Following a single oral dose of 300 mg to nine healthy
adult volunteers, rifabutin was readily absorbed from the gastrointestinal
tract with mean (±SD) peak plasma levels (Cmax) of 375 (±267) ng/mL (range: 141
to 1033 ng/mL) attained in 3.3 (±0.9) hours (Tmax range: 2 to 4 hours).
Absolute bioavailability assessed in five HIV-positive patients, who received
both oral and intravenous doses, averaged 20%.
Total recovery of radioactivity in the urine indicates
that at least 53% of the orally administered rifabutin dose is absorbed from
the gastrointestinal tract. The bioavailability of rifabutin from the capsule
dosage form, relative to an oral solution, was 85% in 12 healthy adult
volunteers. High-fat meals slow the rate without influencing the extent of
absorption from the capsule dosage form. Plasma concentrations post-Cmax
declined in an apparent biphasic manner. Pharmacokinetic doseproportionality was
established over the 300 mg to 600 mg dose range in nine healthy adult
volunteers (crossover design) and in 16 early symptomatic human
immunodeficiency virus (HIV)-positive patients over a 300 mg to 900 mg dose
Due to its high lipophilicity, rifabutin demonstrates a
high propensity for distribution and intracellular tissue uptake. Following
intravenous dosing, estimates of apparent steady-state distribution volume (9.3
± 1.5 L/kg) in five HIV-positive patients exceeded total body water by
approximately 15-fold. Substantially higher intracellular tissue levels than
those seen in plasma have been observed in both rat and man. The lung-to-plasma
concentration ratio, obtained at 12 hours, was approximately 6.5 in four surgical
patients who received an oral dose. Mean rifabutin steady-state trough levels
(Cp,min,ss ; 24- hour post-dose) ranged from 50 to 65 ng/mL in HIV-positive
patients and in healthy adult volunteers. About 85% of the drug is bound in a
concentration-independent manner to plasma proteins over a concentration range
of 0.05 to 1 μg/mL. Binding does not appear to be influenced by renal or
hepatic dysfunction. Rifabutin was slowly eliminated from plasma in seven
healthy adult volunteers, presumably because of distribution-limited
elimination, with a mean terminal half-life of 45 (±17) hours (range: 16 to 69
hours). Although the systemic levels of rifabutin following multiple dosing
decreased by 38%, its terminal half-life remained unchanged.
Of the five metabolites that have been identified,
25-O-desacetyl and 31-hydroxy are the most predominant, and show a plasma
metabolite:parent area under the curve ratio of 0.10 and 0.07, respectively.
The former has an activity equal to the parent drug and contributes up to 10%
to the total antimicrobial activity.
A mass-balance study in three healthy adult volunteers
with 14C-labeled rifabutin showed that 53% of the oral dose was
excreted in the urine, primarily as metabolites. About 30% of the dose is
excreted in the feces. Mean systemic clearance (CL /F) in healthy adult
volunteers following a single oral dose was 0.69 (±0.32) L/hr/kg (range: 0.46
to 1.34 L/hr/kg). Renal and biliary clearance of unchanged drug each contribute
approximately 5% to CL /F.
Pharmacokinetics In Special Populations
Compared to healthy volunteers, steady-state kinetics of
MYCOBUTIN are more variable in elderly patients ( > 70 years).
The pharmacokinetics of MYCOBUTIN have not been studied
in subjects under 18 years of age.
The disposition of rifabutin (300 mg) was studied in 18
patients with varying degrees of renal function. Area under plasma concentration
time curve (AUC) increased by about 71% in patients with severe renal impairment
(creatinine clearance below 30 mL/min) compared to patients with creatinine
clearance (Crcl) between 61-74 mL/min. In patients with mild to moderate renal
impairment (Crcl between 30-61 mL/min), the AUC increased by about 41%. In
patients with severe renal impairment, carefully monitor for rifabutin
associated adverse events. A reduction in the dosage of rifabutin is
recommended for patients with Crcl < 30 mL/min if toxicity is suspected (see DOSAGE
Mild hepatic impairment does not require a dose
modification. The pharmacokinetics of rifabutin in patients with moderate and
severe hepatic impairment is not known.
Malabsorption In HIV-Infected Patients
Alterations in gastric pH due to progressing HIV disease
has been linked with malabsorption of some drugs used in HIV-positive patients
(e.g., rifampin, isoniazid). Drug serum concentrations data from AIDS patients
with varying disease severity (based on CD4+ counts) suggests that rifabutin
absorption is not influenced by progressing HIV disease.
(see also DRUG INTERACTIONS)
Multiple dosing of rifabutin has been associated with induction
of hepatic metabolic enzymes of the CYP3A subfamily. Rifabutin's predominant
metabolite (25-desacetyl rifabutin: LM565), may also contribute to this effect.
Metabolic induction due to rifabutin is likely to produce a decrease in plasma concentrations
of concomitantly administered drugs that are primarily metabolized by the CYP3A
enzymes. Similarly concomitant medications that competitively inhibit the CYP3A
activity may increase plasma concentrations of rifabutin.
Two randomized, double-blind clinical trials (Study 023
and Study 027) compared MYCOBUTIN (300 mg/day) to placebo in patients with
CDC-defined AIDS and CD4 counts ≤ 200 cells/μL. These studies accrued
patients from 2/90 through 2/92. Study 023 enrolled 590 patients, with a median
CD4 cell count at study entry of 42 cells/μL (mean 61). Study 027 enrolled
556 patients with a median CD4 cell count at study entry of 40 cells/μL
Endpoints included the following:
- MAC bacteremia, defined as at least one blood culture
positive for Mycobacterium avium complex (MAC) bacteria.
- Clinically significant disseminated MAC disease, defined
as MAC bacteremia accompanied by signs or symptoms of serious MAC infection,
including one or more of the following: fever, night sweats, rigors, weight loss,
worsening anemia, and/or elevations in alkaline phosphatase.
Participants who received MYCOBUTIN were one-third to
one-half as likely to develop MAC bacteremia as were participants who received
placebo. These results were statistically significant (Study 023: p < 0.001;
Study 027: p = 0.002).
In Study 023, the one-year cumulative incidence of MAC
bacteremia, on an intent to treat basis, was 9% for patients randomized to
MYCOBUTIN and 22% for patients randomized to placebo. In Study 027, these rates
were 13% and 28% for patients receiving MYCOBUTIN and placebo, respectively.
Most cases of MAC bacteremia (approximately 90% in these
studies) occurred among participants whose CD4 count at study entry was
≤ 100 cells/μL. The median and mean CD4 counts at onset of MAC bacteremia
were 13 cells/μL and 24 cells/μL, respectively. These studies did not
investigate the optimal time to begin MAC prophylaxis.
Clinically Significant Disseminated MAC Disease
In association with the decreased incidence of
bacteremia, patients on MYCOBUTIN showed reductions in the signs and symptoms
of disseminated MAC disease, including fever, night sweats, weight loss,
fatigue, abdominal pain, anemia, and hepatic dysfunction.
The one-year survival rates in Study 023 were 77% for the
group receiving MYCOBUTIN and 77% for the placebo group. In Study 027, the
one-year survival rates were 77% for the group receiving MYCOBUTIN and 70% for
the placebo group.
These differences were not statistically significant.
Mechanism Of Action
Rifabutin inhibits DNA-dependent RNA polymerase in
susceptible strains of Escherichia coli and Bacillus subtilis but
not in mammalian cells. In resistant strains of E. coli, rifabutin, like
rifampin, did not inhibit this enzyme. It is not known whether rifabutin
inhibits DNA-dependent RNA polymerase in Mycobacterium avium or in M.
intracellulare which comprise M. avium complex (MAC).
In vitro susceptibility testing methods and diagnostic
products used for determining minimum inhibitory concentration (MIC) values
against M. avium complex (MAC) organisms have not been standardized. Breakpoints
to determine whether clinical isolates of MAC and other mycobacterial species
are susceptible or resistant to rifabutin have not been established.
In Vitro Studies
Rifabutin has demonstrated in vitro activity against M.
avium complex (MAC) organisms isolated from both HIV-positive and
HIV-negative people. While-gene probe techniques may be used to identify these
two organisms, many reported studies did not distinguish between these two
species. The vast majority of isolates from MAC-infected, HIV-positive people
are M. avium, whereas in HIV-negative people, about 40% of the MAC
isolates are M. intracellulare.
Various in vitro methodologies employing broth or solid
media, with and without polysorbate 80 (Tween 80), have been used to determine
rifabutin MIC values for mycobacterial species. In general, MIC values
determined in broth are several fold lower than that observed with methods
employing solid media. Utilization of Tween 80 in these assays has been shown
to further lower MIC values.
However, MIC values were substantially higher for
egg-based compared to agar-based solid media.
Rifabutin activity against 211 MAC isolates from
HIV-positive people was evaluated in vitro utilizing a radiometric broth and an
agar dilution method. Results showed that 78% and 82% of these isolates had MIC
values of ≤ 0.25 μg/mL and ≤ 1.0 μg/mL, respectively, when
evaluated by these two methods. Rifabutin was also shown to be active against
phagocytized, M. avium complex in a mouse macrophage cell culture model.
Rifabutin has in vitro activity against many strains of Mycobacterium
tuberculosis. In one study, utilizing the radiometric broth method, each of
17 and 20 rifampin-naive clinical isolates tested from the United States and
Taiwan, respectively, were shown to be susceptible to rifabutin concentrations
of ≤ 0.125 μg/mL.
Cross-resistance between rifampin and rifabutin is
commonly observed with M. tuberculosis and M. avium complex
isolates. Isolates of M. tuberculosis resistant to rifampin are likely
to be resistant to rifabutin. Rifampicin and rifabutin MIC99 values against 523
isolates of M. avium complex were determined utilizing the agar dilution
method (Heifets, Leonid B. and Iseman, Michael D. Determination of in vitro susceptibility
of Mycobacteria to Ansamycin. Am. Rev. Respir. Dis. 1985; 132(3):710-711).
Table 1 : Susceptibility of M. avium Complex
Strains to Rifampin and Rifabutin
|Susceptibility to Rifampin (μg/mL)
||Number of Strains
||% of Strains Susceptible/Resistant to Different Concentrations of Rifabutin (μg/mL)
|Susceptible to 0.5
||Resistant to 0.5 only
||Resistant to 1.0
||Resistant to 2.0
|Susceptible to 1.0
|Resistant to 1.0 only
|Resistant to 5.0
|Resistant to 10.0
Rifabutin in vitro MIC99 values of ≤ 0.5 μg/mL,
determined by the agar dilution method, for M. kansasii, M. gordonae
and M. marinum have been reported; however, the clinical significance of
these results is unknown.
Liver abnormalities (increased bilirubin and liver
weight) occurred in mice, rats and monkeys at doses (respectively) 0.5, 1, and
3 times the recommended human daily dose based on body surface area comparisons.
Testicular atrophy occurred in baboons at doses 2 times the recommended human
dose based on body surface area comparisons, and in rats at doses 6 times the
recommended human daily dose based on body surface area comparisons.