We investigated the pharmacokinetics of rifabutin in 15 male patients as part of a phase I trial of the treatment of early symptomatic human immunodeficiency virus infection. Six or more patients were studied at each of four different oral dosage levels: 300, 600, 900, and 1,200 mg/day. Twelve studies were also conducted with tracer doses of intravenous radiolabeled ['4C]rifabutin. Blood and urine samples were collected for at least 72 h after the first (day 1) and last (day 28) doses of rifabutin and analyzed by high-pressure liquid chromatography. The plasma concentration data were best described by a two-compartment open model with a terminal half-life of 36 h. Rifabutin was rapidly absorbed, reaching a peak concentration about 2 to 3 h after an oral dose. Peak and trough concentrations for the 1,200-mg dose were 907 and 194 ng/ml, respectively. Total body clearance was 10 to 18 liters/h. Oral bioavailability was 12 to 20%. The drug was moderately bound to plasma proteins with a free fraction of 29 + 2% (mean + standard deviation). About 10% of an administered intravenous dose of rifabutin is excreted into the urine unchanged. Renal clearance was 1.5 0.2 liters/h. The volume of distribution was large (8 to 9 liters/kg), suggesting extensive distribution into the tissues. The area under the curve for the last dose was smaller than that of the first dose, suggesting possible induction of drug-metabolizing enzymes.Rifabutin (ansamycin; LM427) is a semisynthetic rifamycin similar in structure and activity to rifampin (7). In addition to in vitro activity against a variety of gram-negative and gram-positive organisms, it also has activity against Mycobacterium tuberculosis and Mycobacterium avium complex (4, 9). Recent in vitro studies have shown 92% inhibition of reverse transcriptase activity in human immunodeficiency virus-infected lymphocytes when used at a concentration of 0.1 .g/ml (1). As part of a phase I study of rifabutin in patients with early symptomatic human immunodeficiency virus infections, we studied the pharmacokinetics of rifabutin in patients with acquired immunodeficiency syndrome-related complex at four different dosage levels: 300, 600, 900, and 1,200 mg/day. MATERIALS AND METHODSSubjects. Fifteen male patients, ages 28 to 44 years, with early symptomatic human immunodeficiency virus infections were studied after giving informed consent. All patients had either oral thrush or chronic lymphadenopathy but were otherwise in generally good health. Patients were excluded when they had evidence of impaired renal (creatinine clearance of <85% of expected value based on Cockcroft-Gault equation) or hepatic (serum glutamic oxalacetic transaminase or serum glutamic pyruvic transaminase of >60 or bilirubin of >1.2 mg/100 ml) function, known hypersensitivity to rifabutin or rifampin, or recent use of other antiviral agents or immunomodulating agents or of cytolytic or other agents for cancer treatment. All nonessential medications were discontinued prior to enrollment in the trial. Patients were allowed...

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