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PubMed1998

Indinavir-associated lipodystrophy.

BACKGROUND: Lipodystrophies are rare cutaneous disorders characterized by the symmetrical loss of subcutaneous fat from the body surface. The cause of lipodystrophy is not known, but a possible genetic predisposition is likely and either overt diabetes mellitus or insulin resistance are often associated. DESIGN AND METHODS: Case study. PATIENTS: Eight patients who developed either partial or generalized lipodystrophy after protease inhibitor therapy. RESULTS: In all eight patients lipodystrophy occurred after 2-12 months of starting indinavir and was not preceded by weight loss or inflammatory skin disease. Short-term follow-up after withdrawal of therapy showed no change in the patients' appearance. One patient developed glycosuria as lipodystrophy became manifest. In three cases glucose tolerance test was performed revealing a high level of insulin between the first and third hour of loading. CONCLUSIONS: In our view, lipodystrophy is an unwanted side-effect of protease inhibitor therapy causing noticeable disfigurement.

Adult↗
PubMed1999

Clinical cross-resistance between the HIV-1 protease inhibitors saquinavir and indinavir and correlations with genotypic mutations.

OBJECTIVES: To determine the clinical efficacy of the HIV-1 protease inhibitor indinavir (IDV) in saquinavir (SQV)-experienced patients and delineate the developing drug-resistance patterns. DESIGN: Open-label prospective clinical trial. SETTING: University hospital research center. PATIENTS: Ten patients who had completed a SQV monotherapy study in which they had received SQV at a dose of 3600 or 7200 mg daily (two and fourfold the standard dose). INTERVENTIONS: At enrollment patients received IDV for 4 weeks as monotherapy, after which zidovudine (ZDV) and lamivudine (3TC) were added to their drug regimen. Patients then received combination therapy (IDV-ZDV-3TC) for an additional 20 weeks to complete a total of 24 weeks of therapy. MAIN OUTCOME MEASURES: Plasma HIV RNA viral load and CD4+ T-cell counts were monitored. Sequencing of the HIV protease gene was performed to determine the development of resistance mutations. Plasma samples for sequencing were taken before initial SQV therapy, after SQV therapy before starting IDV, and after 24 weeks of IDV therapy. RESULTS: The average duration of high-dose SQV before starting IDV was 58+/-29.2 weeks. A 0.58 log10 RNA copies/ml increase was noted during the 3-week washout phase followed by a mean reduction in plasma HIV RNA viral load of 1.2 log10 RNA copies/ml after 4 weeks of IDV. After the addition of ZDV and 3TC at week 4, HIV RNA continued to fall reaching a mean reduction of 1.96 log10 RNA copies/ml at week 24. Plasma HIV RNA was below 400 RNA copies/ml in six out of nine patients at week 24. CD4+ T-cell counts showed a gradual rise from 328 x 10(6)/l to 453 x 10(6)/l by week 24. SQV therapy had resulted in multiple mutations in the protease gene. Six of the patients had developed five or more mutations: L90M in two, G48V in four (of which three also contained L101), and V82A in three. Patients in whom plasma HIV RNA was not durably suppressed by subsequent IDV combination therapy developed multiple (up to four) additional mutations within 24 weeks, including codons 54, 82 and 93 amongst others. No clear correlation was found between the mutations that had developed in individual patients after SQV and the subsequent efficacy of IDV. CONCLUSION: Prolonged use of SQV at potent doses in the presence of elevated viral load levels resulted in the development of multiple resistance mutations. Individual resistance patterns varied greatly between patients, as did their virological response to therapy. Resistance assays may be useful in identifying which patients will benefit from salvage therapy with a second protease inhibitor.

CD4 Lymphocyte Count↗
PubMed2000

Enhanced penetration of indinavir in cerebrospinal fluid and semen after the addition of low-dose ritonavir.

OBJECTIVE: Penetration of antiretroviral drugs into anatomical HIV-1 reservoirs such as the male genital tract and the central nervous system is important. Data on indinavir (IDV) concentrations in seminal plasma are lacking and IDV concentrations in cerebrospinal fluid are at best borderline. DESIGN: Thirteen patients were treated with zidovudine (or stavudine), lamivudine, abacavir, nevirapine and IDV (1000 mg three times daily). When nevirapine led to low IDV concentrations, IDV was changed into the combination IDV/ritonavir (RTV) 800/100 mg twice daily to improve the pharmacokinetic profile of IDV. METHODS: A serum pharmacokinetic profile, a semen sample and a cerebrospinal fluid sample were collected at weeks 8, 24, 48 and 72. RESULTS: Addition of RTV increased the median IDV trough concentration in serum from 65 to 336 ng/ml (P = 0.005). Median IDV concentration in seminal plasma increased from 141 to 1634 ng/ml (P = 0.002) (n = 9) and in cerebrospinal fluid from 39 (n = 12) to 104 (n = 7) ng/ml (P < 0.001). In six patients with samples collected both before and after the addition of RTV, the IDV concentration in seminal plasma increased 8.2 times [95% confidence interval (CI) 5.2-11.6], and in cerebrospinal fluid 2.4 times (95% CI 1.8-3.9). CONCLUSIONS: IDV penetrates well into the male genital tract. The addition of low-dose RTV not only increases IDV concentrations in serum but also in seminal plasma and cerebrospinal fluid, thereby probably improving the potency of the regimen in these anatomical HIV reservoirs. Higher serum trough levels alone can not sufficiently explain the observed increases in seminal plasma and cerebrospinal fluid concentrations. Inhibition of P-glycoprotein-mediated transport by RTV might be an additional mechanism.

Adult↗
PubMed2000

Continued lamivudine versus delavirdine in combination with indinavir and zidovudine or stavudine in lamivudine-experienced patients: results of Adult AIDS Clinical Trials Group protocol 370.

OBJECTIVE: To compare the virologic activity of continued lamivudine (3TC) versus a switch to delavirdine (DLV) when initiating protease inhibitor therapy in nucleoside-experienced patients. DESIGN: Randomized, open-label, multi-center study. SETTING: Adult AIDS clinical trials units. PATIENTS: Protease and non-nucleoside reverse transcriptase inhibitor-naive patients who had received 3TC plus zidovudine (ZDV), stavudine (d4T), or didanosine (ddl) for at least 24 weeks. INTERVENTIONS: Patients with plasma HIV-1 RNA levels > 500 copies/ml who previously received d4T + 3TC or ddI + 3TC were randomized to ZDV + 3TC + indinavir (IDV) or ZDV + DLV + IDV. MAIN OUTCOME MEASURES: Primary endpoints were the proportion of patients with plasma HIV-1 RNA levels < or = 200 copies/ml at 24 weeks, and occurrence of serious adverse events. The proportion of patients with plasma HIV-1 RNA levels < or = 200 copies/ml at week 48 was a secondary endpoint. RESULTS: At week 24, 58% of subjects in the ZDV + 3TC + IDV arm and 73% in the ZDV + DLV + IDV arm had plasma HIV-1 RNA levels < or = 200 copies/ml (P = 0.29). At week 48, plasma HIV-1 RNA levels were < or = 200 copies/ml in 48% and 83%, respectively (P = 0.007). Rash and hyperbilirubinemia occurred more frequently in the DLV arm than in the 3TC arm. Steady-state plasma IDV levels were higher among patients in the DLV arm as compared with the 3TC arm. CONCLUSIONS: Substituting DLV for 3TC when adding IDV improved virologic outcome in nucleoside-experienced patients. This result might be explained, in part, by the positive effect of DLV on IDV pharmacokinetics.

Acquired Immunodeficiency Syndrome↗
PubMed2000

A comparison of stavudine plus lamivudine versus zidovudine plus lamivudine in combination with indinavir in antiretroviral naive individuals with HIV infection: selection of thymidine analog regimen therapy (START I).

BACKGROUND: No clinical trial results directly comparing two nucleoside analog pairs in a drug regimen for HIV that includes a protease inhibitor are available. OBJECTIVE: To compare the safety and efficacy of stavudine (d4T) + lamivudine (3TC) with zidovudine (ZDV) + 3TC, each in combination with indinavir (IDV). DESIGN: Randomized, open-label, multi-center. SETTING: Fifteen HIV clinical research centers. PATIENTS: Two-hundred and four antiretroviral-naive HIV-1-infected-patients with CD4 cell counts > or = 200 x 10(6)/l and HIV-1 RNA > or = 10,000 copies/ml (bDNA assay), modified to 5000 copies/ml. INTERVENTION: d4T 40 mg twice a day, 3TC 150 mg twice a day plus IDV 800 mg every 8 h compared with ZDV 200 mg every 8 h (modified to 300 mg every 12 h) plus 3TC and IDV. MEASUREMENTS: Primary endpoint: plasma HIV-1 RNA < 500 copies/ml. Additional endpoints: HIV-1 RNA < or = 50 copies/ml; change from baseline in HIV-1 RNA and CD4 cell counts; safety and adverse events. RESULTS: For HIV-1 RNA, 62% of patients on d4T + 3TC + IDV and 54% of patients on ZDV + 3TC + IDV had < 500 copies/ml HIV RNA at weeks 40 through 48 [90% confidence interval, -0.204 to 0.036; P= 0.213], with 49% and 47% respectively achieving < or = 50 copies/ml at 48 weeks (90% CI, -0.134 to 0.096; P = 0.834). Median change in CD4 cell counts at 48 weeks was +227 x 10(6)/l and +198 x 10(6)/l for the d4T- and ZDV-containing arms, respectively. The median time-weighted average change from baseline in CD4 cell counts was significantly greater at 48 weeks in the d4T-containing arm (142 x 10(6)/l versus 110 x 10(6)/l; P = 0.033). Serious adverse events were not significantly different between treatment arms, but there were significant differences for frequency of adverse events of all severity with increased nausea and vomiting in the ZDV-containing arm, and increased diarrhea and rash in the d4T-containing arm. CONCLUSIONS: These results support the choice of d4T + 3TC as a nucleoside analog pair in combination with a protease inhibitor in an initial HIV treatment regimen.

Anti-HIV Agents↗
PubMed2000

Plasma population pharmacokinetics and penetration into cerebrospinal fluid of indinavir in combination with zidovudine and lamivudine in HIV-1-infected patients.

OBJECTIVES: To evaluate plasma population pharmacokinetics and penetration into cerebrospinal fluid (CSF) by indinavir (IDV) in HIV-infected individuals receiving IDV, zidovudine and lamivudine. METHODS: Plasma population pharmacokinetic analysis was performed on 805 IDV plasma values from 171 patients, using a non-linear mixed-effects modeling approach. CSF data from 19 patients were analyzed using an individual approach. RESULTS: Mean individual Bayesian estimates for oral clearance (CL) and volume of distribution (V) by the final model that incorporated interoccasion variability were 0.75 l/h per kg [coefficient of variation (CV) 54.8%] and 1.74 l/kg (CV 82.7%), respectively. Mean model-predicted plasma IDV level at 8 h, maximal level, area under the plasma level-time curve up to 8 h and plasma half-life were 0.42 micromol/l (CV 57.5%), 9.51 micromol/l (CV 47.3%), 29.56 micromol/l x h (CV 46.9%) and 1.50 h (CV 20.9%), respectively. The mean IDV CSF level was 0.11 micromol/l (CV 49.7%) and the mean CSF:plasma concentration ratio was 0.017. CONCLUSIONS: Population estimates of pharmacokinetic parameters of IDV and its CSF penetration were in excellent agreement with previously reported data from individual analyses. Intraindividual interoccasion variability of IDV pharmacokinetics was estimated to be of similar order of magnitude to its interindividual variability, which may affect response to long-term antiretroviral therapy involving IDV. CSF levels of IDV exceeded its in vitro 95% inhibitory concentration of HIV replication. Given that CSF is virtually free of protein, viral suppression in the central nervous system should be achievable with an IDV-containing regimen.

Adult↗
PubMed2002

The effects of cannabinoids on the pharmacokinetics of indinavir and nelfinavir.

BACKGROUND AND OBJECTIVES: The use of cannabinoids for appetite stimulation and the management of wasting and antiretroviral side-effects has become a common practice in the care of HIV-infected individuals. We present pharmacokinetic data from a randomized placebo-controlled study designed to evaluate the metabolic effects of smoked marijuana and dronabinol in HIV-infected patients receiving indinavir (IDV) or nelfinavir (NFV). METHODS: Subjects on stable regimens containing IDV 800 mg every 8 h (n = 28) or NFV 750 mg three time a day (n = 34) were randomized to one of three treatment arms: 3.95% THC marijuana cigarettes, dronabinol 2.5 mg capsules or placebo capsules administered three times daily. Serial blood sampling was performed at baseline and on day 14 of treatment. The changes in NFV and IDV pharmacokinetics were measured as the median percentage change from baseline. RESULTS: At day 14, the 8-h area under the curve (AUC(8)) changed by -10.2% (P = 0.15), maximum concentration (C(max)) by -17.4% (P = 0.46), and minimum concentration (C(min)) by -12.2% (P = 0.28) for patients in the NFV marijuana arm (n = 11). Similar decreases had occurred by day 14 among patients in the IDV marijuana arm (n = 9): AUC8 had changed by -14.5% (P = 0.074), C(max) by -14.1% (P = 0.039), and C(min) by -33.7% (P = 0.65). CONCLUSION: Despite a statistically significant decrease in C(max) of IDV in the marijuana arm, the magnitude of changes in IDV and NFV pharmacokinetic parameters in the marijuana arm are likely to have no short-term clinical consequence. The use of marijuana or dronabinol is unlikely to impact antiretroviral efficacy.

Adult↗
PubMed2003

Efficacy of a twice-daily antiretroviral regimen containing 100 mg ritonavir/400 mg indinavir in HIV-infected patients.

OBJECTIVE: To evaluate the pharmacokinetics, efficacy and tolerability of a low-dose boosted indinavir (IDV)/ritonavir (RTV) regimen [100 mg RTV/400 mg IDV twice daily (bid)] in patients previously receiving a standard IDV regimen [800 mg three times a day (tid)]. METHODS: In a prospective, open-label, cross-over trial, patients with plasma HIV RNA < 200 copies/ml receiving an IDV-containing regimen (800 mg tid) were switched to an RTV/IDV (100/400 mg bid)-containing regimen. Minimal and maximal IDV plasma concentrations ( Cmin and Cmax ) were determined before the switch (day 0), at week 2 and week 4 after the switch. The CD4 cell count and plasma HIV RNA were determined at day 0, week 2 and week 4, then every 8 weeks. The primary end-point was the percentage of patients with plasma HIV RNA below 200 copies ml at week 48. RESULTS: Twenty patients were enrolled. At baseline, on IDV 800 mg tid, median IDV Cmin was 194 ng/ml and median IDV Cmax was 8449 ng/ml. On RTV/IDV (100/400 mg), median IDV Cmin increased to 536 ng/ml at week 2 and 475 ng/ml at week 4, while Cmax decreased to 2983 ng/ml at week 2 and 2997 ng/ml at week 4 ( P < 0.001). The median area under the IDV plasma concentration-time curve measured in seven patients was 25 126 ng.h/ml, and the IDV half-life (t1/2 ) was 4.4 h. All patients had plasma HIV RNA remaining < 200 copies/ml at week 48. Tolerability of RTV/IDV was excellent. CONCLUSION: RTV/IDV (100/400 mg bid) yields significantly higher IDV plasma Cmin and lower IDV Cmax values relative to the standard IDV regimen, thereby improving both tolerability and efficacy.

Adult↗
PubMed2003

Continued indinavir versus switching to indinavir/ritonavir in HIV-infected patients with suppressed viral load.

OBJECTIVE: To compare continued indinavir (IDV) 8-hourly (q8h) with switching to indinavir/ritonavir (IDV/RTV) 12-hourly (q12h) in HIV-positive patients having suppressed viral load with IDV q8h plus two nucleoside reverse transcriptase inhibitors (NRTI). DESIGN: Multicentre, international, randomized, open-label study enrolling HIV-1 infected patients on IDV 800 mg q8h plus two NRTI with CD4 cell counts > or = 100 x 106/l and plasma HIV RNA < 500 copies/ml for > or = 3 months. METHODS: Patients were randomized to continue on the same regimen or to switch to IDV plus liquid RTV (IDV/RTV 800 mg/100 mg q12h). Primary endpoint was the proportion of patients remaining < 500 copies/ml at 48 weeks. RESULTS: A total of 323 patients (IDV/RTV, 162; IDV, 161) were evaluable. At 48 weeks, the proportions of patients with plasma HIV RNA < 500 copies/ml were 93%, 88% and 58% in the IDV/RTV arm versus 92% (P = 1), 86% (P = 0.87) and 74% (P = 0.003) in the IDV arm using on-treatment (OT) and intent-to-treat (ITT) [switches included (ITT, S = I) and switches = failure (ITT, S = F)] analyses respectively. Mean increase in CD4 cell count was 88 x 106/cells/l (IDV/RTV arm) and 60 x 106 cells/l (IDV arm) (P = 0.08). More patients discontinued study medication due to adverse events in the IDV/RTV arm than in the IDV arm (P < 0.001). CONCLUSIONS: Equivalence of continuing IDV q8h versus switching to IDV/RTV (liquid) q12h in suppressed stable patients was demonstrated by OT and ITT S = I analyses. However, the IDV q8h arm performed better when discontinuations were classified as failures. IDV/RTV q12h can be convenient and equally effective for patients able to tolerate it.

Adult↗
PubMed2003

Efficacy of indinavir-ritonavir-based regimens in HIV-1-infected patients with prior protease inhibitor failures.

OBJECTIVE: To assess responses to indinavir (IDV)-ritonavir (RTV)-based regimens among HIV-1 infected patients with prior failure of protease inhibitors, and to assess the effects of adherence to therapy and pre-existing genotypic and phenotypic resistance on this response. METHODS: Twenty-eight patients initiating salvage regimens with IDV-RTV (800 mg and 200 mg twice daily, respectively) plus one or more reverse transcriptase inhibitor (RTI) were identified retrospectively. Genotypic and phenotypic susceptibilities to multiple antiretroviral agents were determined on viral samples collected at initiation of the salvage regimens, and adherence to therapy was determined through patient self-reporting. Response to therapy (viral RNA </= 400 copies/ml) was assessed at the end of and beyond 6 months of follow-up. RESULTS: Based on responses measured in the first 6 months of follow-up, 16 responders and 12 non-responders were identified without differences in baseline demographic factors, laboratory parameters, extent of prior antiretroviral therapy, or characteristics of the RTI components of the new IDV-RTV-based regimens. Adequate adherence was associated with virologic responses (P = 0.005). There were trends for genotypic and phenotypic resistance to be associated with adequate adherence, and, surprisingly, phenotypic resistance to IDV was associated with virologic response rather than with therapeutic failure (P = 0.02). Beyond 6 months of follow-up (mean follow-up 69 weeks), adequate adherence was still associated with virologic response (P = 0.001), but genotypic or phenotypic resistance to IDV were not associated with therapeutic failure. CONCLUSIONS: These results suggest that IDV-RTV-based regimens may be able to overcome IDV resistance. This underscores the importance of drug adherence, potency, and exposure in determining virologic responses to antiretroviral therapy.

Drug Resistance, Viral↗
PubMed2002

Sarcoidosis and interstitial nephritis in a child with acquired immunodeficiency syndrome: implications of immune reconstitution syndrome with an indinavir-based regimen.

A child with perinatally acquired AIDS and profound immunodeficiency was treated with zidovudine, lamivudine and indinavir and had excellent immunologic and virologic response. His subsequent clinical course was complicated by multisystem sarcoidosis characterized by granulomatous hepatitis, nephritis, duodenitis and a CD4+ lymphocytic alveolitis as part of the immune reconstitution syndrome.

Acquired Immunodeficiency Syndrome↗
PubMed2003

Reverse phase high-performance liquid chromatography method for the analysis of amprenavir, efavirenz, indinavir, lopinavir, nelfinavir and its active metabolite (M8), ritonavir, and saquinavir in heparinized human plasma.

The increasing interest in applying therapeutic drug monitoring (TDM) to antiretroviral therapy is related to the observed interindividual variation in antiretroviral pharmacokinetics that results in a wide range of drug exposure from fixed-dosing regimens and the rapid evolution in the availability of phenotypic assays that generate a target 50% inhibitory concentration (e.g., IC(50)) as a basis for adjusting individual antiretroviral dosages. To facilitate the application of TDM, a method for the simultaneous determination of eight species has been developed. This method is used to quantitate efavirenz and the following protease inhibitors: amprenavir, indinavir, lopinavir, nelfinavir and its active metabolite (M8), ritonavir, and saquinavir. The method using reversed-phase high-performance liquid chromatography (RP-HPLC) was validated. Detection is effected using a photodiode-array detector (PDA) scanning at four different wavelengths. This method allows for detection of all analytes to a lower limit of quantitation of 0.1 to 0.2 microg/mL with an interday variation in CV ranging from 3.5% to 10.4%. The method is being applied to a TDM program that is currently being implemented in the authors' laboratory.

Alkynes↗
PubMed2003

Clinical use of a simultaneous HPLC assay for indinavir, saquinavir, ritonavir, and nelfinavir in children and adults.

Protease inhibitor (PI) monitoring may improve the care of human immunodeficiency virus (HIV)-infected patients; however, pediatric data are limited. A high-performance liquid chromatographic (HPLC) assay developed for the simultaneous determination of indinavir, ritonavir, saquinavir, and nelfinavir in 0.2 mL of plasma was used to quantify PI concentrations in HIV patients. The reliability, sensitivity, and specificity of the assay were first verified in stored adult samples. Later, blood collected prospectively from patients aged 2.9 to 42 years of age (10 adults aged 24 to 42 and 15 children aged 2.9 to 18 years) was tested. Nondetectable (below 25-50 ng/mL) concentrations (ND) were found in 33% of adult samples and 24% of pediatric samples. Four patients taking from 13.7 to 28 mg/kg/d of ritonavir (mean of 21.3) had concentrations ranging from ND to 11.4 microg/mL, quite different from predicted values. Correctable, important clinical problems including drug-drug interactions, drug administration problems, and confirmed noncompliance were identified and corrected using modern therapeutic drug monitoring (TDM) techniques. Routine PI monitoring and interpretation (TDM) could improve the care of adult and pediatric HIV patients; especially in patients who do not respond as expected to treatment, develop viral resistance or toxicity, and have questionable compliance.

Adolescent↗
PubMed2003

Clinical use of a simultaneous HPLC assay for indinavir, saquinavir, ritonavir and nelfinavir in children and adults.

PROTEASE INHIBITOR TDM: This study examines the importance of therapeutic drug monitoring (TDM) of protease inhibitors (PI) in adults and children infected with the human immunodeficiency virus (HIV). Pediatric patients were included because information in this population is limited. A high performance liquid chromatographic (HPLC) assay measured indinavir, saquinavir, ritonavir and nelfinavir simultaneously in 0.2 mL of plasma. Initially, the reliability, sensitivity and specificity of the assay were verified in stored samples of plasma from adult patients who had been receiving PIs. Non-detectable concentrations (ND) were <25-50 ng/mL. In 96 out of 293 stored samples from adult patients, selected randomly, concentrations of PIs were ND. In a second prospective study of 10 adults (9 mothers and one father, aged 24-42 years) and 15 children (2.9-18 years) ND levels of PI were observed frequently (27% or 4 out of 15 pediatric subjects). In the latter study, drug-drug interactions, dosing errors, noncompliance and other important problems were identified and corrected. Routine monitoring and interpretation of PI concentrations (TDM) may improve the management of adult and pediatric patients infected with HIV, especially in those who fail to respond, develop adverse effects or viral resistance, or lack compliance.

Adult↗
PubMed2001

Indinavir crystallization around the loop of Henle: experimental evidence.

OBJECTIVE: To determine the probable site of the nephron and the plasma indinavir (IDV) concentration at which intrarenal IDV crystallization occurs. DESIGN: We performed in vitro crystallization experiments in IDV solutions simulating conditions found in the nephron. METHODS: To determine intrarenal IDV concentrations at which conditions in the nephron allow crystallization, several concentrations of IDV basic solutions (0-800 mM) were titrated from pH 4.0 to higher pH values until crystals formed within 1 minute. Based on the combination of pH and ionic strength at which crystals formed, we determined the site of the nephron at which this combination was first attained. Based on the capacity for concentration at that site, we were able to measure the corresponding plasma IDV concentration. RESULTS: Under conditions normally found at the proximal tubule (i.e., pH 6.7 and ionic strength of 200 mM), IDV crystallized at 200 mg/L. Under conditions applying to the loop of Henle, pH 7.4 and ionic strength of 200 mM, IDV crystallized at 125 mg/L, which would correspond to a plasma IDV concentration of 8 mg/L. CONCLUSIONS: IDV crystallization is most likely in the loop of Henle and may already start at plasma IDV concentrations as low as 8 mg/L. Increasing hydration does not reduce the risk of IDV crystallization in the loop of Henle but instead prevents IDV crystallization and aggregation in the lower urinary tract. It remains to be confirmed whether prevention of high IDV plasma concentrations will reduce the risk of IDV crystallization in the loop of Henle.

Crystallization↗
PubMed2005

Indinavir protein-free concentrations when used in indinavir/ritonavir combination therapy.

OBJECTIVE: To describe the in vivo protein-binding characteristics of indinavir (IDV) in the presence of ritonavir (RTV) relative to total IDV plasma concentrations. DESIGN: The ACTG protocol 5055 was a multicenter study comparing the safety and pharmacokinetics of IDV/RTV at doses of 800/200 and 400/400 mg twice daily in HIV-infected adults. METHODS: Forty-four patients underwent a 12-h intensive pharmacokinetic assessment after 2 weeks of therapy. Three plasma samples from 35 patients at Cmax, 6 and 12 h post dose were used to determine the unbound IDV concentrations. Unbound IDV was separated in plasma samples using ultra-filtration and measured using high-performance liquid chromatography with UV detection. RESULTS: Mean IDV protein-bound fraction across all time points in the 800/200 and 400/400 arm were 53.4 and 51.8%, respectively. In the 800/200 arm, percentage binding at Cmax was 50% compared with 56% at 12 h (P = 0.008). In the 400/400 arm, percentage binding at Cmax was 49% compared with 54% at 12 h (P = 0.008). CONCLUSIONS: The extent of plasma protein binding of IDV in this study was less than in previously published data with IDV alone. Although IDV concentrations differed across the arms, the percentage of IDV protein binding at all time points was not different between the 800/200 and 400/400 arms. However, the percentage of IDV protein binding at Cmax was significantly lower compared with 12 h in each arm, possibly suggesting that IDV protein binding is concentration-dependent. These data suggest that RTV affects IDV protein-binding characteristics and IDV also exhibits concentration dependent binding when administered with RTV.

Adult↗
PubMed2005

Absence of association between MDR1 genetic polymorphisms, indinavir pharmacokinetics and response to highly active antiretroviral therapy.

OBJECTIVE: The relationship between MDR1 single nucleotide polymorphisms (SNP) and the pharmacokinetic or pharmacodynamic responses to protease inhibitors has been recently challenged. AIM: The objective of the present study was to determine whether MDR1 genetic polymorphisms in exons 21 and 26 (G2677T/A and C3435T) are in association with indinavir (IDV) plasma concentrations and/or therapeutic response to highly active antiretroviral therapy (HAART) in HIV-infected patients treated with unboosted IDV containing regimens. METHODS: MDR1 genotyping was performed in a population of 139 HIV-1-positive patients followed during 72 weeks, as part of the previous study called ANRS 081 'Trianon'. The primary study was a randomized trial comparing over 72 weeks the efficacy of two antiretroviral drug combinations in a population of adult HIV-1-infected patients: group 1, [lamivudine (3TC) - stavudine (d4T) - IDV (800 mg three times daily)] and group 2, [Nevirapine (NVP) - d4T - IDV (1000 mg three times daily)]. RESULTS: MDR1 SNPs analyzed separately or combined into haplotypes did not show any significant association with IDV pharmacokinetics nor response to HAART. Mean modelled IDV peak and trough concentrations, as well as clearance modelled from pharmacokinetic model, after 8 weeks of therapy were not significantly different between patients carrying the wild-type haplotype GG-CC (at position 2677 and 3435 respectively) and others. CONCLUSIONS: Our results do not support an association between MDR1 genetic polymorphisms and modelled IDV clearance or clinical response to HAART.

Adult↗
PubMed2006

Once-daily directly observed therapy lopinavir/ritonavir plus indinavir as a protease inhibitor-only salvage therapy in heavily pretreated HIV-1-infected patients: a pilot study.

Lopinavir/ritonavir plus indinavir was administered once daily as directly observed protease inhibitor-only therapy in 12 heavily pretreated HIV-1-infected patients with multiple virological failures and advanced immunosuppression (CD4 cell count 95 x 10 cells/microl). The treatment was well tolerated. At weeks 12, 24 and 48, most patients on treatment achieved viral suppression of less than 400 copies/ml and a corresponding median CD4 T-cell count increase. Pharmacokinetic data indicated therapeutic concentrations for both protease inhibitors in most patients.

Adult↗