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PubMed1999

Urological complaints in relation to indinavir plasma concentrations in HIV-infected patients.

OBJECTIVE: To assess the relationship between indinavir-associated urological complaints and indinavir plasma concentrations. DESIGN: Case series, comparing indinavir plasma concentrations in cases with average concentrations in a control group. METHODS: Patients taking 800 mg indinavir three times a day (tid), who presented with overt urological complaints (renal colic, flank pain or haematuria) were selected for the study. Plasma indinavir concentrations were measured by means of a standardized high performance liquid chromatography (HPLC) method. Plasma samples taken at 1.5-8 h after the last indinavir ingestion were included for evaluation. Results were compared with the full pharmacokinetic curves of indinavir plasma concentrations from a control group of 14 patients taking 800 mg indinavir tid without urological complaints, and were expressed as concentration ratios. A ratio of 1 indicated a plasma concentration equalling the average concentration in the control population at the same point in time after the ingestion of indinavir. RESULTS: Seventeen patients (five women) were enrolled and the indinavir concentrations of 15 patients could be evaluated. Fourteen (93%) patients had a concentration above the mean of the controls, 12 (80%) patients had a concentration above the upper 95% confidence limit, and one (7%) patient had a concentration below the lower 95% confidence limit. The mean indinavir concentration in patients with urological complaints (ratio range 0.55-11.49) was significantly higher than the average concentration and the upper 95% confidence limit of the control group (P < 0.05). The results could not be explained by differences in weight, sex or drug interactions. Two patients had chronic active hepatitis B infection. In six patients with indinavir concentrations above the upper 95% limit, indinavir was reduced to 600 mg tid. Upon repeat measurement after the dose adjustment, their indinavir plasma concentrations fell within the 95% confidence interval around the mean of the control population. All six patients remained asymptomatic and had viral loads of less than 500 copies per ml after a follow-up of 5-16 months. CONCLUSIONS: Urological complications occurring during indinavir treatment were associated with elevated indinavir plasma concentrations in 80% of patients in this study. Indinavir plasma concentrations should be monitored upon presentation of urological complaints, on the basis of which dose reductions may be applied if brief interruption and increased hydration are ineffective.

Adult↗
PubMed2004

Indinavir and rifabutin drug interactions in healthy volunteers.

Two studies examined the pharmacokinetics of indinavir and rifabutin when coadministered in healthy subjects. Rifabutin, which induces the expression of cytochrome P450 (CYP) 3A, and indinavir, which inhibits that enzyme system, are frequently coadministered in patients infected with HIV. The second study was undertaken to determine if altering the dose of rifabutin coadministered with indinavir would minimize the drug interaction observed in the first study. Two studies, each with a three-period crossover design, were performed. In study 1, standard doses of rifabutin and indinavir (300 mg of rifabutin qd and 800 mg indinavir q8h) were administered as monotherapy (with placebo to the other drug) or in combination to 10 volunteers for 10 days. In study 2, 150 mg qd of rifabutin together with 800 mg q8h of indinavir, 300 mg qd of rifabutin alone, or 800 mg q8h of indinavir alone was administered to 14 volunteers for 10 days. In study 1, the geometric mean ratio (GMR) (90% confidence interval [CI]) of the AUC((0-8h)) of indinavir, coadministered with rifabutin 300 mg qd compared to indinavir alone (with rifabutin placebo), was 0.66 (0.56, 0.77), while that of the AUC((0-24h)) of rifabutin, coadministered with indinavir compared to rifabutin alone (with indinavir placebo), was 2.73 (1.99, 3.77). In study 2, the GMR (90% CI) of the AUC((0-8h)) of indinavir, coadministered with rifabutin 150 mg qd compared to indinavir alone, was 0.68 (0.60, 0.76), while that of the AUC((0-24h)) of rifabutin, when rifabutin 150 mg qd was coadministered with indinavir compared to rifabutin 300 mg qd alone, was 1.54 (1.33, 1.79). For both studies 1 and 2, indinavir and rifabutin administered alone or in combination were generally well tolerated. No clinical or laboratory adverse experience was serious. These data demonstrate the important pharmacokinetic interactions between indinavir and rifabutin when they are coadministered. Indeed, these observations formed the basis for the subsequent ACTG 365 study that explored dose adjustments for these agents in combination regimens to preserve the sustained antiviral activity of indinavir in the absence of adverse events as a result of elevated circulating levels of rifabutin.

Adult↗
PubMed1999

Indinavir: a review of its use in the management of HIV infection.

Indinavir is a protease inhibitor used in the treatment of patients with HIV infection. Combination antiretroviral therapy with indinavir plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) is associated with greater reductions in viral load, greater increases in CD4+ cell counts, and reduced morbidity and mortality when compared with 2 NRTIs alone. In the landmark clinical trial ACTG 320, the rate of progression to AIDS or death (primary end-point) among zidovudine-experienced patients treated with indinavir, zidovudine and lamivudine was approximately half that of patients who received only zidovudine plus lamivudine (6 vs 11%; p < 0.001). The durability of an indinavir-containing regimen was demonstrated in Merck protocol 035, an ongoing trial in which a significant proportion of patients had sustained viral suppression for up to 3 years. Merck protocol 039, also an ongoing trial, showed a greater effect on surrogate markers of HIV disease progression with indinavir-based triple therapy than with zidovudine plus lamivudine or indinavir monotherapy in patients with advanced disease (median baseline CD4+ count 15 cells/microL). Numerous additional clinical trials have established the beneficial antiviral and immunological effects of indinavir in both antiretroviral-naive and -experienced patients with HIV infection. Indinavir is associated with various drug class-related adverse events, including gastrointestinal disturbances (e.g. nausea, diarrhoea), headache and asthenia/fatigue. A lipodystrophy syndrome has been commonly reported with indinavir and other protease inhibitors combined with NRTIs, but it has also been reported in many protease inhibitor-naive patients, and a definitive causal link has not been established between the syndrome and protease inhibitors. Nephrolithiasis may develop in about 9% of patients receiving indinavir but does not appear to be associated with other protease inhibitors; <0.5% of patients receiving indinavir discontinue the drug because of nephrolithiasis, which may be the extreme end of a continuum of crystal-related renal syndromes. Additional renal problems (e.g. nephropathy) have been reported in small numbers of patients receiving indinavir. In summary, indinavir is a protease inhibitor with well documented efficacy when used as part of combined therapy in patients with HIV infection. Both US and UK treatment guidelines continue to recommend protease inhibitor-based regimens including indinavir as a first-line option. Indinavir is being studied as a twice daily and once daily regimen with a low dosage of ritonavir as a way to alleviate tolerability, drug interaction and patient compliance/adherence issues. Indinavir-containing triple therapy has demonstrated positive effects not only on surrogate markers of disease progression, but also on clinical end-points of mortality and morbidity in patients with HIV disease. Protease inhibitors are a significant advance in the care of patients with HIV infection, and, in an era of evidence-based medicine, indinavir represents an important component of antiretroviral treatment strategies.

Animals↗
PubMed1998

Pharmacokinetic interaction between ritonavir and indinavir in healthy volunteers.

The pharmacokinetic interaction between indinavir and ritonavir was evaluated in five groups of healthy adult volunteers to explore the potential for twice-daily (b.i.d.) dosing of this combination. All subjects received 800 mg of indinavir every 8 h (q8h) on day 2. In addition, subjects in group I received one dose of 800 mg of indinavir on day 1 and 800 mg of indinavir q8h on day 17. Subjects in Groups II and IV each received one dose of 600 mg of indinavir on days 1 and 17, and subjects in groups III and V each received one dose of 400 mg of indinavir on days 1 and 17. During days 3 to 17, ritonavir placebo or ritonavir at 200, 300, 300, or 400 mg q12h was given to groups I, II, III, IV, and V, respectively. Ritonavir at steady state probably inhibited the cytochrome P-450 3A metabolism of indinavir and substantially increased plasma indinavir concentrations, with the area under the plasma concentration-time curve (AUC) increasing up to 475% and the peak concentration in serum (Cmax) increasing up to 110%. The Cmax/trough concentration ratio decreased from 50 in standard q8h regimens to less than 14 when indinavir was administered with ritonavir. For a constant indinavir dose, an increase in the ritonavir dose yielded similar indinavir AUCs, Cmaxs, and concentrations at 12 h (C12s). For a constant ritonavir dose, an increase in the indinavir dose resulted in approximately proportional increases in the indinavir AUC, less than proportional increases in Cmax, and slightly more than proportional increases in C12. Ritonavir reduced between-subject variability in the indinavir AUC and trough concentrations and did not affect indinavir renal clearance. With the altered pharmacokinetic profile, indinavir likely could be given as a b.i.d. combination regimen with ritonavir. This could potentially improve patient compliance and thereby reduce treatment failures.

Adolescent↗
PubMed2000

Indinavir urolithiasis.

Indinavir sulfate is a protease inhibitor that has been found to be extremely effective in increasing CD4+ cell counts and in decreasing HIV-RNA titers in patients with HIV and AIDS. However, patients receiving indinavir also have been noted to have a significant risk for developing urolithiasis. Published reports of indinavir urolithiasis estimate its incidence at between 4 and 13%. Indinavir has a high urinary excretion with poor solubility in a physiologic pH solution. Consequently, patients develop urinary stones that are principally composed of indinavir or of a mixture of indinavir and other substances, such as calcium oxalate. Similar to other forms of urolithiasis, acute flank pain and hematuria are the typical symptoms of indinavir urolithiasis. Indinavir urolithiasis is unique in that computed tomography, which was once thought to be efficacious in identifying all urinary calculi, is not useful in imaging stones that are composed of pure indinavir. Indinavir urolithiasis generally responds to a conservative regimen of hydration, pain control, and the temporary discontinuation of the medication. Only a minority of patients need surgical intervention. Approximately 10% of patients ultimately need to discontinue indinavir therapy altogether. Indinavir is an antiviral agent that has a significant role in the treatment of AIDS. Although urolithiasis is a significant side effect of indinavir use, limiting its clinical application is not the answer. Rather, physicians need to know more about indinavir urolithiasis to help their patients cope with its potential complications.

HIV Protease Inhibitors↗
PubMed1996

Species differences in the pharmacokinetics and metabolism of indinavir, a potent human immunodeficiency virus protease inhibitor.

Indinavir, a potent and specific inhibitor of human immunodeficiency virus protease, is undergoing clinical investigation for the treatment of acquired immunodeficiency syndrome. The studies described herein were designed to characterize the absorption, distribution, metabolism, and excretion of the drug in rats, dogs, and monkeys. Indinavir exhibited marked species differences in elimination kinetics. The plasma clearance was in the rank order: rat (107 ml/min/kg) > monkey (36 ml/min/kg) > dog (16 ml/min/kg). Significant differences in the bioavailability of indinavir also were observed. When given orally as a solution in 0.05 M citric acid, the bioavailability varied significantly from 72% in the dog to 19% in the monkey, and 24% in the rat. These differences in bioavailability were attributed mainly to species differences in the magnitude of hepatic first-pass metabolism. The distribution of indinavir was studied only in rats, both intravenously and orally. Intravenously, indinavir was distributed widely throughout the body. Brain uptake studies showed that indinavir penetrated the blood-brain barrier, but that the penetration was limited. After oral administration, indinavir was distributed rapidly into and out of the lymphatic system. The rapid lymph transfer is of clinical relevance, because a primary clinical hallmark of acquired immunodeficiency syndrome is the depletion of CD4 lymphocytes. Biliary and urinary recovery studies revealed that metabolism was the major route of indinavir elimination in all species, and N-dealkylation, N-oxidation, and hydroxylation seemed to be the major pathways. Although limited to qualitative aspects, the metabolite profile obtained from in vitro microsomal studies generally reflected the in vivo oxidative metabolism of indinavir in all species studies. Results from the chemical and immunochemical inhibition studies indicated the possible involvement of isoforms of the CYP3A subfamily in the oxidative metabolism of indinavir in rats, dogs, and monkeys. This is consistent with our previous studies, which have shown that CYP3A4 is the isoform responsible for the oxidative metabolism of indinavir in human liver microsomes. Furthermore, the in vivo oxidative metabolism of indinavir in rats, dogs, and monkeys was qualitatively similar to that in humans. The high degree of similarity in the metabolite profiles of drug metabolism between animals and humans validates the use of these animal models for toxicity studies of indinavir. Attempts were made to quantitatively extrapolate in vitro metabolic data to in vivo metabolism. With the application of the well-stirred and parallel-tube models, the hepatic clearance and hepatic extraction ratio were calculated using the in vitro Vmax/Km values. In rats, the predicted hepatic clearance (31 ml/ min/kg) and hepatic extraction ratio (0.47) agreed well with the observed in vivo hepatic clearance (43 ml/min/kg) and hepatic extraction ratio (0.68). In addition, the hepatic clearance of indinavir was predicted reasonably well in dogs and monkeys. Based on the in vitro intrinsic clearance of human liver microsomes, a small but significant hepatic first-pass metabolism (ca. 25%) is expected in humans.

Animals↗
PubMed2002

The influence of efavirenz on the pharmacokinetics of a twice-daily combination of indinavir and low-dose ritonavir in healthy volunteers.

OBJECTIVE: This study evaluated the effect of multiple-dose efavirenz on the steady-state pharmacokinetics of the combination of indinavir (800 mg) and low-dose ritonavir (100 mg) twice a day, in which ritonavir is used to increase indinavir plasma concentrations. METHODS: Eighteen healthy male volunteers participated in this multiple-dose, 1-arm, 2-period interaction study. They took a combination of 800 mg indinavir and 100 mg ritonavir with food for 15 days. From days 15 to 29, a once-daily administration of 600 mg efavirenz was added to the combination. Pharmacokinetics of indinavir and ritonavir on days 15 and 29 were compared. RESULTS: Fourteen volunteers completed the study. The addition of efavirenz resulted in significant reductions (P <.01) in indinavir area under the curve (AUC, -25%), trough concentration (C(min), -50%), and maximum concentration (C(max), -17%). All indinavir C(min) levels on day 29 remained equivalent to or above the mean C(min) value described for the regimen of 800 mg indinavir three times a day, without ritonavir (0.15 mg/L). Changes in ritonavir AUC, C(min), and C(max) were -36%, -39%, and -34%, respectively. Pharmacokinetics of efavirenz on day 29 were comparable with published data. CONCLUSIONS: The addition of efavirenz to a combination of 800 mg indinavir and 100 mg ritonavir twice daily results in significant decreases in AUC, C(max), and especially C(min) of indinavir. The dose of indinavir or ritonavir should be increased to maintain similar indinavir drug levels after addition of efavirenz to the indinavir-ritonavir combination. Dose modifications may not be needed in antiretroviral-naive human immunodeficiency virus-infected patients if the reference C(min) of the regimen of 800 mg indinavir 3 times a day is considered to be adequate.

Adult↗
PubMed1998

Effect of fluconazole on indinavir pharmacokinetics in human immunodeficiency virus-infected patients.

To evaluate a potential pharmacokinetic interaction of coadministration of fluconazole, and indinavir, a human immunodeficiency virus (HIV) protease inhibitor, 13 patients were enrolled in a multiple-dose, three-period, placebo-controlled, crossover study. Patients were randomly assigned to receive indinavir at 1,000 mg every 8 h for 7 1/3 days (with fluconazole placebo), fluconazole at 400 mg once daily for 8 days (with indinavir placebo), and indinavir with fluconazole in combination. The pharmacokinetics of both drugs were measured on day 8 of each treatment period. The peak concentration in plasma (Cmax) and the time to reach Cmax were obtained by inspection, and the area under curve (AUC) was calculated for indinavir and fluconazole for each treatment period in which the respective drugs were administered. There was a marginally (P = 0.08) statistically significant decrease in the AUC from 0 to 8 h (AUC(0-8)) for indinavir when it was administered with fluconazole. However, the magnitudes of the decreases in Cmax and the concentration at 8 h postdosing (C8) were not as great as the decrease in AUC(0-8). Although the 90% confidence interval for the geometric mean ratio was within the hypothesized limits, the clinical significance is not clear. Indinavir coadministration with fluconazole had no statistically (P > 0.5) or clinically significant effect on the Cmax and C8 of indinavir. Fluconazole coadministration with indinavir had no statistically or clinically significant effect on the pharmacokinetics of fluconazole. One patient was discontinued because of mild to moderate abdominal pain and diarrhea while on indinavir and fluconazole in combination. No serious adverse experience according to the results of laboratory tests was noted. Total bilirubin levels in serum were mildly increased in most patients treated with indinavir. This was not clinically significant and was not affected by the coadministration of fluconazole. Although the values of the pharmacokinetic parameters for indinavir decrease in the presence of fluconazole, indinavir and fluconazole can be administered concomitantly to HIV-infected patients without adjustment of the dose of either drug, and both drugs are generally well tolerated.

Adolescent↗
PubMed2004

Pharmacokinetics of indinavir and nelfinavir in treatment-naive, human immunodeficiency virus-infected subjects.

AIDS Clinical Trials Group protocol 388 was designed to compare a three-drug regimen (indinavir with dual nucleosides) to a four-drug regimen (indinavir plus nelfinavir or indinavir plus efavirenz with dual nucleosides). Blood samples from patients taking indinavir and nelfinavir were collected over 8 to 12 h following a specified dose and were analyzed with high-performance liquid chromatography. Pharmacokinetic data were derived by using noncompartmental analysis. Following administration of indinavir every 8 h in the absence of nelfinavir (n = 8), the median predose indinavir concentration (C(0)) was 369 ng/ml (range, <10 to 949 ng/ml; one subject had a concentration of <10 ng/ml), and the concentration 8 h after administration of the study dose was 159 ng/ml (range, 85 to 506 ng/ml). In the group receiving 1000 mg of indinavir every 12 h with nelfinavir (n = 10), the median indinavir C(0) was <10 ng/ml (range, <10 to 3740 ng/ml; six subjects had a value of <10 ng/ml), and the C(12 h) was 44 ng/ml (range, <10 to 4236 ng/ml; five subjects had a value of <10 ng/ml), while the subjects who received 1200 mg of indinavir every 12 h with nelfinavir (n = 7) had a C(0) of 146 ng/ml (range, 58 to 5215 ng/ml) and a C(12 h) of 95 ng/ml (range, 12 to 954 ng/ml). Indinavir clearance was significantly lower in the presence of nelfinavir (median [interquartile range], 34.1 liters/h [range, 22.6 to 45.8 liters/h] versus 47.9 liters/h [range, 42.7 to 70.3 liters/h]; P < 0.017). For subjects receiving 1,000 mg of indinavir every 12 h, the median C(0) value for nelfinavir (n = 9) was 1,779 ng/ml (range, <187.5 to 4579 ng/ml), and the C(12 h) was 1554 ng/ml (range, <187.5 to 5,540 ng/ml). Due to the unacceptable number of undetectable indinavir trough concentrations, 1200 mg of indinavir appears to be the preferred dose in a twice-daily regimen that includes nelfinavir.

Adult↗
PubMed2004

Effects of escin on indinavir crystallization time in the urine of patients with HIV-I infection: a multicenter, randomized, open-label, controlled, four-period crossover trial.

BACKGROUND: The combination of indinavir, a protease inhibitor, and reverse-transcriptase inhibitors is widely used in the treatment of HIV-1 infection. However, precipitation of indinavir crystals in the renal tubular lumen due to the drug's aqueous insolubility may result in characteristic symptoms of flank pain or classic renal colic. An in vitro study has shown that addition of escin to synthetic urine containing indinavir delayed the crystallization time of indinavir. OBJECTIVE: This study examined the efficacy and tolerability of the addition of escin to highly active antiretroviral therapy containing indinavir to delay the crystallization time of indinavir in urine. METHODS: This was a multicenter, randomized, open-label, controlled, 4-period crossover trial in which each period lasted 4 weeks. HIV-1-infected adults receiving treatment with indinavir plus 2 nucleoside analogue reverse-transcriptase inhibitors in whom plasma viral loads had been undetectable (HIV-1 RNA <200 copies/mL) for at least 6 months were randomly assigned to 1 of 2 groups based on the timing of the initiation of escin. Group I received escin during the second and third treatment periods, and group II received escin during the first and fourth treatment periods. The primary end point was the in vitro crystallization time of indinavir in 24-hour urine specimens, determined at the end of each 4-week period. Tolerability was assessed based on the number of patients with a rebound in plasma viral load and on the numbers of clinically and biologically relevant adverse events (including those requiring discontinuation of treatment). Clinical and laboratory evaluations were performed throughout each 4-week period. RESULTS: Fifty HIV-1-infected patients were enrolled, 47 were randomized to treatment (40 [85.1%] men, 7 [14.9%] women; median [interquartile range] age, 36 [34-45] years), and 30 completed the study. Urine pH and plasma and urine indinavir concentrations were unaffected by the addition of escin to antiretroviral treatment. The mean time to the onset of crystallization was 14.7 minutes with escin (95% Cl, 11.8-17.5) and 9.9 minutes without it (95% Cl, 6.7-13.1). Therefore, the addition of escin increased the mean crystallization time by 5.5 minutes (95% Cl, 1.5-9.5; P = 0.008), representing the overall capacity of study treatment to inhibit indinavir crystallization in the urine. Three of 47 patients had mild gastrointestinal symptoms associated with escin treatment. No episodes of nephrolithiasis were recorded during the study or after the completion of study treatment. CONCLUSION: The results of this prospective clinical trial of the effect of escin on indinavir crystallization time support the possibility that indinavir-associated nephrolithiasis may be prevented by means other than overhydration. Further research is needed in greater numbers of patients over longer follow-up times.

Adult↗
PubMed2003

No clinically significant pharmacokinetic interactions between voriconazole and indinavir in healthy volunteers.

AIMS: Voriconazole is a new triazole antifungal agent, and is metabolized by the cytochrome P450 isoenzymes CYP2C9, CYP2C19 and to a lesser extent by CYP3A4. Protease inhibitors, such as indinavir, are also metabolized by cytochrome P450 (mainly CYP3A4). As these drugs are likely to be coadministered, these studies were performed to assess the pharmacokinetic interactions, safety and toleration of these drugs when taken together. METHODS: Two randomized placebo-controlled studies were conducted in healthy male volunteers. Study A was an open parallel-group study of the effect of indinavir on the steady-state pharmacokinetics of voriconazole in 18 volunteers (nine subjects in each group). Subjects received voriconazole 200 mg twice daily (days 1-7), then voriconazole 200 mg twice daily + indinavir 800 mg or placebo three times daily (days 8-17). Study B was a double-blind, randomized, two-way crossover study of the effect of voriconazole on the steady-state pharmacokinetics of indinavir in 14 volunteers. They received indinavir 800 mg three times daily + voriconazole 200 mg or placebo twice daily for two 7-day treatment periods separated by a washout period of at least 7 days. Pharmacokinetic parameters were compared within treatment groups at days 7 and 17 in Study A and between treatment groups on day 7 of each period in Study B. All adverse events were recorded. RESULTS: Study A: Seventeen subjects were evaluable for pharmacokinetic analysis (eight voriconazole + indinavir, nine voriconazole + placebo). The day 17/day 7 ratios for Cmax and AUCtau were estimated as 102%[90% confidence interval (CI) 91, 114] and 107% (90% CI 98, 118), respectively. Study B: Fourteen subjects were evaluable for pharmacokinetic analysis in each treatment period. The ratios between the geometric means for indinavir + voriconazole vs. indinavir + placebo were: Cmax, 91% (90% CI 83, 101), AUCtau, 87% (90% CI 77, 100), and Cmin, 101% (90% CI 82, 125). Trough plasma concentrations of indinavir were above the concentration required to inhibit HIV replication (IC95) in both treatment periods. Voriconazole coadministered with indinavir was well tolerated in both studies. CONCLUSIONS: The coadministration of voriconazole and indinavir in healthy volunteers had no clinically significant effect on the pharmacokinetics of either voriconazole or indinavir.

Administration, Oral↗
PubMed1999

The steady-state plasma pharmacokinetics of indinavir alone and in combination with a low dose of ritonavir in twice daily dosing regimens in HIV-1-infected individuals.

OBJECTIVE: To explore the steady-state plasma pharmacokinetics of indinavir in twice daily dosing regimens with and without the co-administration of 100 mg ritonavir. DESIGN: Observational pharmacokinetic study. PATIENTS: HIV-1-infected individuals who use indinavir alone (1200 mg twice daily, n = 6), or the combination of 100 mg ritonavir twice daily plus either 800 mg (n = 6), or 1200 mg indinavir twice daily (n = 2). METHODS: Steady-state pharmacokinetics of indinavir and ritonavir were assessed by drawing 12 blood samples during an 8-h period after ingestion of the medication. RESULTS: Significant differences were observed for indinavir pharmacokinetics between the dosing regimens indinavir 1200 mg twice daily alone and indinavir/ ritonavir 800/100 mg twice daily with respect to the mean trough concentration (0.21 and 0.99 microg/ml, respectively, P = 0.002), the mean maximum concentration (13.79 and 8.74 microg/ml, respectively, P = 0.028), and for the mean plasma elimination half-life (1.6 and 3.2 h, respectively, P = 0.001). The combination indinavir/ritonavir 1200/100 mg twice daily led to very high exposure to indinavir and was not well tolerated. However, the combination indinavir/ritonavir 800/100 mg twice daily was well tolerated and resulted in therapeutic concentrations of indinavir with improved trough concentrations and similar maximum concentrations as observed with the licensed dosage of 800 mg three times daily. CONCLUSION: Combination of indinavir and 100 mg ritonavir in twice daily dosing regimens significantly affects the pharmacokinetic profile of indinavir. The results of this observational study provide a pharmacologic basis for the combination of indinavir (800 mg) and ritonavir (100 mg) in twice daily dosing regimens.

Adult↗
PubMed2001

A retrospective, cohort-based survey of patients using twice-daily indinavir + ritonavir combinations: pharmacokinetics, safety, and efficacy.

OBJECTIVE: To describe the pharmacokinetics, safety, and efficacy of twice-daily indinavir + ritonavir regimens DESIGN: A cohort-based survey of HIV-infected patients who either used indinavir 800 mg + ritonavir 100 mg twice daily or indinavir 400 mg + ritonavir 400 mg twice daily. METHODS: Data were extracted from a database of samples sent to our laboratory for measurement of indinavir + ritonavir plasma concentrations. Patient characteristics, safety, and efficacy measurements were collected by retrospective chart review. RESULTS: 100 Patients using 800-mg indinavir + 100-mg ritonavir twice daily and 32 patients using 400-mg indinavir + 400-mg ritonavir twice daily were eligible. Median peak and trough concentrations of indinavir were 6.8 and 0.77 mg/L in the 800/100 group and 2.6 and 0.45 mg/L in the 400/400 group. The most frequently found side effects were nausea and vomiting, which occurred in 22.1% and 34.9% of the patients in the 800/100 and the 400/400 groups, respectively. Viral load data were analyzed for patients who switched from 800-mg indinavir three times daily to one of the indinavir + ritonavir twice daily regimens. At the time of switch 63% (800/100 group) and 60% (400/400 group) had an undetectable viral load and this increased to 77% and 70%, respectively, during follow-up. Patients who switched to the 400/400 group discontinued treatment more frequently than patients who switched to the 800/100 group (70% vs. 26%, p =.008). CONCLUSIONS: Indinavir + ritonavir regimens show improved pharmacokinetic properties, allowing twice-daily dosing with food. Clinical data suggest that safety and efficacy is at least as good as with indinavir three-times-daily regimens without ritonavir. Prospective, comparative trials are needed to properly assess the role in HIV therapy of these twice-daily indinavir + ritonavir regimens.

Cohort Studies↗
PubMed2005

Population pharmacokinetics of indinavir alone and in combination with ritonavir in HIV-1-infected patients.

AIMS: The aim of the study was to characterize the population pharmacokinetics of indinavir, define the relationship between the pharmacokinetics of indinavir and ritonavir, and to identify the factors influencing the pharmacokinetics of indinavir alone or when given with ritonavir. METHODS: HIV-1-infected patients being treated with an indinavir-containing regimen were included. During regular visits, 102 blood samples were collected for the determination of plasma indinavir and ritonavir concentrations. Full pharmacokinetic curves were available from 45 patients. Concentrations of indinavir and ritonavir were determined by liquid chromatography coupled with electrospray tandem mass spectrometry. Pharmacokinetic analysis was performed using nonlinear mixed effect modelling (NONMEM). RESULTS: The disposition of indinavir was best described by a single compartment model with first order absorption and elimination. Values for the clearance, volume of distribution and the absorption rate constant were 46.8 l h(-1) (24.2% IIV), 82.3 l (24.6% IIV) and 02.62 h(-1), respectively. An absorption lag-time of 0.485 h was detected in patients also taking ritonavir. Furthermore this drug, independent of dose (100-400 mg) or plasma concentration, decreased the clearance of indinavir by 64.6%. In contrast, co-administration of efavirenz or nevirapine increased the clearance of indinavir by 41%, irrespective of the presence or absence of ritonavir. Female patients had a 48% higher apparent bioavailability of indinavir than males. CONCLUSIONS: The pharmacokinetic parameters of indinavir were adequately described by our population model. Female gender and concomitant use of ritonavir and non-nucleoside reverse transcriptase inhibitors strongly influenced the pharmacokinetics of this drug. The results support the concept of ritonavir boosting, maximum inhibition of indinavir metabolized being observed at 100 mg.

Adult↗
PubMed2002

Urinary cytology associated with human polyomavirus and indinavir therapy in HIV-infected patients.

We retrospectively analyzed 155 urine cytology samples (78 from patients treated with indinavir; 77, no indinavir) from 90 HIV+ patients to evaluate possible association between human polyomavirus and hematuria and to describe indinavir-associated urinary cytologic findings. The CD4 count also was recorded. Variables studied included the presence of cellular viral changes consistent with polyomavirus infection (PVCs), microscopic hematuria, multinucleated cells, indinavir crystals, neutrophils, and eosinophils. Twenty-two samples (15.8%) from patients with CD4 counts of more than 200/microL (>200 x 10(6)/L) showed PVCs. Multinucleated cells, of presumed histiocytic origin based on morphologic features and selective immunocytochemical findings, were present in a higher percentage of samples from indinavir-treated patients. Neutrophils were present in a higher percentage of indinavir-treated patients. Indinavir crystals were identified in 9 samples (12%) from patients receiving indinavir The lower percentage of PVCs in HIV+ patients with high CD4 counts likely represents an indirect antipolyomavirus indinavir effect by boosting immunity. Multinucleated cells (presumably histiocytic) and acute inflammation are associated with indinavir therapy. Indinavir crystals have a characteristic fan or circular lamellate appearance. Because indinavir crystals may be associated with genitourinary disease, recognizing and reporting them is clinically relevant in HIV+ patients.

BK Virus↗
PubMed2000

Stimulation of vitamin A(1) acid signaling by the HIV protease inhibitor indinavir.

HIV protease inhibitors (PIs) are effective drugs for the treatment of AIDS. However, PI therapy is sometimes associated with side-effects including increased plasma lipids and altered body fat distribution, although fat redistribution may occur in some patients not treated with PIs. Overdosage with vitamin A(1) acid (all-trans-retinoic acid, ATRA) or its metabolites may cause similar changes in lipid metabolism. Moreover, the PI indinavir and retinoids have been associated with nail, skin, and hair defects, suggesting that indinavir and retinoids may exert their effects through similar molecular mechanisms. This hypothesis was tested by examining the effects of PIs on retinoid signaling in vitro. Mesenchymal stem cells (C3H10T1/2) were cultured in the presence of various PIs (amprenavir, indinavir, nelfinavir, ritonavir, and saquinavir) and synthetic retinoids, and the metabolic response was assessed by measuring the activity of a retinoid-regulated protein, alkaline phosphatase (ALP). Of the PIs tested, only indinavir stimulated ATRA-dependent ALP activity and altered stem cell morphology; the effects of indinavir occurred in the presence of ATRA, but not in its absence. Moreover, indinavir increased the effects of ATRA on lipid accumulation during fat cell differentiation. AGN 193109 (4-[[5,6-dihydro-5, 5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl]ethynyl]-benzoic acid), a retinoic acid receptor (RAR) antagonist, inhibited the synergistic effects of indinavir and ATRA, indicating that indinavir increases RAR signaling. However, indinavir did not potentiate ALP activity in the presence of the RAR agonist CH55 (3,5-di-tert-butylchalcone 4'-carboxylic acid). Unlike ATRA, CH55 does not bind to cytosolic retinoic acid binding protein (CRABP), suggesting that CRABP may regulate the effects of indinavir on RAR signaling. These observations support the proposal that altered retinoid signaling promotes some of the adverse reactions associated with indinavir therapy, such as altered lipid metabolism.

Animals↗
PubMed2000

Prospective study of urinalysis abnormalities in HIV-positive individuals treated with indinavir.

Indinavir is a potent protease inhibitor widely used in combination with reverse-transcriptase inhibitors to treat human immunodeficiency virus (HIV) disease. Individuals treated with indinavir are prone to develop urinary complications, including renal colic, renal calculi, lower urinary tract symptoms, and indinavir crystalluria. Although renal stones secondary to indinavir have been described and characterized, little is known about the onset, frequency, and significance of the crystalluria. To document the longitudinal characteristics of indinavir crystalluria and associated urine abnormalities, 54 asymptomatic indinavir-naive HIV-positive individuals had urinalysis testing initially weekly and then monthly during the first year of indinavir treatment. Six hundred eight urinalyses were performed (11 +/- 2 urinalysis/subject), including 579 microscopy examinations performed by a nephrologist (10 +/- 2 examinations/subject). Baseline urinalysis results were essentially normal. After the start of treatment, indinavir crystalluria was frequently observed (67% of subjects). After the first 2 weeks, indinavir crystalluria remained constant at a frequency of approximately 25% of urine sediments examined at each test point. Other urine abnormalities, principally leukocytes (>/=10/high-power field) and casts, were observed in 39% of subjects. These abnormalities were more severe in five subjects, with concomitant increasing serum creatinine levels in three of them. Additional urine findings include the predominance of low pH (</=5. 5 in 72% of urinalyses) and high specific gravity (>/=1.025 in 66% of urinalyses). In conclusion, abnormal urinalysis results were noted frequently during the first year of treatment with indinavir. The main findings were the high proportion of subjects with crystalluria and the relatively high frequency of crystalluria observed consistently throughout. These findings may occasionally be associated with other urine abnormalities, presumably secondary to indinavir crystalluria.

Adult↗
PubMed2003

Steady-state pharmacokinetic interaction of modified-dose indinavir and rifabutin.

BACKGROUND: Combined administration of the human immunodeficiency virus protease inhibitor indinavir (800 mg every 8 hours) with the antimycobacterial rifabutin (300 mg daily) results in a significant decrease in indinavir concentrations with subsequent risk of treatment failure, as well as a significant increase in rifabutin concentrations with increased toxicity. Therefore this study was designed to evaluate alternative dosing regimens. METHODS: Eighteen healthy volunteers received 300 mg rifabutin daily alone for 14 days and then 1000 mg indinavir every 8 hours plus rifabutin at a reduced dose of 150 mg daily, given at 8 am or noon in a randomized crossover sequence for 14 days. Ten human immunodeficiency virus-infected subjects received 800 mg indinavir every 8 hours for 14 days and then 1000 mg indinavir every 8 hours plus 150 mg rifabutin daily at 8 am for 14 days. Twenty-four-hour pharmacokinetic sampling was performed at the end of each 14-day study period. RESULTS: Indinavir, 1000 mg every 8 hours, coadministered with 150 mg rifabutin daily produced an area under the concentration-time curve similar to that of 800 mg indinavir every 8 hours. The mean area under the concentration-time curve values of rifabutin and 25-desacetyl rifabutin, when 150 mg rifabutin every morning was coadministered simultaneously with 1000 mg indinavir every 8 hours, were 70% and 120% higher than with 300 mg rifabutin daily alone. Drug concentrations were not different when rifabutin and indinavir were administered simultaneously at 8 am or staggered by 4 hours. CONCLUSIONS: Increasing indinavir's dose to 1000 mg every 8 hours when coadministered with rifabutin at a reduced dose of 150 mg daily compensates for rifabutin induction of indinavir metabolism. Rifabutin concentrations were still higher than with rifabutin alone despite a 50% reduction of rifabutin dose, which is the current recommendation when these 2 drugs are combined. The clinical significance of the increase in rifabutin and 25-desacetyl rifabutin concentrations is not known.

Adolescent↗