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DRUG INTERACTIONS |
From the Division of Clinical Pharmacology, Thomas Jefferson University, Philadelphia, Pennsylvania (Dr. Kraft, Dr. Greenberg, Dr. Waldman) and Merck Research Labs, West Point, Pennsylvania (Dr. McCrea, Dr. Winchell, Dr. Carides, Mr. Lowry, Dr. Woolf, Ms. Kusma, Dr. Deutsch).
Address for reprints: Walter K. Kraft, Division of Clinical Pharmacology, Thomas Jefferson University, 132 S. 10th Street, 1170 Main Building, Philadelphia, PA 19107.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: Indinavir • rifabutin • drug interactions • pharmacokinetics • antiretrovirals • HIV
The use of HAART has significantly reduced the incidence of infections due to opportunistic organisms in patients infected with HIV. However, chemoprophylaxis remains an important part of the care of HIV-infected individuals and has survival benefit, even in patients receiving HAART.5 Since disseminated infection with Mycobacterium avium complex (MAC) may occur with advanced immunosuppression, the 2001 guideline from the U.S. Public Health Service and the Infectious Diseases Society of America recommends primary prophylaxis against MAC when the CD4 count falls below 50 cells/µL.6 The macrocyclic antibiotic rifabutin is an alternate agent for use in MAC prophylaxis and has a role in the treatment of disseminated disease.7 In addition, the Centers for Disease Control and Prevention (CDC) guideline for the treatment of tuberculosis in patients infected with HIV endorses the substitution of rifabutin for rifampin in those patients who receive protease inhibitors, as rifabutin causes less induction of drug-metabolizing cytochromes than rifampin.8
Indinavir is primarily metabolized by the cytochrome P450 isoenzyme 3A4 (CYP3A4); it also inhibits CYP3A4.9 Rifabutin is also metabolized by hepatic CYP3A4 but induces its activity.10 Since coadministration of rifabutin and indinavir is common in treating patients infected with HIV, and each drug has an effect on and is metabolized by CYP3A4, it is reasonable to predict some degree of interaction between these two drugs. Evaluation of their pharmacokinetics individually and when coadministered would help define an optimal combination therapy for treatment of patients infected with HIV. Therefore, the first study examined the pharmacokinetics of indinavir and rifabutin when coadministered, and 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.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Subjects
Ten healthy male subjects (5 Caucasian, 4 black, 1 Hispanic) completed study 1, and 14 healthy subjects (12 male [8 Caucasian and 4 Black], 2 female [both Caucasian]) completed study 2. All subjects were nonsmokers between 21 and 41 years of age. All were within 20% of their ideal body weight and were judged to be in good health based on history, physical examination, and laboratory examination (complete blood count, serum electrolytes, creatinine, liver function tests, HIV test, and urinalysis). Subjects with a history of nephrolithiasis, positive hepatitis B surface antigen, liver disease, or elevations in total or direct bilirubin were excluded. Additional exclusion criteria were consumption of excessive alcoholic (more than two drinks) and/or caffeine-containing (more than six 12-oz drinks) beverages per day, use of any prescription medication within 14 days or nonprescription medications within 7 days of start of the study, blood donation or participation in another clinical trial within the previous 4 weeks, and regular use of illicit drugs or a history of drug or alcohol abuse. All subjects provided written informed consent prior to participation in these clinical studies. All protocols were reviewed and approved by the institutional review board of Thomas Jefferson University.
Study Design
Both studies were multiple-dose, randomized, three-period crossover studies. Subjects received, in randomized order, three different treatments, each for 10 days, as described below. Study 1 was a placebo-controlled study. Given that rifabutin and indinavir were generally well tolerated (see Safety) in study 1, and a smaller dose of rifabutin was used, placebo was not administered in study 2. Compliance during periods of home dosing was ensured by diary and telephone contact. All study drugs were supplied by Merck Research Laboratories. For study 1, the placebo for rifabutin grossly matched active rifabutin, and the placebo for indinavir matched active indinavir. Standardized meals were provided during all inpatient stays.
In study 1, treatment A consisted of indinavir 800 mg q8h (4 x 200-mg capsules) and rifabutin placebo, treatment B consisted of rifabutin 300 mg qd (2 x 150-mg capsules) and indinavir placebo, and treatment C consisted of indinavir 800 mg q8h and rifabutin 300 mg qd. Rifabutin was administered at the same time of day for each subject. On day 10 of each period, indinavir/placebo was administered for three doses (q8h). Each period of treatment was separated by at least 10 days. Venous blood samples for the determination of plasma indinavir were collected at time 0 and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, and 8 hours after the morning dose of indinavir on the morning of day 10 for both treatments A and C. Venous blood samples for the determination of plasma rifabutin and 25-O-desacetyl rifabutin, the active metabolite of rifabutin,11 were collected at time 0 and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, and 24 hours after the administration of the last dose of rifabutin on the morning of day 10 for treatments B and C. Liver function tests were performed 4 hours after the last dose of drug, and safety labs (complete blood count, serum electrolytes, and creatinine and urinalysis) and physical examination were performed 24 hours after the last dose of the drug.
In study 2, the dose of rifabutin was decreased to 150 mg when coadministered with indinavir. Subjects in treatment D received indinavir 800 mg q8h, those in treatment E received rifabutin 300 mg qd, and those in treatment F received indinavir 800 mg q8h and rifabutin 150 mg qd. Rifabutin was administered at the same time of day for each subject. On day 10 (treatments D and F), indinavir was administered for three doses (q8h). Concentrations of indinavir, rifabutin, and 25-O-desacetyl rifabutin were determined in samples of venous blood obtained at various intervals, as described for study 1.
Analytical Methods
For both studies, plasma concentrations of indinavir,12 rifabutin, and 25-desacetyl-rifabutin were each determined using high-performance liquid chromatographic (HPLC) methods with ultraviolet detection (UV).
For study 1, indinavir was assayed by Merck Research Laboratories (MRL) as previously described,12 except that the standard curve range was 25 to 5000 ng/mL. The assay limit of quantitation was 25 ng/mL (40.7 nM). Mean intraday accuracy and precision (n = 5) ranged from 97.6% to 105.0% and 1.1% to 3.4%, respectively. Interday precision of quality control (QC) samples was 2.25% at 75 ng/mL and 0.93% at 3500 ng/mL. Rifabutin and 25-O-desacetyl rifabutin were assayed by MDS-Pharma (Lincoln, NE) using a proprietary method. Briefly, the assay method consisted of liquid-liquid extraction of drug, metabolite, and internal standard into an organic solution (hexane/ethyl acetate) followed by separation and evaporation of the organic layer. The residue was reconstituted in a small volume and injected onto an HPLC system with UV detection at 275 nm. The assay limit of quantitation was 5 ng/mL for rifabutin and 2.5 ng/mL for 25-O-desacetyl rifabutin. Replicated standards (n = 5) were all accurate to within 7.4% of nominal values, and the coefficients of variation were all less than 8.6% for both analytes. Interday precision of QC samples was 5.9% at 10 ng/mL and 2.9% at 400 ng/mL for rifabutin and 4.1% at 5 ng/mL and 2.4% at 200 ng/mL for 25-O-desacetyl rifabutin.
For study 2, indinavir, rifabutin, and its 25-desacetyl metabolite were assayed by BAS Analytics (West Lafayette, IN). Indinavir was assayed as previously described,12 except that the last liquid-liquid extraction step was omitted and the calibration curve range was 12,000 to 15,000 ng/mL. The indinavir assay limit of quantitation was 12 ng/mL (19.5 nM). Accuracy and precision ranged from 98.3% to 107.2% and 4.3% to 5.6%, respectively. Interday precision of QC samples was 10.4% at 50 ng/mL, 4.1% at 1000 ng/mL, and 8.5% at 10,000 ng/mL. For rifabutin and 25-O-desacetyl rifabutin, the assay was composed of liquid-liquid extraction into n-butylchloride, followed by separation and evaporation of the organic layer. The residue was reconstituted in an aqueous solution containing 32% acetonitrile and 0.2% trifluoroacetic acid, followed by liquid-liquid extraction with hexane. The aqueous phase was then injected onto an HPLC system with UV detection at 275 nm. The assay limit of quantitation was 5 ng/mL for rifabutin and 3.7 ng/mL for 25-O-desacetyl rifabutin. For rifabutin, mean accuracy and precision ranged from 94.9% to 103.7% and 2.1% to 11.7%, respectively. Interday precision of QC samples was 10.4% at 10 ng/mL, 3.5% at 80 ng/mL, and 2.9% at 400 ng/mL. For 25-O-desacetyl rifabutin, mean accuracy and precision ranged from 98.8% to 101.4% and 1.3% to 8.8%, respectively. Interday precision of QC samples was 7.0% at 5 ng/mL, 3.4% at 40 ng/mL, and 2.3% at 200 ng/mL.
Assays in both studies were checked for cross-interference by assaying plasma samples from treatments in which only the nonassayed drug was administered. For both studies, indinavir concentrations were converted to a molar basis by using a molecular weight of 613.81.
Pharmacokinetic Analysis
For both studies, peak plasma concentration (Cmax), time to peak concentration (tmax), and area under the concentration-time curve over the final dosing interval (AUC(0-8h) for indinavir and AUC(0-24h) for rifabutin and its metabolite) were determined for each treatment in which the respective drugs were administered. Cmax and tmax were obtained directly from the concentration-time data. AUC was calculated by a modified trapezoidal rule using piecewise cubic polynomials.13 Actual sample times recorded by the investigator were used to calculate AUC. Trough plasma concentration (C8h) also was assessed for indinavir. All concentrations below the limit of quantitation were treated as zeroes for pharmacokinetic calculations. Excel (Microsoft, Redmond, WA) was the software used for this analysis.
Statistical Analysis
Power
For study 1, as the primary objective was to evaluate the effect of rifabutin on the pharmacokinetics of indinavir, this study was powered for indinavir only. The large effect seen of indinavir on rifabutin was unexpected in this early study. To address the primary objective of the effect of rifabutin on the AUC of indinavir, the mean standard error (MSE = 0.13) (on the log scale) was estimated from a previous early clinical trial using 600 mg q8h (data on file). Given a three-period crossover study with n = 12 subjects and a Type I error = 0.05 and assuming similar variation of indinavir and rifabutin, there was a 99% probability that the observed 90% confidence interval (CI) for the ratio of geometric mean AUC (indinavir and rifabutin/indinavir alone) would fall within the equivalence interval (0.5, 2.0) if the true ratio was 1.0. There was an 80% probability that the 90% CI would fall within the equivalence interval (0.64, 1.56) if the true ratio was 1.0.
For study 2, the objectives were to evaluate both the effect of rifabutin on indinavir and indinavir on rifabutin with an adjusted rifabutin dose. For this study, data (MSE) from study 1 were used in the power calculations as follows. In study 1, the observed AUC ratio of rifabutin, when rifabutin was administered with indinavir relative to rifabutin 300 mg alone, was 2.73. Based on these results, it was assumed that the AUC ratio of rifabutin with half the dose, relative to rifabutin alone, could be as high as 1.37. Therefore, if the true ratio was 1.37, given the same three-period design with 15 subjects, there was an 83% probability that the observed 90% CI for the ratio of geometric mean AUCs (combination/rifabutin alone) could fall within the equivalence interval (0.50, 2.0). For the effect of rifabutin on indinavir, the MSE = 0.034 (on the log scale) was used. Given the same three-period crossover design with 15 subjects, a Type I error = 0.05, and a similar variation as seen in study 1, there was a 99% probability that the observed 90% CI for the ratio of the geometric mean AUCs (combination/indinavir alone) would fall within the equivalence interval (0.5, 2.0), assuming the true ratio was 1.0.
Methods
Although the clinical design of both studies was a standard three-period crossover, the usual linear model (and the consequent ANOVA analysis)—with subject, period, treatment, and carryover effects entered as independent variables—was modified to accommodate the following particular feature of these drug interaction trials. Unlike a conventional three-period crossover study, in these studies, subjects receiving indinavir alone provide no data for assessing the effect of the coadministration of rifabutin with indinavir on the pharmacokinetics of rifabutin. This assessment involves only a comparison of two of the three treatment groups (i.e., rifabutin 150 mg and indinavir combined vs. rifabutin 300 mg alone). Similarly, subjects receiving rifabutin 300 mg alone provided no data for assessing the effect of the coadministration of rifabutin 150 mg with indinavir on the pharmacokinetics of indinavir. To account for this, a classification variable called "pair" was defined to capture the variability due to the different pairs of periods in which two treatments were compared. This variable "pair" is based on a model proposed by Ciminera et al.14 It was of interest to test whether the treatment comparisons varied across the three different pairs (i.e., the treatment-by-pair interaction). The interaction was tested using the contrast proposed by Ciminera et al through the use of a modified three-period ANOVA model on log-transformed data. The modified ANOVA model initially contained terms for subject, period, treatment, carryover, and period-by-carryover interaction. A contrast containing both carryover and period-by-carryover effects15 was run to test the treatment-by-pair interaction. In the case of a nonsignificant interaction (p > 0.05), a second ANOVA model was run in which the carryover and period-by-carryover terms were dropped from the model. A 90% confidence interval was constructed about the treatment differences using the results of the ANOVA. In both studies, the treatment-by-pair interaction was found to be nonsignificant, and therefore no interaction terms were included in the final models. The antilogs of the upper and lower limits were then calculated to obtain the confidence interval for the ratio of geometric means. SAS version 6.12 (SAS Institute, Cary, NC) was used to analyze the data.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Plasma profiles of indinavir were consistently lower when indinavir was administered with rifabutin (Figure 1). The AUC(0-8h), Cmax, and C8h of indinavir were lower when coadministered with rifabutin 300 mg daily (Table I). For AUC(0-8h), the geometric mean ratio (90% CI) for combination/monotherapy was 0.66 (0.56, 0.77). For C8h, the geometric mean ratio (90% CI) was 0.61 (0.50, 0.75). The arithmetic means of indinavir tmax with and without rifabutin were identical at 0.8 ± 0.2 hours. Conversely, plasma concentrations of rifabutin (Figure 2) and its 25-desacetyl metabolite (Figure 3) were increased upon coadministration of rifabutin and indinavir. The point estimates for the geometric mean AUC(0-24h) and Cmax for rifabutin increased more than twofold when coadministered with indinavir (Table II). The AUC(0-24h) and Cmax of 25-desacetyl rifabutin were similarly increased when coadministered with indinavir (Table II).
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These observations were indicative of a clinically important pharmacokinetic interaction on coadministration of indinavir and rifabutin. The decreased plasma concentrations of indinavir were considered clinically significant due to the propensity of HIV to develop resistance in the face of decreased concentrations of protease inhibitors. Conversely, the increases in circulating rifabutin concentrations were considered clinically significant due to a potential increase in concentration-dependent toxicity. Consequently, study 2 was undertaken to determine if altering the dose of rifabutin coadministered with indinavir could minimize the drug interaction observed in study 1.
Study 2: Comparison of Rifabutin 150 mg Daily Coadministered with Indinavir 800 mg q8h and Rifabutin 300 mg Daily Alone
Sixteen healthy male and 4 healthy female subjects with a mean age of 28.3 years (range, 20-40) and a mean weight of 70.5 kg (range, 50.5-96.8) began the study. Six subjects were discontinued from the study: 4 subjects were discontinued for personal reasons not related to study drug, and 2 subjects discontinued due to adverse experiences considered drug related (see Safety). Data from all 20 subjects who were enrolled in the study were included in the safety analysis. Data from the 14 subjects who completed the study were included in the pharmacokinetic analysis.
Plasma profiles of indinavir were decreased when indinavir was coadministered with 150 mg rifabutin (Figure 4) to an extent that was similar to that observed with the coadministration with 300 mg rifabutin (study 1, Figure 1). Coadministration with rifabutin 150 mg daily resulted in a decrease in the AUC(0-8h), Cmax, and C8h of indinavir (Table III). For AUC(0-8h), the geometric mean ratio (90% CI) for combination/monotherapy was 0.68 (0.60, 0.76). For C8h, the geometric mean ratio (90% CI) was 0.60 (0.51, 0.72). The arithmetic means of indinavir tmax with and without rifabutin were 0.9 ± 0.4 hours and 1.3 ± 0.9 hours, respectively.
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Plasma concentrations of rifabutin (Figure 5) and 25-desacetyl-rifabutin (Figure 6) were higher when 150 mg rifabutin was coadministered with indinavir compared to plasma concentrations of these analytes when 300 mg rifabutin was administered alone. The geometric mean ratio (90% CI) for AUC(0-24h) in the combination versus monotherapy arms was 1.54 (1.33, 1.79); for Cmax, it was 1.29 (1.05, 1.59) (Table IV). Similarly, the AUC(0-24h) and Cmax of 25-desacetyl rifabutin were higher when rifabutin 150 mg was coadministered with indinavir compared to rifabutin 300 mg alone (Table IV). The geometric mean ratio was 4.05 for AUC(0-24h) and 2.43 for Cmax. The arithmetic mean of rifabutin tmax with and without indinavir was identical at 3.5 ± 1.0 hours. The arithmetic mean of 25-desacetyl rifabutin tmax with and without indinavir was 3.5 ± 1.4 hours and 3.9 ± 0.9 hours, respectively.
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Safety and Tolerability
The combinations of indinavir 800 mg q8h and rifabutin at either 300 mg daily or 150 mg daily were generally well tolerated. There were no serious adverse events in either study.
In study 1, 4 of 11 subjects had clinical adverse experiences that were mild and possibly related to the study drug. Taste perversion was the most common drug-related clinical adverse experience and occurred on indinavir alone, on indinavir and rifabutin, and on rifabutin alone.
Two of 3 subjects had laboratory adverse experiences that were judged possibly related to the study drug. One subject had liver function and hematologic abnormalities and was discontinued from the study. He had an increase in alanine aminotransferase (ALT) while on indinavir alone, an increase in aspartate aminotransferase (AST) while on indinavir and rifabutin, and increases in ALT and AST while off the drug. All increases in transaminase values were less than twofold. Although he had increases in bilirubin while on indinavir, his highest total bilirubin was 1.6 mg/dL. Also, this subject developed leukopenia (1.7 x 109/L from baseline of 5.3 x 109/L), decreased circulating neutrophils (prestudy, 51%; postdose, 8%), and decreased circulating platelets (prestudy, 235 x 109/L; postdose, 137 x 109/L) while on indinavir and rifabutin. Following 8 days off the drug, his circulating leukocytes, neutrophils, and platelets returned to within normal limits. The second subject had increases in transaminases: AST and ALT while on indinavir alone and increases in AST while on rifabutin alone. All increases were less than twofold.
In study 2, 5 of 10 subjects had clinical adverse experiences judged by the investigator to be drug related. Of these drug-related clinical adverse experience, 1 subject experienced upper respiratory infection symptoms while on indinavir and rifabutin, 1 subject had mild abdominal pain while on combination therapy, 1 subject developed vaginitis while on rifabutin alone, and 1 subject had a change in bowel patterns on rifabutin and dyspepsia while on indinavir. A fifth subject was discontinued for a rash judged as probably related to treatment while on indinavir and rifabutin 150 mg.
Four of 5 subjects had drug-related laboratory adverse experiences. Two subjects had increases in transaminases: 1 subject had an increase in AST (< 3-fold) while on indinavir and rifabutin 150 mg, and 1 subject had increases in AST and ALT while on rifabutin 300 mg alone (a transient 5-fold increase that decreased to 
2-fold within 2 days). Two subjects had decreases in circulating neutrophils that were possibly related to the study drug. One had a decrease in circulating neutrophils of 34% (with a total WBC of 3.3) during washout (4 days following completion of period 2, rifabutin 300 mg alone) and was discontinued. Within 8 days, his circulating neutrophils returned to within normal limits at 61% (with a total WBC of 5.0). The other subject experienced decreases in circulating neutrophils of 34% (with a total WBC of 3.4) on day 11, period 2 while on rifabutin 300 mg alone. Within 7 days, his neutrophils returned to within normal limits at 48%, and he completed the study.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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The greater than 30% decrease in geometric mean plasma indinavir AUC and trough concentration when coadministered with rifabutin, compared to indinavir alone, is likely clinically important. Concentrations of protease inhibitors that are subtherapeutic select for a drug-resistant virus and eventually lead to failure of the treatment.19 This occurs despite the fact that such drug-resistant viruses tend to be less virulent.20 The goal of a rational schedule for dosing with indinavir is to maintain antiviral efficacy. In a similar fashion, supratherapeutic concentrations of rifabutin found in study 1 might be expected to increase the incidence of concentration-dependent side effects.
Because pharmacokinetic interactions between indinavir and rifabutin were observed in study 1, study 2 was conducted in which rifabutin was administered at one-half the standard daily dose (150 mg) in combination with indinavir, and rifabutin 300 mg alone was used as the reference arm. The predication was that 150 mg rifabutin with indinavir would have a similar exposure to 300 mg rifabutin when used alone. In this study, the dose of indinavir was not increased because it was presumed that induction of CYP3A4 by lower doses of rifabutin would have a smaller impact on circulating indinavir concentrations. Surprisingly, the AUC and the geometric mean ratio of the AUC of indinavir when administered with rifabutin 300 mg and 150 mg were nearly identical. That plasma concentrations of indinavir were decreased by the same magnitude with full doses (300 mg) and reduced doses (150 mg) of rifabutin suggests that both doses of rifabutin induced the metabolism of indinavir by CYP3A4 to a similar extent. In contrast, administration of rifabutin 150 mg daily with indinavir resulted in circulating rifabutin concentrations that were 1.54-fold higher than those achieved by administering rifabutin 300 mg alone. This is substantially less than the 2.73-fold increase in the geometric mean rifabutin AUC when 300 mg daily of rifabutin was administered with indinavir.
Treatments administered in these studies were generally well tolerated, without a clear difference in the pattern of adverse experiences observed during combination therapy and monotherapy. The laboratory experiences, for studies 1 and 2, appeared to indicate that leukopenia/neutropenia was occurring with rifabutin 300 mg alone and rifabutin 300 mg and indinavir. Neutropenia may be associated with the use of rifabutin; therefore, an increase in rifabutin concentrations when coadministered with indinavir may have contributed to the laboratory adverse experience in the healthy subject in study 1.
The limitations imposed by available rifabutin dosage strength, coupled with the lack of efficacy data for alternate-day dosing, suggest that the modest increase in rifabutin concentrations noted in study 2 are in a range that would maintain efficacy with reasonable safety. The rifabutin-associated neutropenia noted in healthy volunteers is noted less often in HIV-infected patients.21 In contrast, the need to avoid a subtherapeutic indinavir concentration suggests the requirement of a higher indinavir dose when coadministered with rifabutin. Therefore, the results described herein resulted in a subsequent study sponsored by the AIDS Clinical Trials Group (ACTG 365) in which the regimen of indinavir 1000 mg q8h and rifabutin 150 mg daily was evaluated in healthy volunteers and HIV-seropositive patients.22 In this study, systemic exposure of indinavir was similar between 800 mg administered alone and 1000 mg administered with 150 mg rifabutin. Rifabutin concentrations were increased by 70%. These pharmacokinetic observations are the basis of the present recommendation of indinavir 1000 mg q8h when coadministered with rifabutin at 150 mg q24h.23 However, the clinical importance of the increase in rifabutin remains unknown.
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FOOTNOTES |
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Supported by a grant from Merck & Co., Inc. and NIH Training Grant 5T32 GM08562 (Dr. Kraft). Ms. Kusma, Mr. Lowry, and Drs. McCrea, Winchell, Carides, Woolf, and Deutsch are employees of Merck Research Labs. No author has any other potential conflict of interest.
Submitted for publication August 28, 2003; Revised version accepted December 22, 2003.
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REFERENCES |
|---|
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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1. Peng C, Ho BK, Chang TW, Chang NT: Role of human immunodeficiency virus type 1-specific protease in core maturation and viral infectivity. J Virol 1989;63: 2550-2556.
2. Kaul DR, Cinti SK, Carver PL, Kazanjian PH: HIV protease inhibitors: advances in therapy and adverse reactions, including metabolic complications. Pharmacotherapy 1999;19: 281-298.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
3. Gulick RM, Mellors JW, Havlir D, Eron JJ, Gonzalez C, McMahon D, et al: Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. N Engl J Med 1997;337: 734-739.
4. Hammer SM, Squires KE, Hughes MD, Grimes JM, Demeter LM, Currier JS, et al: A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. N Engl J Med 1997;337: 725-733.
5. McNaghten AD, Hanson DL, Jones JL, Dworkin MS, Ward JW, and the Adult/Adolescent Spectrum of Disease Group: Effects of antiretroviral therapy and opportunistic illness primary chemoprophylaxis on survival after AIDS diagnosis. AIDS 1999;13: 1687-1695.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
6. Masur H, Kaplan JE, Holmes KK: Guidelines for preventing opportunistic infections among HIV-infected persons—2002: recommendations of the U.S. Public Health Service and the Infectious Diseases Society of America. Ann Intern Med 2002;137: 435-478.
7. Benson C, Williams P, Currier J, Holland F, Hojczyk P, Mahon L, et al: ACTG 223: an open, prospective, randomized study comparing efficacy and safety of clarithromycin plus ethambutol, rifabutin, or both for treatment of MAC disease in patients with AIDS [abstract 249]. Paper presented at the 6th Conference on Retroviruses and Opportunistic Infections, Chicago, January 31-February 4, 1999.
8. Centers for Disease Control and Prevention: Prevention and treatment of tuberculosis among patients infected with human immunodeficiency virus: principles of therapy and revised recommendations. MMWR 1998;47: RR-20.
9. Chiba M, Hensleigh M, Nishime JA, Balani SK, Lin JH: Role of cytochrome P450 3A4 in human metabolism of MK-639, a potent human immunodeficiency virus protease inhibitor. Drug Metab Dispos 1996;24: 307-314.[Abstract]
10. Li AP, Reith MK, Rasmussen A, Gorski JC, Hall SD, Xu L, et al: Primary human hepatocytes as a tool for the evaluation of structure-activity relationship in cytochrome P450 induction potential of xenobiotics: evaluation of rifampin, rifapentine and rifabutin. Chemico-Biological Interact 1997;107: 17-30.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
11. Blaschke TF, Skinner MH: The clinical pharmacokinetics of rifabutin. Clin Infect Dis 1996;22(Suppl. 1): S15-S22.
12. Woolf E, Haddix Au H, Matuszewski B: Determination of L-753 524, a human immunodeficiency virus protease inhibitor, in human plasma and urine via high-performance liquid chromatograph with column switching. J Chromatogr 1995;692: 45-52.
13. Yeh KC, Small RD: Pharmacokinetic evaluation of stable piecewise cubic polynomials as numerical integration functions. J Pharmacokinet Biopharm 1989;17: 721-740.[CrossRef][Medline] [Order article via Infotrieve]
14. Ciminera JL, Bolognese JA, Gregg MH: The statistical evaluation of a three-period two-treatment crossover pharmacokinetic drug interaction study. Biometrics 1987;43: 713-718.[Medline] [Order article via Infotrieve]
15. Tomasko L, Bolognese JA, Hesney M, Holder DJ: Comparison of two modeling procedures for the three-period, two-treatment crossover pharmacokinetic drug interaction study [abstract]. Paper presented at the 17th International Biometric Conference, Hamilton, Canada, August 8-12, 1994.
16. Merck and Co.: Crixivan (indinavir) package insert. West Point, PA, March 1999.
17. Dautzenberg B: The use of rifabutin in Europe for the treatment of mycobacterial infection in AIDS patients. Infection 1997;25: 63-68.[Medline] [Order article via Infotrieve]
18. Cocchiara G, Benedetti MS, Vicario GP, Ballabio M, Gioia B, Vioglio S, et al: Urinary metabolites of rifabutin, a new antimycobacterial agent, in human volunteers. Xenobiotica 1989;19: 7869-7880.
19. Mascolini M: The rolling uncertainties of antiprotease prescribing. J Int Assoc Physicians AIDS Care 1996;2: 6-10.
20. Clumeck N: Choosing the best initial therapy for HIV-1 infection. N Engl J Med 1999;341: 1925-1926.
21. Flexner C, Barditch-Crovo PA: Severe neutropenia among healthy volunteers given rifabutin in clinical trials [letter]. Clin Pharmacol Ther 2003;73: 159-169.[CrossRef][Medline] [Order article via Infotrieve]
22. Hamzeh FM, Benson C, Gerber J, Currier J, McCrea J, Deutsch P, et al: Steady-state pharmacokinetic interaction of modified-dose indinavir and rifabutin. Clin Pharmacol Ther 2003;73: 159-169.
23. Panel on Clinical Practices for Treatment of HIV Infection: Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. Available: http://aidsinfo.nih.gov/guidelines/adult/AA_020402.html#table18
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 S. A. Krikorian and D. C. Rudorf Drug-Drug Interactions and HIV Therapy: What Should Pharmacists Know? Journal of Pharmacy Practice, August 1, 2005; 18(4): 278 - 294. [Abstract] [PDF]
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