Rifabutin clinical pharmacology

# Clinical Pharmacology

## Pharmacokinetics

### 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 g/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 are more variable in elderly patients (>70 years).

### Pediatric
The pharmacokinetics of MYCOBUTIN 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 6174 mL/min. In patients with mild to moderate renal insufficiency (Crcl between 3061 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).