microl plasma, spiked with internal standard, was extracted with 500 microl 0.1 M ammonium hydroxide solution and 5 ml tert. -butyl ether. After drying under a nitrogen stream, the residue was redissolved in an eluent consisting of 50 mM phosphate buffer, pH 5.40 and acetonitrile (50:50, v/v). Chromatographic separation was accomplished on a C-18 column using a non-linear gradient elution and ultraviolet detection at 215 nm.

Carbamates↗
PubMed2002

[A clinical trial using zidovudine and lamivudine plus indinavir triple therapy in Chinese individuals with human immunodeficiency virus infection].

OBJECTIVE: Evaluation of high active antiretroviral therapy (HAART) in human immunodeficiency virus and acquired immunodeficiency syndrome (HIV/AIDS) patients receiving combined antiretroviral therapy in China. METHODS: We initiated the first efficacy trial of zidovudine (AZT) 600 mg/d and lamivudine (3TC) 300 mg/d (brand name: Combivir) plus indinavir (2 400 mg/d) in 15 Chinese chronically infected with HIV in May 1999 at Beijing. RESULTS: There was a rapid reduction of 2.7 log in the plasma viremia levels in 15 cases 3 months, after treatment, from a mean baseline of 90 743 copies/ml. The mean CD(4) cell counts increased by 67 cells/microliter from a baseline mean value of 471 cells/microliter and the mean CD(8) cell counts reduced by 192/microliter after 12 months of therapy. The ratio of CD(4)/CD(8) increased from 0.35 to 0.56. The average naive CD(4) cell (CD(45)RA + CD(62)L +) count and naive CD(8) cell (CD(45)RA + CD(62)L +) count increased 42 and 19/microliter respectively after one-year treatment. This drug regimen was well tolerated, with mild nausea in all, transient elevated serum bilirubin in three and kidney stone in two patients. CONCLUSION: It is effective for the virus with different genotype. The results will form a scientific foundation for the development of therapeutic strategies for HIV infection in China.

Adult↗
PubMed2003

Intracellular indinavir pharmacokinetics in HIV-infected patients: comparison with plasma pharmacokinetics.

OBJECTIVE: To determine intracellular concentrations of indinavir (IDV) and investigate the relationship between plasma and intracellular IDV pharmacokinetics in HIV-infected patients. METHODS: A pharmacokinetic study of 10 patients receiving IDV plus dual nucleoside analogue therapy. Peripheral blood mononuclear cells were isolated by density gradient centrifugation and cell counts estimated. IDV was extracted from cells in the presence of 60% methanol and evaporated to dryness. Both plasma and intracellular IDV samples were assayed by high performance liquid chromatography linked to mass spectrometry. Data were subjected to non-compartmental pharmacokinetic analysis. RESULTS: The mean intracellular IDV area under the curve over 8 h (AUC0-8) was lower than the plasma AUC0-8 (7574 +/- 1003 vs 25060 +/- 4171 ng/ml/h; P<0.004). However, both the elimination half-life (t1/2) and the mean residence time (MRT) of IDV intracellularly were prolonged compared with plasma (t1/2: 2.0 +/- 0.3 vs 1.2 +/- 0.09 h; MRT: 3.6 +/- 0.6 vs 2.1 +/- 0.1 h; P<0.05). All patients were responsive to therapy at the time of the study, as assessed by HIV plasma RNA levels. Individual plasma versus intracellular time course results suggest that, due to the prolonged intracellular half-life, some patients may achieve acceptable intracellular IDV concentrations despite sub-therapeutic plasma levels. Similarly, potentially inadequate intracellular concentrations may occur despite therapeutic plasma concentrations. CONCLUSIONS: There is no significant intracellular accumulation of IDV within the lymphocytes of HIV-1-infected patients relative to plasma. However, intracellular concentrations are compatible with reported IDV-free drug concentrations in plasma. The intracellular elimination half-life and mean residence time of IDV are significantly prolonged compared with plasma. This may in part explain why certain patients maintain adequate viral suppression despite sub-therapeutic plasma IDV levels.

Adult↗
PubMed2003

Vasodilator agents protect against indinavir nephrotoxicity.

Indinavir (IDV) is a protease inhibitor widely used in AIDS treatment. A sustained elevation of creatinine was identified in IDV-treated patients. We have previously demonstrated that IDV causes renal vasoconstriction in rats. The objective of this study was to investigate the mechanism of IDV-induced vasoconstriction and the effect that the vasodilator agents L-arginine (LA), nifedipine (NF), as well as magnesium supplementation (Mg), have on IDV-induced nephrotoxicity. Male Wistar rats were kept on fast overnight and given free access to water. IDV (80 mg/kg BW) and NF (3 mg/kg BW) were given by gavage for 15 days. LA (1.5%) and MgCl2 x 6H2O (1%) were added to drinking water. Six groups were studied: Control (n=6): normal rats treated with vehicle, a 0.05 M citric acid solution; IDV (n=7): IDV-treated rats; IDV+LA (n=6): IDV- and LA-treated rats; IDV+NF (n=7): IDV- and NF-treated rats; IDV+Mg (n=7): IDV- and MgCl2-treated rats; IDV+Mg+L-NAME (n=9): IDV- and MgCl2-treated rats, supplemented with L-NAME (2.5 mg/l in drinking water). Clearance studies and evaluations of urinary nitrite (NO2) excretion were performed on day 16. No changes in blood pressure were observed. NO2 excretion decreased in IDV-treated rats. LA and NF protected against IDV effects, improving GFR (IDV+LA, 1.95 +/- 0.10; IDV+NF, 1.94 +/- 0.07 vs IDV, 1.15 +/- 0.07 ml/min, P<0.001) and RBF (IDV+LA, 7.83 +/- 0.09; IDV+NF, 7.63 +/- 0.14 vs IDV, 6.17 +/- 0.25 ml/min, P<0.001). These results suggest that IDV-induced vasoconstriction is mediated by NO and Ca2+ channels. Magnesium also ameliorated GFR and RBF in IDV-treated rats (GFR IDV+Mg, 1.77 +/- 0.08 ml/min, P<0.001; RBF IDV+Mg, 7.35 +/- 0.158 ml/min, P<0.001). Magnesium protection is not NO-mediated since it was not blocked by L-NAME. In conclusion, LA, NF and Mg protect against IDV-induced nephrotoxicity in rats. This study may have potential clinical implications for prevention of IDV-induced nephrotoxicity.

Animals↗
PubMed2004

Spectrophotometric determination of indinavir in bulk and pharmaceutical formulations using bromocresol purple and bromothymol blue.

A simple, sensitive and selective method for the determination of indinavir (IND) in bulk and in pharmaceutical formulations is described. The method is based on extraction of this drug into chloroform as ion-pair with sulphonphthalein dyes as bromocresol purple (BCP) and bromothymol blue (BTB). The optimum conditions of the reactions were studied and optimized. The absorbance of the yellow products was measured at 427 nm for IND-BCP and 420 nm for IND-BTB. The calibration graphs were linear over the range 4.0-60.2 microg x ml(-1) of drug in chloroform, using the two dyes. The composition of the ion-pairs was established by the molar ratio method. For IND the molar ratio was determined to be 1:1 by measurement of first derivative signals at 273 nm. A calibration graph was established for 3.0-70.6 microg x ml(-1) of IND for first derivative spectrophotometry. The developed method was applied successfully for the determination of IND in pharmaceutical formulations. The data obtained were compared the data given by first derivative spectrophotometry. No differences were found.

Anti-HIV Agents↗
PubMed2004

Comparison of two reduced-dose regimens of indinavir (600 mg vs 400 mg twice daily) and ritonavir (100 mg twice daily) in healthy volunteers (COREDIR).

OBJECTIVE: To assess the pharmacokinetics and tolerability of reduced dosages of twice daily indinavir (IDV) boosted by low-dose ritonavir (RTV) in healthy volunteers. METHODS: Pharmacokinetics and tolerability of IDV/RTV twice daily (600/100 mg and 400/100 mg) were assessed in a randomized crossover design in 16 healthy volunteers. Each dosage was taken twice daily for 2 weeks before 12 h pharmacokinetics were obtained. RESULTS: Sixteen subjects were included, with a mean age +/- SD of 30 +/- 4 years; seven female, nine male. Fifteen subjects completed the study. After dose reduction of IDV AUC, Cmax and Cmin decreased significantly. In the 400 mg group three out of 15 subjects had IDV levels below 0.10 mg/l vs none in the 600 mg group. All subjects reported mild to moderate side effects throughout the study period, which were more severe in the 600 mg group (mostly renal, dry skin/lips, paresthesias/oral discomfort). In the 600 mg group four subjects reported dysuria and one subject discontinued because of flank pain, whereas two subjects reported dysuria and no subject discontinued in the 400 mg group, respectively. Eight subjects developed crystalluria without a significant difference between both groups. No significant change in serum creatinine was observed. CONCLUSIONS: IDV/RTV 400/100 mg twice daily resulted in significant lower IDV exposure, with three out of 15 subjects revealing Cmin values below the recommended threshold for wild-type virus of 0.10 mg/l. Tolerability, however, was lower in the 600 mg IDV group. Therapeutic drug monitoring in the individual patient appears to be necessary to guarantee appropriate drug levels and simultaneously minimize toxicity.

Adult↗
PubMed2005

Dose reduction for the management of indinavir-related toxicity in human immunodeficiency virus type 1-infected patients in Taiwan: clinical and pharmacokinetic assessment.

This study evaluated the feasibility of reducing the indinavir (IDV) dosage in Taiwanese patients receiving the standard IDV/ritonavir (RTV) dosage of 800/100 mg twice a day who had undetectable plasma human immunodeficiency virus type 1 (HIV-1) RNA but had developed IDV-related toxicities. After dosage reduction to IDV/RTV 600/100 mg twice a day, the dose-related toxicity decreased and plasma HIV RNA remained undetectable at 24 weeks post-switch in all patients. The maximal plasma concentration (Cmax) and area under the plasma concentration-time curve of IDV decreased significantly (median, 6.3 vs 4.3 microg/mL and 1892 vs 1292 microg.min/mL, p=0.01 and 0.001, respectively) but the minimal plasma concentration remained at a similar level (median, 1.0 vs 0.8 microg/mL, p=0.12). This study found that the reduction in the dosage of IDV in HIV-1 infected patients receiving the standard IDV/RTV regimen guided by therapeutic drug monitoring decreased the Cmax, dose-related toxicity and medical cost without compromising viral control.

Acquired Immunodeficiency Syndrome↗
PubMed2005

[Consequences of replacing abacavir for indinavir in successful antiretroviral treatment of a patient with HIV infection].

INTRODUCTION: Simplification of combined antiretroviral therapy in HIV-infected patients is possible, but virological success can be compromised by the development or emergence of resistant viruses. CASE: Worsening renal functioning in a patient under successful combination antiretroviral therapy resulted led to the replacement of indinavir by abacavir. Eight weeks later, his viral load rose and he developed a mutant virus resistant to all the nucleoside analogs. DISCUSSION: Our case report illustrates the danger of streamlining combined antiretroviral therapy composed only of nucleoside analogs in patients already successfully treated with nucleoside analogs, by exposing them to the risk of the emergence of a mutant virus.

Aged↗