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Antimicrobial Agents and Chemotherapy, July 2001, p. 1972-1976, Vol. 45, No. 7
Núcleo de Doenças Infecciosas
Centro Biomédico, Universidade Federal de Espírito Santo,
Vitória, Brazil1; Division of
Infectious Diseases, Tuberculosis Research Unit, Case Western Reserve
University, Cleveland, Ohio2;
PathoGenesis Corporation, Seattle,
Washington3; and University of Arkansas
for Medical Sciences, Little Rock, Arkansas4
Received 11 May 2000/Returned for modification 21 October
2000/Accepted 27 March 2001
Rifalazil, also known as KRM-1648 or benzoxazinorifamycin, is a new
semisynthetic rifamycin with a long half-life of approximately 60 h. Rifalazil has potent bactericidal activity against
Mycobacterium tuberculosis in vitro and in animal models of
tuberculosis (TB). Prior studies in healthy volunteers showed that
once-weekly doses of 25 to 50 mg of rifalazil were well tolerated. In
this randomized, open-label, active-controlled phase II clinical trial,
65 subjects with sputum smear-positive pulmonary TB received one of the
following regimens for the first 2 weeks of therapy: 16 subjects
received isoniazid (INH) (5 mg/kg of body weight) daily; 16 received
INH (5 mg/kg) and rifampin (10 mg/kg) daily; 17 received INH (5 mg/kg) daily plus 10 mg of rifalazil once weekly; and 16 received INH (5 mg/kg) daily and 25 mg of rifalazil once weekly. All subjects were then
put on 6 months of standard TB therapy. Pretreatment and day 15 sputum
CFU of M. tuberculosis were measured to assess the
bactericidal activity of each regimen. The number of drug-related adverse experiences was low and not significantly different among treatment arms. A transient decrease in absolute neutrophil count to
less than 2,000 cells/mm3 was detected in 10 to 20% of
patients in the rifalazil- and rifampin-containing treatment arms
without clinical consequences. Decreases in CFU counts were comparable
among the four treatment arms; however, the CFU results were
statistically inconclusive due to the variability in the control arms.
Acquired drug resistance did not occur in any patient. Studies focused
on determining a maximum tolerated dose will help elucidate the full
anti-TB effect of rifalazil.
With good patient compliance
facilitated by a directly observed therapy (DOT) program with adequate
resources, current 6-month, short-course chemotherapy regimens for the
treatment of tuberculosis (TB) can achieve cure rates of 90% or more
(2, 12). Resources for implementation of DOT are not
available in many developing countries where the burden of tuberculosis
is high. The World Health Organization estimates that only 21% of all
TB cases are currently treated in areas covered by DOT
(21). Despite these advances, the global resurgence of TB
serves as a reminder that new drugs are needed that could potentially
shorten the duration of treatment or reduce the number of doses
required during the course of treatment.
Rifalazil, also known as KRM-1648 or benzoxazinorifamycin, is a new
rifamycin derivative related to rifampin and rifabutin. Preclinical
studies with rifalazil demonstrated significant in vitro activity
against Mycobacterium tuberculosis. In vitro MIC studies
have shown that rifalazil is 64-fold more active than rifampin and 4- to 8-fold more active than rifabutin against many isolates of M. tuberculosis (5). In murine models of TB, rifalazil was more effective than rifampin in reducing the time required for
organ sterilization (10). Furthermore, one in vitro study suggested that some M. tuberculosis strains resistant to
rifampin may not be cross resistant to rifalazil (20).
Like rifampin, but unlike rifabutin, the metabolism of rifalazil does
not appear to be dependent on hepatic cytochrome P450 enzymes (6,
11). In addition, animal studies show that, unlike both rifampin
and rifabutin, rifalazil is not an inducer of hepatic cytochrome P450 (11). Therefore, the potential for clinically significant
drug interactions with other drugs, including the human
immunodeficiency virus (HIV) protease inhibitors, may be lower for
rifalazil than for other rifamycins in use (7).
Importantly, its longer terminal half-life can make dosing less frequent.
Clinical studies of rifalazil in normal healthy human volunteers using
doses of 25 to 50 mg demonstrated a dose-related incidence in the
number and severity of adverse events (AE) (14; PC-KRM-004, a
randomized double-blind intermittent-dose study of the safety and
pharmacokinetics of KRM-1648 in normal volunteers, study report, 1999 [PathoGenesis Corp., Seattle, Wash.]). The predominant AE were
flu-like symptoms, including chills, fever, and myalgias. Additionally,
transient dose-dependent decreases in the total white blood cell
counts, absolute neutrophil counts (ANC), and platelet count were
observed in some patients. Flu-like symptoms and transient neutropenia
also have been reported in 4 to 22% and 3 to 12% of patients,
respectively, treated with rifampin and rifabutin in some studies
(1, 4, 17, 18). The mean terminal half-life
(t1/2) of rifalazil in six healthy volunteers receiving 25 mg of rifalazil once weekly for 4 weeks was approximately 61 h, with a maximum concentration (Cmax)
of 44 ng/ml (14).
In this report we describe the first experience with rifalazil in human
subjects with pulmonary TB. The primary objective of this phase II
clinical trial was to evaluate the safety and pharmacokinetics of low
doses of rifalazil administered once weekly to HIV-noninfected patients
with newly diagnosed sputum smear-positive pulmonary TB. We also
assessed the microbiologic activity of rifalazil by comparing the
bactericidal activity in sputum of rifalazil (10 mg or 25 mg once
weekly) plus isoniazid (INH) (5 mg/kg of body weight/day) for 14 days
and the bactericidal activity in sputum of INH (5 mg/kg/day) or INH (5 mg/kg/day) plus rifampicin (10 mg/kg/day) for 14 days.
This open-label randomized clinical trial was conducted at the
Hospital Universitário Cassiano Antonio de Moraes of the
Universidade Federal do Espírito Santo (UFES) in Vitória,
Brazil. The study protocol was approved by the institutional review
boards of UFES and Case Western Reserve University and University
Hospitals of Cleveland, Ohio. All patients gave written informed
consent for study participation and received pre- and post-HIV test counseling.
Adults who were 18 years of age or older with newly diagnosed initial
episodes of sputum smear-positive (acid-fast bacilli detected)
pulmonary TB were eligible for study participation. HIV-infected
patients; patients with suspected miliary or meningeal TB, severe
hemoptysis (greater than 50 ml during the previous week), or suspected
drug-resistant TB; and pregnant or lactating women were excluded from
the study.
Patients were randomized to one of four treatment groups for the
initial 14 days of anti-TB treatment: (i) INH, 300 mg once daily
(treatment group H); (ii) INH, 300 mg once daily, plus rifampin (450 mg
for patients weighing less than 50 kg and 600 mg for those over 50 kg)
daily (treatment group HR); (iii) INH, 300 mg once daily, plus
rifalazil, 10 mg on day 1 and day 8 (treatment group HRz10); or (iv)
INH, 300 mg once daily, plus rifalazil, 25 mg on day 1 and day 8 (treatment group HRz25). All drugs were administered orally, under DOT,
in the early morning one-half hour after breakfast. Patients in the
rifalazil treatment arms received a standard lipid-rich meal including
a cheeseburger with bacon one-half hour before each rifalazil dose; a
lipid-rich meal increases the absorption of rifalazil (PathoGenesis
Corp. study report). At the conclusion of the 14-day study period, all
patients were treated with 6 months of standard short-course
chemotherapy, with 2 months of daily INH, rifampin, pyrazinamide, and
ethambutol followed by 4 months of daily INH and rifampin. All patients
were hospitalized for the first 14 days of the study for DOT and
specimen collection.
Sputum collection and processing.
Twelve-hour pooled sputum
collections were used for all quantitative studies done during the
first 28 days of the study. Two sputum samples were collected before
the study drug was started to establish baseline counts of M. tuberculosis CFU. Two posttreatment samples were collected, on
days 14 and 15, to assure collection of an evaluable endpoint. Samples
were collected at baseline (day 1) and on days 3, 4, 8, 11, 14, 15, and
28. Spot sputum specimens were obtained at day 42 and monthly after 2, 3, 4, 5, and 6 months of anti-TB therapy for routine qualitative
acid-fast bacillus smear and cultures to assess response to standard
treatment (9).
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.7.1972-1976.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Safety and Bactericidal Activity of Rifalazil in
Patients with Pulmonary Tuberculosis
ABSTRACT
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
Quantitative culture (CFU assay). Serial 10-fold dilutions were prepared by adding 0.5 ml of the sediment to 4.5 ml of 0.25% Tween 80 (Sigma catalog no. P1754) in 0.9% saline. From each dilution (100 to 10-5), 60 µl was inoculated on selective and nonselective sides of Middlebrook 7H10 agar biplates supplemented with oleic acid albumin-dextrose-catalase. The medium was made selective by the addition of final concentrations of polymyxin B (200 U/ml), carbenicillin (50 mg/ml) trimethoprim (20 mg/ml), and amphotericin B (10 mg/ml). Plates were sealed, incubated at 37°C in 5 to 10% CO2, and examined after 2, 3, 4, and 6 weeks. Colonies were counted on plates with dilutions yielding 10 to 50 visible colonies and expressed as log10 CFU per milliliter of undiluted sputum.
The selective 7H10S medium was included to compensate for fungal contamination and resulting nonevaluable quantitative cultures. Yajko et al. have shown that M. tuberculosis CFU counts may be slightly decreased when agar containing antibiotics is used for cultivation (22). For this reason, changes in CFU counts are usually reported from cultures grown on identical media. In this study, the mean change in CFU from the two different media for each of the treatment groups was compared and found to be similar. Therefore, CFU counts taken from selective plates (7H10S) were used if pretreatment or posttreatment samples grown on nonselective media were nonevaluable. Ultimately, data from 7H10 and 7H10S media were used for 44 and 15 patients, respectively.Species identification of isolates and drug susceptibility testing. Pretreatment and day 14 or 15 sputum isolates from each patient were confirmed as M. tuberculosis by using the BACTEC para-nitro-acetyl amino-hydroxy-propiophenone susceptibility method (15) Susceptibility testing against isoniazid, rifampin, streptomycin, ethambutol, and pyrazinamide was performed on pretreatment and day 14 or 15 sputum isolates from each patient using standard BACTEC methods (16). The indicated critical concentrations of the following were used: INH, 0.1 µg/ml; rifampin, 2.0 µg/ml; streptomycin, 2.0 µg/ml; ethambutol, 2.5 µg/ml; and pyrazinamide, 100 µg/ml.
Pharmacokinetics.
Samples for the determination of rifalazil
concentrations in plasma were collected and kept at 4°C until
processing, which took place within 1 h of collection. Collections
were performed at 0 h (predose) and at 3, 6, 8, 12, 24, 48, and
72 h postdose. Plasma samples were divided in aliquots and stored
at 
70°C, for up to 3 months. Trough levels were measured prior to
administration of the second dose on day 8; peak levels were measured
6 h after dosing on days 1 and 8. Plasma samples were analyzed at
PathoGenesis Corp. by high-performance liquid chromatography using a
Beckman Ultrasphere ODS, column (diameter, 5 µm; 4.6 by 250 mm), and
quantitated by measuring visible absorbance of the column effluent at
600 nm.
Endpoints. Safety was assessed by measuring the incidence of AE and changes in serum chemistry and hematology measurements. The microbiological endpoint was the bactericidal activity of rifalazil as assessed by comparing the mean change in CFU per milliliter (log10) of M. tuberculosis in sputum from baseline (day 1) to day 15 (day 14 was used if the day 15 sample was nonevaluable) between treatment groups. The H treatment arm was used as a control for comparison with the rifalazil treatment groups. The higher CFU-per-milliliter count from the two pretreatment samples for each patient was used as the baseline count.
Statistical analysis. All patients who received at least one dose of study drug were included in the safety analysis. An AE was defined as treatment emergent if (i) it was not present at baseline and occurred after the start of medication, (ii) it was present at baseline but increased in severity after the start of study medication, or (iii) it was considered by the investigator to be related to study medication.
The study was powered to detect a 1.0-log10 or greater mean decrease in CFU per milliliter from baseline to day 15 among the two rifalazil treatment groups compared to the INH-alone treatment group, assuming a standard deviation of 1.0 log10 CFU/ml for the mean change for each treatment group. The statistical test used was analysis of variance. Patients were excluded from the analysis of microbiologic activity if nontuberculous mycobacteria were isolated from any sputum culture, overgrowth of contaminating flora occurred on Middlebrook 7H10S plates, fewer than 10 CFU/ml were measured from prescreening and baseline sputum samples, more than 48 h elapsed between sputum collection and processing, or less than 5 ml of sputum was collected.| |
RESULTS |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Patient disposition. Sixty-five patients received at least one dose of study medication and were included in the safety evaluation. Six patients were not evaluable for the microbiologic activity analysis for the following reasons: withdrawal on day 5 for treatment of concomitant bacterial pneumonia (n = 1), contamination of sputum specimens (n = 4), and initial INH mono-resistance (n = 1). These six patients were similarly distributed among the four treatment groups.
AE.
AE attributed to study drug treatment with either INH,
rifampin, or rifalazil and occurring in 15% or more of patients in any
study arm are presented in Table 1.
Arthralgias, fever, myalgias, and taste perversion occurred among more
patients in either rifalazil treatment arm than among those in
treatment arms not receiving rifalazil. Although not statistically
significant, the overall incidence of these AE was higher in the HRz25
treatment group than in the HRz10 treatment group, suggesting that the
AE could be dose dependent. Other AE were distributed similarly among
the four treatment groups. The difference between the proportion of patients with AE in the HRz25 and H treatment groups was not
statistically significant (P > 0.05) using Fisher's
exact test.
|
Hematologic effects.
Transient decreases in ANC to fewer than
2,000 cells/mm3 occurred in subjects in all treatment
groups except H (Table 2). Of the seven
patients in the three rifamycin-receiving treatment arms who
experienced decreases in ANC to fewer than 2.00 × 103
cells/mm3, the fall in ANC occurred by study day 8 in four
subjects. One patient in the HRz10 group had a decrease in ANC to fewer
than 1,000 cells/mm3. This decrease occurred on day 13 of
short-course chemotherapy, 20 days after the patient's last dose of
rifalazil, and was felt by the investigator to be related to standard
short-course chemotherapy. The ANC in this patient increased to more
than 1,000/mm3 by day 15 of short-course chemotherapy.
Decreases in ANC were transient in all patients.
|
Hepatic, renal, and electrolyte effects. Significant increases in serum aspartate and alanine aminotransferase levels occurred in only one patient (HRz25 treatment group). The increases were felt unlikely to be related to rifalazil, as the patient's elevated transaminases were first detected on study day 21, 13 days after the last dose of rifalazil and 7 days after beginning standard short-course chemotherapy. No significant abnormalities in serum electrolytes, renal function, or other biochemical parameters occurred in any treatment group.
Pharmacokinetics. Pharmacokinetic parameters were determined following the first dose of rifalazil administered to the patients. Approximate dose proportionality is evident as illustrated by the Cmax values (13.5 ± 4.6 and 26.4 ± 11.0 ng/ml for the 10- and 25-mg doses, respectively) and the AUC values (280.1 ± 119.7 and 610.3 ± 253.4 for the 10- and 25- mg doses, respectively). The t1/2 values are approximately the same as well (8.7 ± 2.7 and 8.6 ± 3.6), indicating no saturation of drug elimination at these doses.
Although the variability in the high-performance liquid chromatography assay was very low as estimated by WinNonLin software, in previous studies (14) the peak drug level after one dose of 25 mg of rifalazil, as measured by the Cmax level, appeared to be higher in normal volunteers than that observed for TB patients in our study. The Cmax value after the 25-mg dose from this study (26.4 ng/ml) was one-third lower than that observed in normal volunteers (39.3 ng/ml) (14)
a
statistically significant difference. The time to
Cmax value was also somewhat delayed in the TB
patients. The corresponding AUC values were comparable between TB
patients and normal subjects.
Microbiologic activity.
Microbiologic activity was assessed by
measuring the decrease in sputum bacillary load, measured as CFU per
milliliter of sputum at the end of 2 weeks of study drug treatment.
Differences in the mean decrease of CFU per milliliter for treatment
groups HR, HRz10, and HRz25 were not statistically significant from
those observed for the control group (H) due to higher-than-expected standard deviation; however, the HR group showed the greatest mean
decrease (Table 3). For groups HR, HRz10,
and HRz25 the mean decrease in CFU per milliliter and the median
decrease were similar; for treatment group H, the median decrease was
lower than the mean decrease, suggesting greater variability in results among patients in this group.
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DISCUSSION |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Rifalazil at dosages of 10 and 25 mg once weekly was well tolerated by patients with smear-positive pulmonary TB. The rates of transient neutropenia in the two treatment groups receiving rifalazil were comparable to that in the group receiving daily rifampin. Additionally, flu-like symptoms clearly developed in only one (6.3%) patient in the HRz25 treatment group. Flu-like symptoms were observed at a three- to fourfold higher rate in healthy volunteers at this same dose (14; PathoGenesis Corp. study report). The low rate of significant AE in the present study suggests that patients with active TB may be able to tolerate doses higher than 25 mg weekly.
An interesting finding suggested by this study is that TB patients may not absorb rifalazil as rapidly as normal subjects. The mean Cmax value for TB patients from this study was significantly lower than that for healthy volunteers (14). Food effects are well documented for rifamycins in general, and it is possible that absorption was not optimized in this study (13). We attempted to optimize rifalazil absorption in our study patients by administering the drug on scheduled dosing days one-half hour after a standard meal containing a lipid-rich sandwich. Many patients in all treatment groups presented intestinal parasitic infections. Although concomitant specific treatment was provided it is not clear whether this could influence drug absorption. In future studies of rifalazil in TB patients, this issue will require further investigation.
The unexpectedly high variance of the CFU counts for the H and HR treatment groups makes it difficult to fully interpret the results for bactericidal activity. Given the variance in CFU counts, the study had only a 59% power to detect a 1.0-log10 difference in CFU per milliliter between the rifalazil-containing treatment groups and the H treatment group, which was lower than the 88% power used to calculate the sample size for the original study design.
In this 2-week study, we were unable to demonstrate a significant "rifamycin" effect on sputum CFU counts. Neither rifampin nor rifalazil significantly decreased sputum CFUs when compared to INH. In a study by Jindani et al. the bactericidal activities of INH and rifampin were additive, although this was demonstrated in a small number of patients (n = 4) and the standard deviation was not provided (8). Based on our data from a larger study, we conclude that short-term quantitative sputum culture may not be the best indicator of the antimycobacterial activity of rifamycins. Though not yet fully validated, changes in sputum levels of M. tuberculosis antigens such as 85B and mRNA may be more sensitive as early indicators of rifamycin efficacy and warrant further exploration (3, 19). Further studies are needed to determine the maximal tolerated dose of rifalazil and to explore its microbicidal activity at higher doses.
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ACKNOWLEDGMENTS |
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We acknowledge the patients and staff of the Tuberculosis Clinic and Clinical Research Center of the Hospital Universitário Cassiano Antônio de Moraes and the Núcleo de Doenças Infecciosas of the UFES for their invaluable assistance with the study.
This study was supported by contract NO1-AI 45244 (Tuberculosis Prevention and Control Research Unit) of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and PathoGenesis Corporation.
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FOOTNOTES |
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* Corresponding author. Mailing address: Núcleo de Doenças Infecciosas, Centro Biomédico, Universidade Federal do Espírito Santo, Av. Marechal Campos, 1468, Vitória, Espírito Santo CEP 29040-091, Brazil. Phone: 55 (27) 335-7204. Fax: 55 (27) 335-7206. E-mail: rdietze{at}npd.ufes.br.
Present address: Division of Tuberculosis Elimination-NCHSTP,
Centers for Disease Control and Prevention, Atlanta, GA 30333.
Present address: New Jersey School of Medicine and Dentistry,
Newark, New Jersey.
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Materials and Methods
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Discussion
References
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Antimicrobial Agents and Chemotherapy, July 2001, p. 1972-1976, Vol. 45, No. 7
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.7.1972-1976.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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