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Absorption: 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 dose-proportionality was established over the 300 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 to 900 mg dose range.
Distribution: 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,minss; 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.
Metabolism: 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.
Excretion: 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 (CLs/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 CLs/F.
Pharmacokinetics in Special Populations
Geriatric: Compared to healthy volunteers, steady-state kinetics of MYCOBUTIN (rifabutin) are more variable in elderly patients ( > 70 years).
Pediatric: The pharmacokinetics of MYCOBUTIN (rifabutin) have not been studied in subjects under 18 years of age.
Renal Insufficiency: 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 insufficiency (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 insufficiency (Crcl between 30-61 mL/min), the AUC increased by about 41%. A reduction in the dosage of rifabutin is recommended for patients with Crcl < 30 mL/min (see DOSAGE AND ADMINISTRATION).
(see also PRECAUTIONS - DRUG INTERACTIONS)
Rifabutin induces the enzymes of the cytochrome P450 3A subfamily (CYP3A) and therefore may reduce the plasma concentrations of drugs that are principally metabolized by those enzymes. Rifabutin is also metabolized by CYP3A. Thus, some drugs that inhibit CYP3A may significantly increase plasma concentrations of rifabutin.
Fluconazole: Fluconazole (200 mg/day for 2 weeks) increased the AUC of rifabutin (300 mg/day for 2 weeks) by 82% and Cmax by 88% in 12 HIV-infected patients who were on zidovudine (500 mg/day) maintenance therapy (see PRECAUTIONS - DRUG INTERACTIONS). Rifabutin did not affect the pharmacokinetics of fluconazole.
Itraconazole: Coadministration of itraconazole (200 mg/day) with rifabutin (300 mg/day) in six HIV-infected patients reduced both the AUC and Cmax of itraconazole by 70% to 75% (see PRECAUTIONS - DRUG INTERACTIONS).
Dapsone: Rifabutin (300 mg/day) decreased the AUC of dapsone (50 mg/day) in HIV-infected patients (n=16) by about 27% to 40%.
Sulfamethoxazole-trimethoprim: Coadministration of rifabutin (300 mg/day) and sulfamethoxazole-trimethoprim (double strength) in 12 HIV-infected patients decreased the AUC of sulfamethoxazole-trimethoprim by about 15% to 20%. When trimethoprim was given alone, the AUC of trimethoprim was decreased by 14% and the Cmax by 6%. Sulfamethoxazole-trimethoprim did not alter the pharmacokinetics of rifabutin.
Delavirdine: In 7 HIV-infected patients, rifabutin (300 mg/day) decreased delavirdine (400 mg q 8h) AUC by about 80%, Cmax by about 75%, and mean trough plasma concentrations by about 95%. Based on comparisons with historical data, delavirdine appeared to increase the AUC of rifabutin by at least 100% (see PRECAUTIONS - DRUG INTERACTIONS).
Didanosine: In 12 HIV-infected patients, coadministration of rifabutin (300 or 600 mg/day) and didanosine (167-375 mg BID) did not alter the pharmacokinetics of either drug.
Indinavir: In healthy volunteers, coadministration of indinavir (800 mg q 8h) and rifabutin (300 mg/day) decreased the AUC of indinavir by about 30% and increased the AUC of rifabutin by about 200% (see PRECAUTIONS - DRUG INTERACTIONS).
Nelfinavir: Coadministration of nelfinavir (750 mg q 8h for 8 days) and rifabutin (300 mg/day for 7-8 days) decreased the AUC and Cmax of nelfinavir by about 32% and 25%, respectively, and increased the AUC and Cmax of rifabutin by about 207% and 146%, respectively (see PRECAUTIONS - DRUG INTERACTIONS).
Ritonavir: Coadministration of ritonavir (500 mg q 12h) and rifabutin (150 mg/day) increased the AUC and Cmax of rifabutin by more than 400% and 250%, respectively (see PRECAUTIONS - DRUG INTERACTIONS).
Zidovudine: In 16 HIV-infected patients on zidovudine (100 or 200 mg q 4h), rifabutin (300 or 450 mg/day) lowered the Cmax and AUC of zidovudine by about 48% and 32%, respectively. However, zidovudine levels remained within the therapeutic range during coadministration of rifabutin. Zidovudine did not affect the pharmacokinetics of rifabutin.
In studies conducted in healthy volunteers, rifabutin (300 mg) did not alter the pharmacokinetics of ethambutol (n=10) or isoniazid (n=10).
Clarithromycin: In studies conducted in HIV-infected patients, coadministration of rifabutin (300 mg/day) and clarithromycin (500 mg q 12h) decreased the AUC of clarithromycin by about 50% (n=12) and increased the AUC of rifabutin by about 75% (n=14) (see PRECAUTIONS - DRUG INTERACTIONS).
Methadone: Rifabutin did not alter the pharmacokinetics of methadone in 24 HIV-infected, methadone-maintained, former intravenous drug users.
Oral contraceptives: In 22 healthy female volunteers receiving an oral contraceptive (35 mcg ethinylestradiol (EE) and 1 mg norethindrone (NE) daily for 21 days), rifabutin decreased EE (AUC) and Cmax by 35% and 20%, respectively, and NE AUC by 46% (see PRECAUTIONS - DRUG INTERACTIONS).
Theophylline: Rifabutin did not alter the pharmacokinetics of theophylline when coadministered in 11 healthy volunteers.
Other drugs: The structurally similar drug, rifampin, is known to reduce the plasma concentrations of a number of other drugs (see prescribing information for rifampin). Although rifabutin is a weaker enzyme inducer than rifampin, rifabutin may be expected to have some effect on those drugs as well.
Two randomized, double-blind clinical trials (study 023 and study 027) compared MYCOBUTIN (rifabutin) (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 (mean 58).
Endpoints included the following:
- MAC bacteremia, defined as at least one blood culture positive for M. avium complex 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 (rifabutin) 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 (rifabutin) and 22% for patients randomized to placebo. In study 027, these rates were 13% and 28% for patients receiving MYCOBUTIN (rifabutin) 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 (rifabutin) 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 (rifabutin) and 77% for the placebo group. In study 027, the one-year survival rates were 77% for the group receiving MYCOBUTIN (rifabutin) 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 MIC99 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 (Ref. Heifets, Leonid B. and Iseman, Michael D. 1985. Determination of in vitro susceptibility of Mycobacteria to Ansamycin. Am. Rev. Respir. Dis. 132 (3):710-711).
SUSCEPTIBILITY OF M. AVIUM COMPLEX STRAINS TO RIFAMPIN
|% of Strains Susceptible/Resistant to Different Concentrations of Rifabutin (µg/mL)|
|Susceptibility to Rifampin (µg/mL)||Number of Strains||Susceptible to 0.5||Resistant to 0.5 only||Resistant to 1.0||Resistant to 2.0|
|Susceptible to 1.0||30||100.0||0.0||0.0||0.0|
|Resistant to 1.0 only||163||88.3||11.7||0.0||0.0|
|Resistant to 5.0||105||38.0||57.1||2.9||2.0|
|Resistant to 10.0||225||20.0||50.2||19.6||10.2|
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 all species tested, in rats at doses 5 times, in monkeys at doses 8 times, and in mice at doses 6 times the recommended human daily dose. Testicular atrophy occurred in baboons at doses 4 times the recommended human dose, and in rats at doses 40 times the recommended human daily dose.
Last reviewed on RxList: 6/16/2008
This monograph has been modified to include the generic and brand name in many instances.
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