Pharmacokinetics of rifabutin

Abstract

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...

Intracellular Time Course, Pharmacokinetics, and Biodistribution of Isoniazid and Rifabutin following Pulmonary Delivery of Inhalable Microparticles to Mice

“…This observation lends useful support to the expected therapeutic action and pharmacological indices (2) of the two drugs: isoniazid has the highest EBA among anti-TB drugs (9), but this activity ceases rapidly, primarily through emergence of resistance (11,12). Maintaining bactericidal concentrations of rifabutin in alveolar macrophages, caseous lesions, and general lung tissue as well as blood is desirable in the case of this drug (3,4,31,32). Since the inherent physicochemical properties and biopharmaceutics of these two agents lead to just such a situation upon dosing, the principal tasks of the drug delivery system reduce to (i) ensuring a more favorable biodistribution, such that the drugs are targeted to the site of infection and the target organs of toxicity are protected, and (ii) sustaining drug delivery such that the relative pharmacokinetics of the two agents are not modified except for enhancing duration of action.…”

“…The biopharmaceutics of both isoniazid (15,35,36) and rifabutin (3,4,31,32), both in humans and mice, are well known, and good correlations between the two species in terms of both kinetic data and therapeutic outcome have been observed (1).…”

“…It is also speculated that, following uptake of microparticles, uninfected macrophages could traffic to lung areas where infected cells congregate. It has been demonstrated in animal experiments that inhaled microparticles target the drug payload to alveolar macrophages (21, 30) and enhance the efficacy of the incorporated agents (33, 34; Sen et al, PCT patent application PCT/IB2003/004694).The biopharmaceutics of both isoniazid (15,35,36) and rifabutin (3,4,31,32), both in humans and mice, are well known, and good correlations between the two species in terms of both kinetic data and therapeutic outcome have been observed (1).This report addresses the single-dose pharmacokinetics of isoniazid and rifabutin in polylactide microparticles administered by dry-powder inhalation to mice. Khuller et al have extensively investigated the steady-state pharmacokinetics of various anti-TB drugs in different formulations administered to animals by nebulization (23)(24)(25)(26)40).…”

In vivo activities of newer rifamycin analogs against Mycobacterium avium infection

“…CGP 29,861 was found to have modest activity against isolate A in the beige mouse but was toxic at 20 mg/kg (data not shown). The disparity between the in vitro and in vivo data for isolate A may reflect differences in bioavailability, protein binding, and macrophage penetration among the newer rifamycins (6,16,19,21). To study further these agents in the beige mouse model, correlation of in vivo efficacy with serum or tissue rifamycin levels is planned.…”

Tolerance and Pharmacokinetic Interactions of Rifabutin and Azithromycin

“…Currently recommended doses for use in combination treatment of DMAC are azithromycin at 500 mg daily and rifabutin at 300 mg daily (18). Rifabutin is an inducer of hepatic microsomal cytochrome P-450 enzymes and is known to have significant pharmacokinetic interactions with several therapeutic agents, including clarithromycin (7,16). Pharmacokinetic interactions between these two drugs could have important implications for the safety and effectiveness of DMAC therapy.…”