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PubMed1997

Indinavir urinary stones as origin of upper urinary tract obstruction.

The development of HIV protease inhibitors has dramatically improved the treatment prognosis of HIV-infected patients. The treatment, however, is associated with the potential for adverse events that are unique to protease inhibitors. One of them, Indinavir, can lead to the development of urinary stones. Three weeks after starting treatment with Indinavir, Zidovudine and Lamivudine, a 66-year-old patient developed symptomatic hydronephrosis on the right side due to multiple Indinavir stones blocking the ureter. Microhematuria and characteristic crystals were found in the urine. After interruption of treatment and increased fluid intake, the crystallurea was not longer detectable and the patient became asymptomatic within 3 days. Nephrostomy and ureteral stent placement were not necessary. Patients on treatment with Indinavir are required to maintain a fluid intake of at least 1.5-2 l/day to reduce the risk of crystallization and urinary stones. Pharmacologic metaphylaxis to prevent crystallization is not recommended.

Aged↗
PubMed2003

Influence of goldenseal root on the pharmacokinetics of indinavir.

Goldenseal root was identified as the most potent inhibitor of CYP3A4 in a study that tested 21 popular herbal products for in vitro inhibitory activity. The purpose of this investigation was to examine the influence of goldenseal root on the disposition of the CYP3A4 substrate indinavir in humans. Using a crossover study design, the pharmacokinetics of indinavir were characterized in 10 healthy volunteers before and after 14 days of treatment with goldenseal root (1140 mg twice daily). Indinavir was given as a single 800-mg oral dose, and blood samples were collected for 8 hours following the dose. No statistically significant differences in peak concentration (11.6 vs. 11.9 mg/L) or oral clearance (26.8 vs. 23.9 mg*h/L) were observed following treatment with goldenseal root. Half-life and time to reach peak concentration were also unchanged by goldenseal. These results suggest that patients being treated with indinavir can safely take goldenseal root and that interactions with other drugs metabolized by CYP3A4 in the liver are unlikely.

Adult↗
PubMedDate not supplied

A critical evaluation of the therapeutic range of indinavir.

OBJECTIVE: To provide a summary of the patient population, study characteristics, and important findings of the key studies in the literature evaluating concentration-effect relationships and the therapeutic range for indinavir. DATA SOURCES: Literature search strategy involved using MEDLINE (1966-July 2001) and AIDSLINE (MEDSCAPE) databases (up to July 2001). Reference lists from primary literature and review articles were also examined, and conference abstracts were obtained. STUDY SELECTION: English-language articles were considered suitable for review if the clinical trials in HIV patients reported on concentration-effect relationships and/or pharmacokinetic breakpoints or threshold concentrations. A search of the literature identified 20 peer-reviewed references from 18 separate studies including journal articles and conference abstracts. DATA EXTRACTION: The targeted pharmacokinetic parameters and breakpoint values, the rationale for their selection or method of identification, and other study details and limitations were summarized. DISCUSSION: This article highlights the heterogeneity of studies evaluating the therapeutic range of indinavir and provides a summary of important findings of the key studies in the literature evaluating concentration-effect relationships and therapeutic range. Tables are provided to enable clinicians to make use of currently available information on the therapeutic range of indinavir. CONCLUSIONS: There is insufficient evidence to recommend a general therapeutic range for indinavir. Future investigations should incorporate both pharmacokinetics and pharmacodynamics in order to define a broadly applicable therapeutic range.

Adult↗
PubMed1999

Indinavir-associated maculopapular eruption.

Indinavir-associated adverse dermatologic reactions are rare but do occur. A 39-year-old man who was positive for the human immunodeficiency virus and had no known allergy, developed an erythematous, maculopapular eruption several hours after switching to a new triple-drug regimen consisting of stavudine, didanosine, and indinavir. The eruption completely resolved 2 weeks after he discontinued the antiretroviral combination. To preserve future treatment options, the patient was sequentially rechallenged with each agent and confirmed indinavir as the cause. The patient tolerated and responded to a new combination of stavudine, didanosine, and nelfinavir. The rapid onset of the adverse reaction suggested that it might have been immunoglobulin-E mediated. No cross-sensitivity between indinavir and nelfinavir was apparent.

Adult↗
PubMed1999

[Treatment of complicated renal colic in patients treated with indinavir: value of double J stents].

OBJECTIVE: Evaluation of the treatment of complicated ureteric stones in patients treated with indinavir. PATIENTS AND METHODS: From March 1997 to May 1998, 10 patients (7 males, 3 females, aged 30 to 56 years), treated by triple combination therapy for HIV infection, were drained for stones attributed to indinavir (CRIXIVAN), which had become obstructive and complicated. The duration of treatment with indinavir ranged from 14 days to 2 years. No patient had a history of urological disease. One patient presented with bilateral stones. All patients presented complicated clinical features: fever in 3 cases; severe pain in 8 cases, with delayed excretion more than 4 hours on IVU in 6 cases. All stones were radiolucent except for one slightly radioopaque stone. The stone was situated in the lumbar ureter in 3 cases, iliac ureter in 1 case and pelvic ureter in 8 cases. RESULTS: In 10 out of 11 cases, a double J stent was inserted, preceded by drainage by simple ureteric catheter (infected urine) in 1 case and by percutaneous nephrostomy (PCN) with antegrade insertion of the stent (failure of the retrograde route) in 1 case. No complementary stone fragmentation or extraction treatment was necessary after this procedure. Stents were left in place for 3 to 7 weeks. In one case, a stone of the lumbar ureter required PCN followed by extracorporeal lithotripsy. CONCLUSION: In the case of complications requiring a urological procedure, insertion of a double J stent allows curative treatment of very friable indinavir stones, which are fragmented by passage of the stent.

Adult↗
PubMed2000

Simultaneous HPLC assay for quantification of indinavir, nelfinavir, ritonavir, and saquinavir in human plasma.

BACKGROUND: HIV protease inhibitors are recommended as part of combination antiretroviral therapy. Dual protease inhibitor therapy is also being used clinically. Consequently, a simultaneous assay for indinavir, nelfinavir, ritonavir, and saquinavir was developed. METHODS: Indinavir, nelfinavir, ritonavir, and saquinavir were extracted from plasma (250 microL) with methyl-t-butyl ether at basic pH after addition of an internal standard (A-86093). The compounds were separated on a Keystone BetaBasic C4 column (250 x 3 mm i.d.) at 40 degrees C with a mobile phase of acetonitrile-50 mmol/L ammonium formate buffer, pH 4.1 (52:48, by volume) at a flow rate of 0.5 mL/min. Indinavir, nelfinavir, ritonavir, and the internal standard (A-86093) were detected at 218 nm, and saquinavir was detected at 235 nm. The method was validated by analysis of five triplicate analyses of calibrators along with quality-control samples at three different concentrations prepared in human plasma. RESULTS: The extraction recovery was 87-92%. Within-run accuracy for quality-control samples was 6-8%, with CVs of 2-8%. Limits of quantification were 40-50 microg/L for indinavir, nelfinavir, and ritonavir, and 20 microg/L for saquinavir. Cross-validation with a liquid chromatography-mass spectroscopy method for saquinavir and nelfinavir was conducted with patient samples. Regression analysis revealed a good correlation (r(2) >0.94) between methods. Larger variations at concentrations >4000 microg/L were observed with nelfinavir. Interference with drugs commonly used in AIDS patients was not observed. Pharmacokinetic profiles for two patients on dual protease therapy were determined. CONCLUSIONS: A reliable and rugged simultaneous HPLC assay for four HIV protease inhibitors was developed. The assay method is convenient for clinical laboratories involved in therapeutic drug monitoring for HIV protease inhibitors. The assay has enough sensitivity to conduct pharmacokinetic studies in patients taking more than one HIV protease inhibitor along with other antiretroviral medications.

Chromatography, High Pressure Liquid↗
PubMed1998

Improvement in immune function due to treatment with indinavir despite severe immune deficiency.

To study the virological, immunological and clinical effects of the protease inhibitor indinavir in human immunodeficiency virus (HIV)-infected patients with CD4 counts < 50 cells/mm3, indinavir was added to prior treatment with nucleoside analogues in a prospective open-label study in 23 HIV-infected patients with median CD4 count of 10 cells/mm3 and median serum HIV-1 RNA load of 27,508 copies/ml. Addition of indinavir induced a decrease in HIV-1 RNA levels to < 400 copies/ml in 15 patients that was maintained until week 36 of the study in 8 (35%) patients. The median increase in CD4 cell counts was 92 cells/mm3 (range 55-258 cells/mm3) and in CD8 counts was 245 cells/mm3 (range 51-1552 cells/mm3) at week 30. The treatment induced a significant CD8 T cell expansion, consisting in the first 6 weeks of predominantly memory CD45RO+ cells and followed by expansion of naive cells from week 12 on, and a significant decrease in the proportion of activated CD8/CD38 cells. In addition, significant increases in T cell proliferation following stimulation with phytohaemagglutinin and significant decreases in the rates of spontaneous apoptosis of CD4+ and CD8+ T cells were observed. In conclusion, the addition of indinavir induced restoration of both memory and naive CD8 T cells. Corresponding evidence of improving T cell function, as assessed by enhanced lymphoproliferative capacity and diminished propensity to undergo apoptosis, provides evidence for treatment-induced regeneration of immune function even in patients with severe immunodeficiency.

Adult↗
PubMedDate not supplied

[Simultaneous quantitative determination of amprenavir and indinavir in human plasma by high-performance liquid chromatography].

A reversed-phase high-performance liquid chromatographic assay for the determination of the HIV protease inhibitors amprenavir (Agenerase) and indinavir (Crixivan) in human plasma is described, using a mobile phase consisting of 0.50 M phosphate buffer (adjusted to pH 5,5) - Milli-Q water - acetonitrile (120: 1,080: 800, v/v/v). A solid-phase extraction using C18 extraction columns (Discovery columns 100 mg, 1 ml Supelco) and a liquid-liquid extraction with 0.5 ml hydrogenocarbonate/carbonate buffer (adjusted to pH 10.6) and 6 ml methyl ter-butyl ether have been compared. The liquid-liquid extraction has been chosen to be easier and cheaper. The method has been validated over the range of 60 to 3,000 ng/ml for amprenavir and 20 to 3,000 ng/ml for indinavir using a 0.5 ml sample volume. The specificity, linearity, accuracy and precision have been studied. The limit of detection was respectively for amprenavir and indinavir 15 and 4 ng, and the limit of quantification was 60 and 20 ng/ml. Stability tests under various conditions were performed. This assay can readily be used in a hospital laboratory for the routine monitoring of plasma concentrations of amprenavir in HIV-infected patients. The trough plasma concentrations average has been determined in patients treated by amprenavir and indinavir for seven months.

Anti-HIV Agents↗
PubMed2001

[Urinary lithiasis secondary to indinavir in an HIV-positive patient].

OBJECTIVE: Indinavir is a protease inhibitor used in the treatment of HIV with a lithogenic capacity as a urological side effect. The pathogenesis, diagnosis and treatment of indinavir urolithiasis are briefly reviewed. METHODS: A 37-year-old male, seropositive for HIV on treatment with indinavir, lamiduvine and zidovudine, consulted for colicky left lumbar pain, nausea, vomiting and dark urine for the past three days. RESULTS: Patient evaluation showed a nonfunctioning left kidney and ureterohydronephrosis of unknown origin. URS showed a yellowish, friable material with a mucinous appearance that occupied the entire lumen of the ureter. Fragmentation was achieved with the lithotriptor probe. Six months later the patient had fully recovered and was asymptomatic. CONCLUSIONS: The incidence of protease inhibitor-induced urolithiasis is increasing. This condition should be distinguished from uric acid calculi whose treatment will aggravate the indinavir urolithiasis.

Adult↗
PubMed2004

ATP binding cassette multidrug transporters limit the anti-HIV activity of zidovudine and indinavir in infected human macrophages.

OBJECTIVES: To investigate whether P-glycoprotein (P-gp) and multidrug resistance proteins (MRPs), which limit the bioavailability of HIV protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs), modulate the anti-HIV activity of NRTIs, non-NRTIs and PIs in vitro. DESIGN: We used primary cultures of major HIV target cells: human monocyte-derived macrophages (MDMs) and lymphocytes. METHODS: P-gp and MRP expression in response to long-term zidovudine (3'-azido-3'-deoxythymidine; AZT) or indinavir treatment was quantified by RT-PCR. MDM and lymphocytes were infected in vitro with HIV-1/Ba-L and HIV-1-LAI, respectively, and treated with antiretroviral drugs. We evaluated the activity of these drugs in combination with PSC833, a P-gp inhibitor, and/or probenecid, an MRP1 inhibitor. Intracellular AZT triphosphate derivative (AZT-TP) was quantified by HPLC-MSMS. P-gp ATPase activity was measured with inside-out native membrane vesicles enriched in P-gp. RESULTS: Levels of MDR1, mrp4 and mrp5 mRNA were high following AZT treatment. In infected MDM, PSC833 and probenecid increased the anti-HIV activity of AZT and indinavir. AZT (5 nM) decreased HIV replication by 34% alone and by 72% in combination with P-gp/MRP inhibitors. Indinavir (10 nM) gave 14% inhibition alone and 81% in combination. The increase in anti-HIV activity of AZT was correlated with an increase in intracellular AZT-TP concentration. However, unlike PIs, neither AZT nor its metabolites interacted with P-gp. CONCLUSION: AZT increases the expression of multidrug transporters, thereby decreasing its pharmacological activity. The cellular efflux of AZT probably involves MRP4 or MRP5. In contrast, increases in indinavir anti-HIV activity require the inhibition of both P-gp and MRP1.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2006

Electrochemical methods for determination of the protease inhibitor indinavir sulfate in pharmaceuticals and human serum.

Indinavir sulfate is an inhibitor of the human immunodeficiency virus (HIV) protease. The aim of this study was to determine indinavir levels in serum and pharmaceuticals, by means of electrochemical methods using the hanging mercury drop electrode (HMDE). Indinavir exhibited irreversible cathodic waves over the pH range 2.00-12.00 in different supporting electrolytes. The current-concentration plot was rectilinear over the range from 8 x 10(-7) M to 8 x 10(-6) M with a correlation coefficient of 0.996 for differential pulse voltammetry (DPV) and 8 x 10(-7) M to 1 x 10(-5) M with correlation of 0.999 M for osteryoung square ware voltammetry (OSWV) in Britton-Robinson buffer at pH 10.00. The wave was characterized as being irreversible and diffusion-controlled. The proposed methods were fully validated and successfully applied to the determination of indinavir in capsules and spiked human serum samples with good recoveries. The repeatability and reproducibility of the methods as well as precision and accuracy (such as supporting electrolyte, serum samples) were determined. No electroactive interferences from the endogenous substances were found in serum samples.

Capsules↗
PubMed1999

Role of pharmacokinetics in the discovery and development of indinavir.

The discovery of indinavir is a successful example in which pharmacokinetic and metabolic information were incorporated into drug design. The use of animal and in vitro human metabolic data in predicting the oral bioavailability and hepatic clearance in humans was critical in selecting indinavir as a drug candidate for development. In its development stage, pharmacokinetics continued to play an important role in identifying the key properties of indinavir in vivo, which allowed the characterization and prediction of the time course of drug action under physiological and pathological conditions. This review describes the role of pharmacokinetics and drug metabolism in the discovery and development of indinavir.

Journal Article↗
PubMed2000

Developmental toxicity of the HIV-protease inhibitor indinavir in rats.

BACKGROUND: Indinavir is an antiviral agent used for the treatment of HIV infection. We studied its developmental toxicity in rats. METHODS: Pregnant animals were treated orally with 500 mg indinavir/kg body weight (bw) from day 6 to 15 of gestation (once daily) or from day 9 to 11 (twice daily). Fetuses were evaluated for external and skeletal anomalies on day 21 of gestation. In addition, 19 rats were treated from day 9 of gestation to day 24 postnatally with 500 mg indinavir/kg bw once daily; a control group of 17 rats was treated with the vehicle accordingly. Developmental landmarks were recorded. Sixteen offspring each were studied on postnatal days 7, 14, 21, and 35 for hepatic enzyme activity. Liver tissue was examined by electron microscopy. RESULTS: Fetal examination on day 21 of pregnancy showed no treatment-related effects on number, weight, and viability of the fetuses; however, an increased incidence was noted in the supernumerary ribs and variations of the vertebral ossification centers in both indinavir-treated groups. Postnatal evaluation showed delayed fur development, eye opening, and descensus testis. The most striking finding was unilateral anophthalmia, observed in 7 pups (3%) from 2 out of 19 litters exposed to indinavir, but not in controls. Only minor changes in hepatic monooxygenase activities occurred in dams. Electron microscopy of liver samples showed hepatocellular inclusions of lipids and myelin figure-like structures in maternal livers and infiltration with granulocytes in offspring livers. CONCLUSIONS: Further studies on reproductive toxicity, including combinations of three or more antiretroviral agents as used therapeutically, are needed to determine the hazards of such a treatment.

Abnormalities, Drug-Induced↗
PubMed2006

Simple and sensitive high-performance liquid chromatography method for the quantitation of indinavir in rat plasma and central nervous system.

A simple and sensitive RP-HPLC method using UV detection (215 nm) was developed for the determination of indinavir concentrations in rat plasma, cerebrospinal fluid (CSF), and brain tissue homogenates. Biological samples were processed using a combination of acid pretreatment and liquid-liquid extraction with verapamil used as the internal standard. This method produced a linear response throughout the indinavir concentration range of 0.05-30 microM in plasma and 0.05-2.5 microM in CSF and brain with a LOD of 12.5 nM for plasma and CSF, and 6.25 nM for brain homogenate. Due to its high sensitivity, this assay is particularly useful for the quantitative determination of indinavir concentrations in brain and CSF.

Animals↗
PubMed2004

Lipid lowering therapy with fluvastatin and pravastatin in patients with HIV infection and antiretroviral therapy: comparison of efficacy and interaction with indinavir.

BACKGROUND: Lipoprotein disorders in HIV-positive patients receiving highly active antiretroviral therapy (HAART) are becoming a major concern in HIV treatment, since there is growing evidence for an association between HAART-induced hyperlipidemia and increased cardiovascular risk. Yet relatively few data are available on the possible interactions of HAART and treatment with statins. PATIENTS AND METHODS: In this prospective study, 25 HIV-positive, treatment-experienced patients (five female, 20 male, all Caucasian) were treated with either fluvastatin or pravastatin. Total cholesterol, low density lipoprotein (LDL) and high density lipoprotein (HDL) levels, and serum triglycerides were determined at regular intervals, as well as therapeutic drug monitoring to assess possible drug interactions. RESULTS: In 13 pravastatin-treated patients, a decrease in total cholesterol levels (from 7.12 mmol/l to 6.29 mmol/l) after 12 weeks of therapy was seen. In 12 patients treated with fluvastatin, a permanent reduction of total cholesterol (from 6.46 mmol/l to 5.31 mmol/l) after 12 weeks was observed. The reduction of LDL levels was 30.2% in the fluvastatin group and 14.4% in the pravastatin group. In eight patients receiving an indinavir-containing HAART, indinavir plasma levels were not significantly influenced. No effect on triglycerides or HDL was observed. CONCLUSION: Fluvastatin and pravastatin are efficient in lowering total and LDL cholesterol levels in HIV-positive patients receiving HAART. Furthermore, no influence on indinavir plasma levels could be observed. Therefore, both compounds seem to be a viable treatment option in HAART-induced hypercholesterolemia.

Adult↗
PubMed2002

Structural elucidation of metabolites of ritonavir and indinavir by liquid chromatography-mass spectrometry.

The structural elucidation of metabolites of ritonavir and indinavir, HIV-protease inhibitor drugs, by liquid chromatography-electrospray ionization mass spectrometry is described. Ritonavir and indinavir were biotransformed separately by incubation with transplant quality human liver microsomes. The incubation mixture was then analyzed by HPLC coupled to ion trap (ITMS) and triple quadrupole mass analyzers. The metabolites retained most of the structural features of the parent molecules. Baseline chromatographic resolution of isobaric species by gradient elution HPLC permitted rapid structural identification of these metabolites. Both drugs were biotransformed primarily by oxidative and hydrolytic pathways to numerous metabolites that retained many of the features of the parent molecules. Triple quadrupole and ion trap mass spectrometry were applied jointly to thoroughly detect and thoroughly characterize these metabolites. Furthermore, retention-time and data-dependent scanning assured acquisition of detailed MS-MS spectra for rapid detection of metabolic pathways of ritonavir and indinavir. Comparison of the ITMS and triple quadrupole data showed qualitative and quantitative differences in the mass spectral patterns, suggesting that these instruments should be used in parallel to ensure comprehensive metabolite detection and characterization by LC-MS.

Chromatography, High Pressure Liquid↗
PubMed2000

Indinavir concentrations and St John's wort.

St John's wort reduced the area under the curve of the HIV-1 protease inhibitor indinavir by a mean of 57% (SD 19) and decreased the extrapolated 8-h indinavir trough by 81% (16) in healthy volunteers. A reduction in indinavir exposure of this magnitude could lead to the development of drug resistance and treatment failure.

Administration, Oral↗
PubMedDate not supplied

[Indinavir and renal lithiasis].

Indinavir is a new specific and potent drug that inhibits, like other antiretroviral agents, the protease of immune deficiency virus (HIV) or acquired immune deficiency syndrome (AIDS), an enzyme necessary to maduration and replication of the virus. Indinavir has the capacity to bind the active site causing a decrease in plasma of HIV1-RNA and an increase of T-CD4 helper lymphocytes. The aim of this work is to study in HIV and/or AIDS patients treated with indinavir the crystalluria and the formation of renal calculi due to the clearance of this drug. Two out of nine patients studied in this work presented abundant crystalluria and one of them presented spontaneously passed renal stone. Urinary crystals were studied under polarized-light microscopy and renal stone was analyzed by infrared spectroscopy.

HIV Infections↗