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At least 19 recordsLinked to original sources
PubMed2006

Low urine pH is associated with reduced indinavir crystalluria in indinavir-treated HIV-infected individuals.

Indinavir is a potent HIV-1 protease inhibitor included in current antiretroviral therapeutic regimens. It is associated with renal and urological complications ascribed to indinavir crystalluria. We have previously reported that indinavir crystalluria is frequently observed soon after initiation of therapy. In a cohort of 54 asymptomatic indinavir-naive HIV-1-infected individuals during their first year of treatment with indinavir, approximately 25% of urinalyses (U/A) contained indinavir crystals. Because the determinants of the crystalluria are unknown, we examined the relationship between urine specific gravity (SG) and pH, singly and in combination, and indinavir crystalluria in these subjects. A total of 579 U/A were obtained from the study subjects at their scheduled monthly outpatient medical assessments. The frequency of indinavir crystalluria was lower in U/A with lower pH, irrespective of the SG. Conversely, U/A with high pH (> or = 6.0) had a higher frequency of indinavir crystalluria, which was further influenced by the urine SG. As a result, nearly half of the U/A (46.7%) with high pH (> or = 6.0) and intermediate-high SG (> or = 1.015) contained indinavir crystals. In conclusion, the frequency of indinavir crystalluria in asymptomatic HIV-1 infected individuals during their first year of treatment with indinavir was markedly influenced by the urine pH and SG. Our findings suggest that low urine pH may have a protective effect against indinavir crystalluria across the entire range of urine SG.

Adult↗
PubMed2003

Administration of indinavir and low-dose ritonavir (800/100 mg twice daily) with food reduces nephrotoxic peak plasma levels of indinavir.

BACKGROUND: The objective of this study was to compare indinavir peak plasma (Cmax) values after administration of indinavir/ritonavir 800/100 mg on an empty stomach or with food. High indinavir Cmax values have been associated with indinavir-related nephrotoxicity. METHODS: This was an open-label, randomized, two-treatment, two-period, cross-over pharmacokinetic study performed at steady state. HIV-infected patients who had been using indinavir/ritonavir 800/100 mg twice daily for at least 4 weeks were randomized to take this combination with a light breakfast (two filled rolls and 130 ml of fluid) on a first study day, and without food on a second day, or in the reverse order. The pharmacokinetics of indinavir and ritonavir were assessed after plasma and urine sampling during 12 h. RESULTS: Data for nine patients were evaluated. Administration of indinavir/ritonavir 800/100 mg on an empty stomach resulted in a higher indinavir Cmax [geometric mean (GM) ratio - fasting/fed and 95% confidence interval (CI): 1.28 (1.08-1.52), P=0.01] and a trend to a shorter indinavir tmax (P=0.07) compared to administration with food. The mode of administration of indinavir/ritonavir did not affect plasma indinavir Cmax and AUC values, parameters that have been associated with the antiviral efficacy of indinavir, nor the urinary excretion of indinavir. CONCLUSIONS: Administration of indinavir/ritonavir 800/100 mg on an empty stomach results in a higher indinavir Cmax compared to ingestion with a light meal. Stated the other way round, intake with a light meal reduces indinavir Cmax, which probably reflects a food-induced delay in the absorption of indinavir. It is recommended to administer indinavir/ritonavir 800/100 mg with food, as a possible means to prevent indinavir-related nephrotoxicity in patients who start or continue with this regimen.

Adult↗
PubMed2006

The use of pharmacokinetically guided indinavir dose reductions in the management of indinavir-associated renal toxicity.

OBJECTIVES: Indinavir is associated with nephrotoxicity. Therapeutic drug monitoring of indinavir improves clinical outcome, but there is little data regarding therapeutic drug monitoring for patients with established indinavir-associated renal impairment. We prospectively studied the use of therapeutic drug monitoring in patients with virological success but established nephrotoxicity on an indinavir-containing regimen. METHODS: We measured indinavir C(trough)/C(2h), serum creatinine, pyuria, blood pressure (BP), weight and HIV RNA. The major endpoint of interest was the number of patients achieving a normal creatinine level 20 weeks following final indinavir dose adjustment. Primary analysis was by intention to treat (ITT). RESULTS: A total of 35 patients were enrolled; mean (SD) age 40.3 (5.8) years; mean (SD) BMI 21.5 (2.8) kg/m(2). At baseline 6/35 (17%) had a serum creatinine concentration within normal limits, but were offered enrolment because of previous nephrotoxicity (nephrolithiasis and/or abnormal serum creatinine), and a screening pharmacokinetic profile associated with increased nephrotoxicity risk. By ITT analysis 11/35 (31%) had normal creatinine at study end (P = 0.18). Of the 29 patients with abnormal creatinine at baseline, 7/29 (24.1%) had normal creatinine at study end (P = 0.016). Patients had a median (IQR) indinavir per dose adjustment over the study of 400 (400-800) mg. We observed improvements in estimated creatinine clearance, pyuria, resting BP and indinavir pharmacokinetic profile. HIV RNA control was maintained with continued immune recovery despite lower indinavir doses. CONCLUSIONS: Patients experiencing nephrotoxicity on an indinavir-containing regimen were safely maintained on indinavir by means of therapeutic drug monitoring. Parameters of renal function improved but did not return to baseline values, at least in the short-term.

Adult↗
PubMed2002

Intestinal metabolism promotes regional differences in apical uptake of indinavir: coupled effect of P-glycoprotein and cytochrome P450 3A on indinavir membrane permeability in rat.

The purpose of this study was to investigate transport and metabolism contributions to low indinavir permeability in rat ileum and enhanced drug permeability in the jejunum. Permeability models utilized included single pass in situ rat intestinal perfusion and rat intestinal tissue mounted in Ussing chambers. Intestinal metabolism was measured by fractional appearance of metabolite (F(met)), determined as the percentage of the predominant metabolite M6 over luminal loss of indinavir in the perfusion model. Among the results, indinavir exhibited bidirectional transport across rat ileum. Verapamil and cyclosporin A inhibited net flux by 37 and 38%, respectively. Intestinal metabolism of indinavir was most significant in upper jejunum (F(met) = 65.78 +/- 19.02%), decreasing in midjejunum (F(met) = 31.58 +/- 5.63%). M6 was not detectable in ileum or colon. Western blot analysis of rat intestinal mucosal tissue samples confirmed that the axial expression of CYP3A was consistent with the regional pattern of formation of M6. Intestinal metabolism was saturable and could be inhibited by the CYP3A inhibitor, ketoconazole. A low luminal concentration of indinavir (1 microM) was associated with high F(met) (87.90 +/- 14.30%), whereas a high luminal concentration of indinavir (50 microM) was associated with low F(met) (35.84 +/- 11.59%). In the presence of ketoconazole, both F(met) and permeability of indinavir were reduced in the jejunum. These results suggest that 1) intracellular metabolism of indinavir enhances apical uptake of indinavir in the rat jejunum as a function of the increased concentration gradient generated across the epithelial cell membrane and 2) the efflux transporter P-glycoprotein limits apical uptake of indinavir in the ileum, resulting in low apparent permeability.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

High indinavir Cmin is associated with higher toxicity in patients on indinavir-ritonavir 800/100 mg twice-daily regimen.

We retrospectively evaluated the incidence of side effects and treatment intervention according to indinavir trough concentration in 63 patients taking indinavir-ritonavir 800/100 mg twice daily. Median indinavir trough concentration was 1446 ng/mL at 800/100 mg twice daily associated with 60% of measured toxicity. Among patients with indinavir trough concentration >500 ng/mL, 46 of 49 had a dosage adjustment and 17 have had more than two dosage adjustments. The primary reason for dosage adjustment was toxicity in 69% (43 cases). Renal and cutaneous toxicity were predominant.After dosage adjustment, median indinavir trough concentration was 459 ng/mL, which was associated with 8% of toxicity. Trough concentrations >500 ng/mL were correlated with increased toxicity (p <.05) and more treatment intervention (p =.02). In conclusion, achievement of indinavir trough concentrations <500 ng/mL appears to be safe, and an optimal concentration range for indinavir trough concentration could be 150 to 500 ng/mL for an indinavir-ritonavir twice daily regimen.

Adult↗
PubMed1999

Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. Study 006 Team.

BACKGROUND: Efavirenz is a nonnucleoside reverse-transcriptase inhibitor of human immunodeficiency virus type 1 (HIV-1). We compared two regimens containing efavirenz, one with a protease inhibitor and the other with two nucleoside reverse-transcriptase inhibitors, with a standard three-drug regimen. METHODS: The study subjects were 450 patients who had not previously been treated with lamivudine or any nonnucleoside reverse-transcriptase inhibitor or protease inhibitor. In this open-label study, patients were randomly assigned to one of three regimens: efavirenz (600 mg daily) plus zidovudine (300 mg twice daily) and lamivudine (150 mg twice daily); the protease inhibitor indinavir (800 mg every eight hours) plus zidovudine and lamivudine; or efavirenz plus indinavir (1000 mg every eight hours). RESULTS: Suppression of plasma HIV-1 RNA to undetectable levels was achieved in more patients in the group given efavirenz plus nucleoside reverse-transcriptase inhibitors than in the group given indinavir plus nucleoside reverse-transcriptase inhibitors (70 percent vs. 48 percent, P<0.001). The efficacy of the regimen of efavirenz plus indinavir was similar (53 percent) to that of the regimen of indinavir, zidovudine, and lamivudine. CD4 cell counts increased significantly with all combinations (range of increases, 180 to 201 cells per cubic millimeter). More patients discontinued treatment because of adverse events in the group given indinavir and two nucleoside reverse-transcriptase inhibitors than in the group given efavirenz and two nucleoside reverse-transcriptase inhibitors (43 percent vs. 27 percent, P=0.005). CONCLUSIONS: As antiretroviral therapy in HIV-1-infected adults, the combination of efavirenz, zidovudine, and lamivudine has greater antiviral activity and is better tolerated than the combination of indinavir, zidovudine, and lamivudine.

Adult↗
PubMedDate not supplied

Randomized, double-blind trial comparing indinavir alone, zidovudine alone and indinavir plus zidovudine in antiretroviral therapy-naive HIV-infected individuals with CD4 cell counts between 50 and 250/mm3.

Treatment with indinavir has been shown to result in marked decreases in viral load and increases in CD4 cell counts in HIV-infected individuals. A randomized double-blind study to evaluate the efficacy of indinavir alone (800 mg q8h), zidovidine alone (200 mg q8h) or the combination was performed to evaluate progression to AIDS. 996 antiretroviral therapy-naive patients with CD4 cell counts of 50-250/mm3 were allocated to treatment. During the trial the protocol was amended to add lamivudine to the zidovudine-containing arms. The primary endpoint was time to development of an AIDS-defining illness or death. The study was terminated after a protocol-defined interim analysis demonstrated highly significant reductions in progression to a clinical event in the indinavir-containing arms, compared to the zidovudine arm (p<0. 0001). Over a median follow-up of 52 weeks (up to 99 weeks), percent reductions in hazards for the indinavir plus zidovudine and indinavir groups compared to the zidovudine group were 70% and 61%, respectively. Significant reductions in HIV RNA and increases in CD4 cell counts were also seen in the indinavir-containing groups compared to the zidovudine group. Improvement in both CD4 cell count and HIV RNA were associated with reduced risk of disease progression. All three regimens were generally well tolerated.

Adult↗
PubMed1998

Low plasma concentrations of indinavir are related to virological treatment failure in HIV-1-infected patients on indinavir-containing triple therapy.

All human immunodeficiency virus type 1 (HIV-1)-infected patients who started to use indinavir (800 mg three times a day) as part of their triple drug regimen were included in a study to determine the importance of low plasma concentrations of indinavir as a cause of virological treatment failure. The indinavir concentration and a number of patient characteristics at baseline were tested as risk factors for virological treatment failure (defined as a viral load above 200 copies/ml after 24 weeks of treatment) in univariate and multivariate analyses; 65 patients were included. Virological treatment failure occurred in 36.9% of the patients. Multivariate analysis showed that a low plasma concentration of indinavir (odds ratio 0.1), a high viral load at baseline (odds ratio 2.6) and pretreatment with another protease inhibitor (odds ratio 10.0) were independent factors related to virological treatment failure. Monitoring of indinavir plasma concentrations may be an important tool for the optimization of triple drug combination therapy.

Acquired Immunodeficiency Syndrome↗
PubMed2002

Risk factors for indinavir-related renal colic in HIV patients: predictive value of indinavir dose/body mass index.

In a prospective study evaluating risk factors for indinavir-related renal colic in 555 HIV-infected patients receiving highly active antiretroviral therapy, followed-up fir 24 months, 23.6% developed one or more renal colic episodes, and 50 patients stopped indinavir. No correlation was observed between renal colic onset and sex, age, CD4 cell count, history, and hepatitis B or C virus co-infection, but baseline anthropometric values were significantly related to the onset of renal colic.

Adult↗
PubMed2003

Assessment of adherence to triple antiretroviral treatment including indinavir: role of the determination of plasma levels of indinavir.

OBJECTIVE: To assess the contribution of the determination of concentrations of indinavir (IND) in plasma to the assessment of self-reported adherence and keeping of appointments to withdraw drugs from the hospital pharmacy. PATIENTS AND METHODS: Adherence was assessed using three criteria: questionnaires, punctuality at appointments to withdraw drugs, and plasma concentrations of IND. Blood samples were obtained from 106 HIV-infected patients who had been receiving IND in combination with two nucleoside reverse transcriptase inhibitors for longer than 6 months. Logistic regression analysis was carried out, and receiver operating characteristic curves were drawn. RESULTS: The kappa index showed a low concordance for the three measures. When pharmacy appointments and self-report are used together, the nondetection of drug levels is more reliably predicted (AUC = 0.75). With the viral load as the gold standard, plasma levels contribute nothing to the information given by the other two measures combined (AUC = 0.63, AUC = 0.64). CONCLUSION: Measurement of adherence to highly active antiretroviral therapy is complex. Because there is no gold standard for it, we demonstrated that each of three common adherence measures has shortcomings that can be minimized in a combined measurement system. Indinavir plasma levels appear to provide no additional information, so further studies are undoubtedly necessary.

Adult↗
PubMed2000

A comparison of stavudine, didanosine and indinavir with zidovudine, lamivudine and indinavir for the initial treatment of HIV-1 infected individuals: selection of thymidine analog regimen therapy (START II).

OBJECTIVE: Comparison of stavudine (d4T), didanosine (ddI) and indinavir (IDV) with zidovudine (ZDV), lamivudine (3TC) and IDV in HIV-1 infected patients. DESIGN: Randomized, open-label. SETTING: Fourteen HIV Clinical Research Centers. PATIENTS: Two-hundred and five patients with less than 4 weeks antiretroviral treatment, naive to 3TC and protease inhibitors and with CD4 cell counts > or = 200 x 10(6)/l and plasma HIV-1 RNA levels > or = 10,000 copies/ml. INTERVENTIONS: Stavudine 40 mg and ddI 200 mg twice daily plus IDV 800 mg every 8 h compared with ZDV 200 mg every 8 h or 300 mg twice daily, 3TC 150 mg twice daily plus IDV. MAIN OUTCOME MEASURES: The proportion of patients with plasma HIV-1 RNA levels < 500 copies/ml and < or = 50 copies/ml and changes in CD4 cell counts were compared. RESULTS: In an analysis of the primary endpoint, 61% of patients on d4T + ddI + IDV and 45% of patients on ZDV + 3TC + IDV had all HIV-1 RNA values obtained between weeks 40 and 48 < 500 copies/ml [95% confidence interval (CI) for the difference between proportions, 1.7-30.3%; P = 0.038]. In an intent-to-treat analysis, the percentage of all patients randomized with all HIV-1 RNA levels < 500 copies/ml between 40 and 48 weeks were 53% for the d4T + ddI + IDV arm and 41% for the ZDV + 3TC + IDV arm (95% CI, -1.4% to 25.7%; P = 0.068). At 48 weeks 41% and 35% were < or = 50 copies/ml for the stavudine- and ZDV-containing arms respectively (P > 0.2). The median time-weighted average increases in CD4 cells count over 48 weeks were 150 x 10(6)/l cells for the d4T arm and 106 x 10(6)/l cells for the ZDV arm (P= 0.001). The occurrence of serious adverse events was not significantly different between arms. CONCLUSION: The combination of stavudine, ddl and IDV resulted in potent antiretroviral effects over a 48-week period, comparable or superior to zidovudine, 3TC and IDV supporting the use of stavudine, ddI and a protease inhibitor as an initial antiretroviral treatment.

Adolescent↗
PubMed2004

Pharmacokinetics of indinavir and ritonavir administered at 667 and 100 milligrams, respectively, every 12 hours compared with indinavir administered at 800 milligrams every 8 hours in human immunodeficiency virus-infected patients.

Human immunodeficiency virus (HIV) patients on nucleoside or nucleotide reverse transcriptase inhibitors with HIV RNA at <1,000 copies/ml were randomized in an open-label study to administration of combined indinavir/ritonavir (IDV/RTV) at 667/100 mg every 12 h (q12h) or IDV alone at 800 mg q8h to determine the regimens' pharmacokinetics. On day 14, plasma IDV and RTV levels were determined over 24 h. Noncompartmental pharmacokinetics (minimum concentration of drug in serum [C(min)], area under the concentration-time curve from 0 to 24 h [AUC(0-24)], and maximum concentration of drug in serum [C(max)]) were expressed as geometric mean values with 90% confidence intervals (CI). The primary hypothesis was that the lower bound of the protocol-specified 90% CI for the geometric mean C(min) ratio of the combination compared to IDV alone regimen would be >/=2. Twenty-seven patients were enrolled, and 24 (15 male; average age, 42 years) completed the study. The C(min), AUC(0-24), and C(max) for IDV/RTV compared to IDV alone were 1,511 versus 250 nM, 119,557 versus 77,034 nM . h, and 10,428 versus 10,407 nM, respectively. Corresponding relationships for IDV/RTV compared to IDV alone were a 6.0-fold increase in C(min) (90% CI, 4.0, 9.3), an increase in AUC(0-24) (1.5-fold, 90% CI, 1.2, 2.0), and no increase in C(max). Adverse events were similar and generally mild, with no cases of nephrolithiasis. The geometric mean ratio of IDV C(min) for IDV/RTV compared to IDV was at least 2 by a lower bound of the 90% CI, satisfying the primary hypothesis. The C(max) was not increased, suggesting an IDV/RTV 667/100-mg toxicity profile may be similar to that of unboosted IDV.

Area Under Curve↗
PubMed1998

Pharmacokinetic drug-drug interaction study of delavirdine and indinavir in healthy volunteers.

The potential pharmacokinetic drug-drug interaction between delavirdine, a nonnucleoside analogue reverse transcriptase inhibitor, and indinavir, an inhibitor of HIV protease, was evaluated in healthy volunteers. Subjects received a single 800-mg dose of indinavir sulfate on day 1 (baseline). Delavirdine mesylate 400 mg was administered three times daily on days 2 through 10. On day 9, a single 400-mg dose and on day 10 a single 600-mg dose of indinavir were given along with morning doses of delavirdine. Pharmacokinetic evaluations of indinavir were made on days 1, 9, and 10, and of delavirdine on days 8, 9, and 10. Fourteen healthy male volunteers completed the study. Single doses of indinavir had no clinically important effects on the pharmacokinetics of delavirdine. Mean indinavir Cmax values for the 400-mg and 600-mg doses administered concomitantly with delavirdine were dose proportionally lower than that observed following the 800-mg dose administered alone. Mean Tmax values were similar and ranged from 1.0 +/- 0.3/hour for indinavir 800 mg administered alone to 1.3 +/- 0.4/hour for indinavir 600 mg administered with delavirdine. These results indicate that delavirdine had no clinically important effect on the rate of indinavir absorption. In contrast, the mean indinavir AUC0-infinity, value following the 400-mg dose administered with delavirdine was only 14% lower than the baseline value determined for the 800-mg indinavir dose (25,400 +/- 6960 nM hour versus 29,600 +/- 7920 nM hour), and the mean indinavir AUC0-infinity value for the 600-mg indinavir dose administered with delavirdine (42,700 +/- 9800 nM hour) was 44% greater than the baseline value. All differences among mean AUC0-infinity values were statistically significant. Mean indinavir half-life values were slightly longer when indinavir was given in a dose with delavirdine than when indinavir was administered alone. These results suggest that delavirdine inhibits metabolism of indinavir and support the possibility of a reduction in the magnitude or frequency of indinavir dosage when given in combination with delavirdine.

Administration, Oral↗