Steady‐state pharmacokinetic interaction of modified‐dose indinavir and rifabutin
Fayez M. HamzehConstance A. BensonJohn G. GerberJudith S. CurrierJackie McCreaPaul DeutschPing RuanHulin WuJin LeeCharles Flexner
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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. Clinical Pharmacology & Therapeutics (2003) 73 , 159–169; doi: 10.1067/mcp.2003.3Keywords:
Rifabutin
Indinavir
Crossover study
An animal model of disseminated Mycobacterium haemophilum infection was utilized to compare treatment with azithromycin, ciprofloxacin, rifabutin, and the combination of clarithromycin with rifabutin. Following subcutaneous challenge with M. haemophilum, local and disseminated infection occurred only in immunosuppressed mice. For disseminated infection, ciprofloxacin was relatively ineffective therapy. Clarithromycin and rifabutin alone significantly reduced the tissue burden in the spleen after 4 weeks of therapy. Combination therapy with rifabutin and clarithromycin was superior to 4 weeks of treatment with the individual agents. When immunosuppressed mice were treated for 20 weeks with the combination of rifabutin and clarithromycin, the tissue burden remained reduced in the spleen at 1 month following the completion of therapy. Combined rifabutin and clarithromycin provide effective treatment for M. haemophilum in this model.
Rifabutin
Combination therapy
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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. Clinical Pharmacology & Therapeutics (2003) 73 , 159–169; doi: 10.1067/mcp.2003.3
Rifabutin
Indinavir
Crossover study
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A 40-year-old woman who had received warfarin potassium (3 mg/day) for deep-vein thrombosis was diagnosed with atypical mycobacteriosism, and concomitant administration of rifampicin, clarithromycin and ethambutol was commenced. The PT-INR of this patient, which had been maintained at around 2.0, was found to have markedly decreased 9 days after beginning co-administration of warfarin and the anti-mycobacterium drugs, suggesting rifampicin induced warfarin metabolism, which is well documented. In view of the decrease in PT-INR, the warfarin dosage was increased up to 5.5 mg/day to attain a PT-INR level in the therapeutic range, but this did not alter the level.Rifampicin was changed to rifabutin since drug-drug interaction is considered to be generally less severe than with rifampicin. However, as there had been no increase in PT-INR, the administration of rifabutin was ceased. A rise in PT-INR was observed 17 and 31 days after the withdrawal of the rifabutin and rifampicin, respectively.Warfarin is known to be metabolized by cytochrome P450 (CYP) isoforms 2C9 and 3A4 and rifampicin has been reported to be a potent inducer of CYP3A4 and 2C9. Although rifabutin has the ability to induce CYP3A4, there have been few reports of drug-drug interaction with warfarin. However, the current case provides the first evidence for rifabutin exerting an influence on warfarin metabolism.In conclusion, our findings suggest that not only rifampicin but also rifabutin induce warfarin metabolism and that its pharmacological effects could be attenuated when combined with these drugs.
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Concomitant
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Rifabutin
Rifamycin
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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.
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Indinavir
Crossover study
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We investigated the potential of the azalide, azithromycin, and rifabutin in preventing disseminated infection due to Mycobacterium avium complex (MAC) in beige mice. Azithromycin 200 mg/kg, rifabutin (30 mg/kg or 60 mg/kg) were administered by gavage 6 days before mice were challenged orally with 108cfu MAC and daily for 10 days thereafter during which time the mice were again challenged with the same inoculum on alternate days (days +1, +3, +5, +7, and +9). Sixty-four days later, the presence of bacteria in the blood and the number of viable bacteria in liver, spleen and appendix were estimated. Treatment with azithromycin and 60 mg/kg/day rifabutin but not 30 mg/kg/day, significantly decreased the incidence of bacteraemia and the number of bacteria in the appendix. The administration of azithromycin resulted in significantly fewer MAC in the liver and spleen but not in the appendix whereas the converse was true of 60 mg/kg rifabutin. Our results indicate that both azithromycin and rifabutin can prevent MAC disseminated infection, but that the azalide is more effective than the rifamycin in reducing the burden of infection.
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Clarithromycin and rifabutin are among the most promising drugs for the therapy of infections caused by Mycobacterium avium or other atypical mycobacteria. Since synergism of combined drugs is important in order to achieve strong anti-mycobacterial activity, the combined inhibitory effects of antibacterial agents should also be investigated when agents are evaluated for possible use in antimycobacterial drug therapy. In the present study we examined the antimycobacterial activity of clarithromycin, rifabutin, and their combination against 51 clinical isolates of the M. avium complex from patients with acquired immune deficiency syndrome (AIDS) with disseminated mycobacteriosis. A concentration-dependent inhibition was seen for each drug. The antibacterial effect was significantly more pronounced for the combined drugs than for the agents tested separately. Synergism, against up to 88% of the strains tested, was seen for the tested drugs combined at different concentrations. All 51 M. avium strains were susceptible to the combination of 4 mg/I Clarithromycin and 2 mg/I rifabutin.
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Antimycobacterial
Mycobacterium avium-intracellulare infection
Mycobacterium avium complex
Rifamycin
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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 800mg 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 1.5-8h 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 800mg 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 600mg 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.
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ABSTRACT The effect of multiple doses of rifabutin (150 mg) on the pharmacokinetics of saquinavir-ritonavir (1,000 mg of saquinavir and 100 mg of ritonavir [1,000/100 mg]) twice daily (BID) was assessed in 25 healthy subjects. Rifabutin reduced the area under the plasma drug concentration-time curve from 0 to 12 h postdose (AUC 0-12 ), maximum observed concentration of drug in plasma ( C max ), and minimum observed concentration of drug in plasma at the end of the dosing interval ( C min ) for saquinavir by 13%, 15%, and 9%, respectively, for subjects receiving rifabutin (150 mg) every 3 days with saquinavir-ritonavir BID. No effects of rifabutin on ritonavir AUC 0-12 , C max , and C min were observed. No adjustment of the saquinavir-ritonavir dose (1,000/100 mg) BID is required when the drugs are administered in combination with rifabutin. The effect of multiple doses of saquinavir-ritonavir on rifabutin pharmacokinetics was evaluated in two groups of healthy subjects. In group 1 ( n = 14), rifabutin (150 mg) was coadministered every 3 days with saquinavir-ritonavir BID. The AUC 0-72 and C max of the active moiety (rifabutin plus 25- O -desacetyl-rifabutin) increased by 134% and 130%, respectively, compared with administration of rifabutin (150 mg) once daily alone. Rifabutin exposure increased by 53% for AUC 0-72 and by 86% for C max . In group 3 ( n = 13), rifabutin was coadministered every 4 days with saquinavir-ritonavir BID. The AUC 0-96 and C max of the active moiety increased by 60% and 111%, respectively, compared to administration of 150 mg of rifabutin once daily alone. The AUC 0-96 of rifabutin was not affected, and C max increased by 68%. Monitoring of neutropenia and liver enzyme levels is recommended for patients receiving rifabutin with saquinavir-ritonavir BID.
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Ritonavir
Saquinavir
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Rifampin is an important drug in the treatment of tuberculosis, but administration of rifampin in combination with protease inhibitors is complicated because of drug-drug interactions. A prospective, controlled, multiple-dose study involving 6 HIV-infected patients receiving a combination of indinavir (800 mg) and ritonavir (100 mg) twice a day was performed to evaluate whether the inducing effect of rifampin on the drug-metabolizing enzyme cytochrome P450 (CYP) 3A4 could be overcome by the inhibitory effect of ritonavir. Pharmacokinetic evaluations of steady-state concentrations of indinavir and ritonavir were performed before and after administration of rifampin (300 mg every day for 4 days). An 87% reduction (from 837 to 112 ng/mL) in median indinavir and a 94% reduction (from 431 to 27 ng/mL) in median ritonavir concentrations were seen 12 h after the last dose of rifampin was administered (P = .031). These results strongly indicate that the administration of rifampin with a combination of indinavir (800 mg) and ritonavir (100 mg) could lead to subtherapeutic concentrations of indinavir.
Indinavir
Ritonavir
Protease inhibitor (pharmacology)
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