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Antimicrobial Agents and Chemotherapy, May 1999, p. 1230-1233, Vol. 43, No. 5
Hoechst Marion Roussel, Kansas City, Missouri
641341; Department of Clinical Pharmacy
Services, Maine Medical Center, Portland, Maine
041022; College of Medicine, University
of Vermont, Burlington, Vermont 054013; and
Division of Infectious Diseases,4
Department of Pharmacy Research,5 and
Office for Research,6 Hartford
Hospital, Hartford, Connecticut 06102
Received 19 June 1998/Returned for modification 1 November
1998/Accepted 1 March 1999
Rifapentine is undergoing development for the treatment of
pulmonary tuberculosis. This study was conducted to characterize the
single-dose pharmacokinetics of rifapentine and its 25-desacetyl metabolite and to assess the effect of food on the rate and extent of
absorption in participants infected with human immunodeficiency virus
(HIV). Twelve men and four women, mean age, 38.6 ± 6.9 years, received a single 600-mg oral dose of rifapentine in an open-label, randomized two-way, complete crossover study. Each volunteer received rifapentine following a high-fat breakfast or during a fasting period.
Serial blood samples were collected for 72 h and both rifapentine
and its metabolite were assayed by a validated high-performance liquid
chromatography method. Pharmacokinetics of rifapentine and
25-desacetylrifapentine were determined by noncompartmental methods.
Mean (± the standard deviation) maximum concentrations of rifapentine
in serum and areas under the curve from time zero to infinity following
a high-fat breakfast were 14.09 ± 2.81 and 373.63 ± 78.19 µg/ml, respectively, and following a fasting period they were
9.42 ± 2.67 and 256.10 ± 86.39 µg · h/ml,
respectively. Pharmacokinetic data from a previously published healthy
volunteer study were used for comparison. Administration of rifapentine with a high-fat breakfast resulted in a 51% increase in rifapentine bioavailability, an effect also observed in healthy volunteers. Although food increased the exposure of these patients to rifapentine, the infrequent dosing schedule for the treatment of tuberculosis (e.g.,
once- or twice-weekly dosing) would be unlikely to lead to
accumulation. Additionally, autoinduction has been previously studied
and has not been demonstrated with this compound, unlike with rifabutin
and rifampin. Rifapentine was well tolerated by HIV-infected study
participants. The results of our study suggest that no dosage
adjustments may be required for rifapentine in HIV-infected patients
(Centers for Disease Control and Prevention classification A1, A2, B1,
or B2) undergoing treatment for tuberculosis.
Rifapentine, a new rifamycin
derivative, inhibits RNA synthesis by interacting with bacterial
DNA-dependent RNA polymerase (13). Rifapentine has
demonstrated activity against medically important mycobacterium
species, including the Mycobacterium avium complex (MAC) and
M. tuberculosis, both in vitro and in vivo (5, 6, 9,
12). Patients suffering from AIDS are commonly afflicted with
mycobacterial infections secondary to various immune system deficiencies, requiring prophylaxis or treatment with a variety of
anti-infective agents, including rifamycin derivatives.
The pharmacokinetic profile of rifapentine has been previously
characterized in healthy volunteers (1, 2, 4, 7, 8, 10, 11,
14-16). It should be noted that four of these rifapentine
pharmacokinetic studies (4, 14-16) were conducted by using
a rifapentine formulation that is available only in the Republic of
China. Following oral administration of single doses, rifapentine was
absorbed slowly with peak concentrations in plasma (Cmax) observed 4 to 5 h after dose
administration. An important pharmacokinetic feature of rifapentine is
the longer terminal elimination half-life (t1/2)
of 13 to 14 h, compared with 2 to 3 h for rifampin, which may
allow extended dosing intervals in patients suffering from
mycobacterial infections. The primary elimination pathway for
rifapentine was characterized as desacetylation to an active
metabolite, 25-desacetylrifapentine, followed by fecal and renal
excretion of both the parent drug and the metabolite. Less than
17% of the oral dose of rifapentine was excreted in the urine
(11). Single-dose pharmacokinetics of rifapentine are
reasonably predictive of multiple-dose pharmacokinetics, due in part to
the lack of autoinduction and the infrequency of drug administration
with the multiple-dose regimen used for tuberculosis (e.g., once or
twice weekly) (7).
The intent of this study was to characterize the single-dose
pharmacokinetics of rifapentine and its active metabolite,
25-desacetylrifapentine, in participants seropositive for human
immunodeficiency virus (HIV) following dosing in both fasted and fed
states and to compare the data obtained to those previously published
on healthy volunteers (8).
(This research was presented, in part, at the 37th Interscience
Conference on Antimicrobial Agents and Chemotherapy in 1997 [10].)
Study design and patient population.
The study was designed
as an open-label, randomized, two-way crossover trial involving 16 HIV-infected participants. Prospective HIV-infected participants
belonging to Centers for Disease Control and Prevention (CDC)
classification system category A1, A2, B1, or B2 (based on the 1993 CDC
HIV classification system and expanded AIDS surveillance definition)
were considered eligible for enrollment (3). HIV testing
consisted of repeated reactive screening by enzyme-linked immunosorbent
assay and specific antibody identification by a supplemental test
(Western blotting). Candidates were between 19 and 55 years of age and
within 15% of the ideal body weight and weighed at least 40 kg. A
complete medical history was recorded, and prospective participants
underwent pre- and poststudy physical examinations, urine toxicology
screening, hepatitis B serology testing, 12-lead electrocardiography,
and serum pregnancy testing. Pre- and poststudy laboratory evaluations
were also conducted and included hematological testing, urinalysis, and
blood chemistry profiling. Participants were excluded if, upon prestudy
evaluation, it was determined that clinically significant findings
existed following physical, cardiac, or laboratory examinations. The
comparator group consisted of 20 healthy, young (18 to 45 years old)
male volunteers who had participated in a previous, single-dose (600 mg) rifapentine pharmacokinetic study (8) similar in design.
Drug administration.
Participants were randomized to receive
both of the following treatments separated by a 14-day washout period:
treatment A, 600 mg of rifapentine (four 150-mg tablets) with a
high-fat breakfast; treatment B, 600 mg of rifapentine (four 150-mg
tablets) following a 10-h fasting state. The meal consisted of
approximately 850 calories from 33 g of protein, 55 g of fat,
and 58 g of carbohydrates. During the course of the study, the
participants refrained from the use of other medications.
Blood sample collection.
Blood samples for plasma drug
concentration determinations were collected prior to drug
administration and at 2, 4, 5, 6, 7, 8, 10, 12, 18, 24, 36, 48, and
72 h after oral administration of rifapentine. Each sample
collection was immediately preceded by the drawing from the venous
access site of a 3-ml sample which was discarded. Blood samples (5 ml)
were collected from an indwelling catheter placed in the antecubital
vein of the forearm. Samples were drawn into heparinized, evacuated
specimen collection tubes. Samples were centrifuged at 2,000 × g under refrigerated conditions (0 to 4°C) for 10 min, and
the plasma was subsequently stored at Analytical procedures.
Rifapentine and
25-desacetylrifapentine concentrations in plasma were determined by a
validated high-performance liquid chromatography method by Phoenix
International Life Sciences, Inc. The validated assay standard curve
ranges were 0.5 to 60 and 0.4 to 50 µg/ml for rifapentine and
25-desacetylrifapentine, respectively. The batch-to-batch mean accuracy
percentages for the quality control samples of rifapentine and
25-desacetylrifapentine were 89.7 to 101.1% and 90.9 to 100.8%,
respectively. The respective mean percent coefficients of variation
(precision) for the quality control samples were 2.1 to 7.3% and 2.2 to 10.5%.
Pharmacokinetic analysis.
Rifapentine pharmacokinetic
parameters were determined by using noncompartmental methods from
plasma drug concentration-versus-time data. The area under the plasma
rifapentine concentration-time curve from time zero to 72 h
(AUC0-72) was determined by using the linear trapezoidal
rule, and the AUC from time zero to infinity (AUC0- Statistical analysis.
Comparisons between treatments were
done by analysis of natural-log-transformed data. A three-way analysis
of variance using PROC MIXED in SAS with terms for subject, treatment,
and period was performed for each parameter. From this analysis,
estimated treatment differences and 90% confidence intervals for
treatment differences were calculated. The log-transformed results were transformed back to the original scale to obtain treatment ratios and
90% confidence intervals for the ratio of treatment means.
Safety assessment.
Safety measures included prestudy and
poststudy vital sign (heart rate, respiration rate, temperature, and
blood pressure) measurements, 12-lead electrocardiography, physical
examinations, and clinical laboratory testing. Any adverse event
observed by the investigator or reported by the subject during the
study period was recorded.
Twelve men and four women were enrolled in the study and received
the study drug (mean age ± standard deviation [SD], 38.6 ± 6.9 years; mean weight ± SD, 74.3 ± 12.6 kg). The median
CD4 count was 307 (range, 225 to 489) cells/mm3. The CDC
classification breakdown is as follows: A1, 2 patients; A2, 10 patients; B1, 0 patients; B2, 5 patients. One participant not included
in the analysis was enrolled and withdrew consent prior to receiving
the study drug. In addition, following the successful completion of one
study period, one participant tested positive for tetrahydrocannabinol
prior to receiving rifapentine during the second study period and was
immediately eliminated from the study. This participant's data from
the first study period were used in the final analysis of data. The
comparator group consisted of 20 healthy, nonsmoking men between the
ages of 18 and 45 years (mean age ± SD, 25.7 = 8.2 years)
and weighing within 10% of the ideal body weight (8).
Pharmacokinetics.
Plasma rifapentine and
25-desacetylrifapentine pharmacokinetic data for HIV-infected subjects
and healthy young males are presented in Table
1. The mean plasma
concentration-versus-time curves for rifapentine and
25-desacetylrifapentine in both the fasted and fed states in
HIV-infected volunteers are illustrated in Fig. 1A and
B. The mean comparative plasma drug
concentration-versus-time curves of rifapentine and
25-desacetylrifapentine in HIV-infected volunteers and in healthy young
men are presented in Fig. 1C and D.
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Pharmacokinetics of Rifapentine in Subjects
Seropositive for the Human Immunodeficiency Virus: a Phase I Study
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
20°C prior to shipment to
Phoenix International Life Sciences, Inc., Montreal, Quebec, Canada,
for plasma drug concentration determination.
)
was estimated by dividing the last plasma drug concentration by the
terminal elimination rate constant (
z).
z was estimated by the linear least-squares
regression of the log plasma drug concentration-time data from the
terminal elimination phase. The t1/2 was
calculated from the equation t1/2 = 0.693/z. Peak plasma drug concentrations (Cmax) and times to Cmax
(Tmax) were obtained by visual inspection of the
concentration-versus-time profiles for each participant. Oral clearance
(CLpo) was calculated by dividing the dose by the plasma
AUC0-.
RESULTS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
TABLE 1.
Comparison of plasma rifapentine and
25-desacetylrifapentine pharmacokinetic data for HIV-infected
participants and healthy, young male volunteers
View larger version (29K):
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FIG. 1.
(A and B) Mean plasma drug concentrations in both the
fed and fasted states. (A) Rifapentine in HIV-infected volunteers. (B)
25-Desacetylrifapentine in HIV-infected volunteers. (C) Comparison of
mean plasma rifapentine concentrations in HIV-infected volunteers and
healthy subjects. (D) Comparison of mean plasma 25-desacetylrifapentine
concentrations in HIV-infected volunteers and healthy subjects.
for 25 of 31 profiles,
indicating that the sampling scheme was appropriate for the
AUC0- calculations.
Plasma rifapentine concentrations peaked 4.8 to 5.3 h after
dosing, on average, in the HIV-infected subjects. The disposition of
rifapentine in HIV-infected subjects was monophasic, with a mean
terminal t1/2 of 16.5 to 17.6 h.
AUC0- and Cmax increase of 51 and 53% were observed when rifapentine was given with a high-fat
breakfast, respectively. However, there was no statistically
significant difference between the rates of rifapentine absorption in
the fasted and fed states (P = 0.326).
The 25-desacetyl metabolite formed slowly, with peak plasma drug
concentrations observed 15.6 to 19.6 h after rifapentine administration. The plasma drug concentration-versus-time profile of
25-desacetylrifapentine mimicked the profile of rifapentine with a
t1/2 of 14.2 to 18.3 h. Similar
concentrations of rifapentine and 25-desacetylrifapentine in plasma
were observed 24 h after dosing. However, higher concentrations of
25-desacetylrifapentine, compared with the parent compound rifapentine,
in plasma persisted at the final sample collection time at 72 h
after dosing.
When rifapentine was administered during fasting, the mean
Cmax and AUC0- of rifapentine
were both 20% lower in HIV-infected subjects than in healthy, young
male subjects. However, the mean Cmax and
AUC0- of the active metabolite 25-desacetylrifapentine
in HIV-infected subjects were 10 and 21% higher, respectively, than in
healthy subjects. The mean CLpo of rifapentine was 30%
higher in HIV-infected subjects than in healthy males. The
t1/2s of rifapentine and its metabolite
25-desacetylrifapentine were similar between the HIV-infected and
healthy volunteers. Although concentrations of the parent drug in
plasma were slightly lower in the HIV-infected subjects, those of its
active metabolite were slightly higher than in healthy young males,
indicating that rifapentine would provide equal coverage for M. tuberculosis in the HIV-infected and healthy volunteers.
Safety. Both of the treatments were well tolerated by HIV-infected subjects. No serious adverse events occurred during the study that were attributable to rifapentine. A total of 21 adverse events occurred, 4 events (headache and nausea) were assessed by the investigator as possibly treatment related, and 17 were assessed as not treatment related.
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DISCUSSION |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Mycobacterial diseases continue to plague various geographic domains of the world. In certain areas of the United States and throughout many other countries of the world, tuberculosis, including multiple-drug-resistant tuberculosis, remains a therapeutic challenge to clinicians. As HIV emerged, later stages of infection (CD4 counts of <100 cells/mm3) were associated with a higher frequency of MAC infection. Both of these mycobacterial diseases are reported with increased frequency in immunocompromised patients, including those patients in various stages of HIV infection. Rifapentine appears to be at least as active in vitro as previous rifamycin compounds for the treatment of these diseases while offering an extended t1/2 that prolongs both serum and intracellular drug concentrations.
The recent introduction of protease inhibitors has created a paradigm shift, dramatically changing the treatment of HIV and AIDS. Fewer patients are progressing to the traditional advanced stages of AIDS, and therefore, reduced numbers of patients are being treated for and given prophylaxis against the more common opportunistic infections. Efforts to pursue rifapentine development were recently discontinued for MAC indications. The main reason for this was that there were not enough patients available for enrollment in efficacy trials. The development of resistance to the current protease inhibitor regimens, perpetuated by nonadherence and tolerability issues, could realign the previous paradigm of disease progression.
Since Mycobacterium species often cause infection intracellularly, it is important to also examine the intracellular drug penetration potential of new antimycobacterial therapies. Mor et al. compared the intracellular activities of rifapentine and rifampin against M. tuberculosis in an experimental model of intracellular infection (9). Once-weekly exposures of infected macrophages to rifapentine concentrations equal to that achieved following administration of a 600-mg dose resulted in a marked reduction of the mycobacterial burden that was maintained over the 4-week study period. The study also concluded that rifapentine demonstrated a greater ability to penetrate macrophages, achieving a four- to fivefold greater ratio of intracellular accumulation than rifampin.
In our study, food significantly increased the extent of absorption of rifapentine in participants seropositive for HIV (P < 0.001). In fact, the mean concentrations of both rifapentine and 25-desacetylrifapentine in plasma exceeded the MICs for at least 90% of the MAC strains tested 24 h after dosing (4 µg/ml) and for at least 90% of the M. tuberculosis strains tested (0.06 to 0.25 µg/ml) 3 days after dosing (5, 6, 9, 12). The effect of seropositivity for HIV did not appear to impact the pharmacokinetics of rifapentine, as the pharmacokinetic profiles of our participants were similar to those of healthy volunteers (8). In addition, the administration of rifapentine was well tolerated by participants seropositive for HIV, as adverse events during the study period were mild and infrequent. The single-dose pharmacokinetic profile of rifapentine compares similarly with its multiple-dose pharmacokinetic profile, suggesting that dosing modifications for HIV-seropositive patients are unnecessary (7). This is not surprising, since the infrequency of the multiple-dose regimen (administration once or twice weekly for the treatment of tuberculosis) did not result in significant accumulation and autoinduction of rifapentine metabolism did not occur.
Rifapentine offers the advantage of a compound with an extended t1/2 that provides therapeutic plasma drug concentrations against M. tuberculosis for at least 72 h after dosing. For patients with tuberculosis who require lengthy therapeutic courses with multiple and often complex medication regimens, extended-interval dosing offers enhanced compliance potential.
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ACKNOWLEDGMENT |
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This work was supported by Hoechst Marion Roussel, Inc.
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FOOTNOTES |
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* Corresponding author. Mailing address: Maine Medical Center, Department of Clinical Pharmacy Services, 22 Bramhall St., Portland, ME 04102. Phone: (207) 871-6294. Fax: (207) 871-6273. E-mail: rowens{at}clinic.net.
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REFERENCES |
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Materials and Methods
Results
Discussion
References
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Antimicrobial Agents and Chemotherapy, May 1999, p. 1230-1233, Vol. 43, No. 5
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Copyright © 1999, American Society for Microbiology. All rights reserved.
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