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Pharmacokinetics of rifabutin
M H Skinner1, M Hsieh, J Torseth
1Division of Clinical Pharmacology, Stanford University Medical Center, California 94305.
Antimicrobial Agents and Chemotherapy
|August 1, 1989
Summary
This study on rifabutin pharmacokinetics in HIV patients found rapid absorption and a 36-hour half-life. Results suggest potential enzyme induction with repeated dosing.
Area of Science:
- Pharmacology
- Clinical Pharmacy
- Drug Metabolism
Background:
- Rifabutin is an antibiotic used in treating infections, including those in patients with human immunodeficiency virus (HIV).
- Understanding its pharmacokinetic profile is crucial for optimizing treatment regimens and managing potential drug interactions.
Purpose of the Study:
- To investigate the pharmacokinetics of oral rifabutin in male patients with early symptomatic HIV infection.
- To determine key pharmacokinetic parameters such as absorption, distribution, metabolism, and excretion (ADME) at various dosage levels.
Main Methods:
- Phase I clinical trial involving 15 male patients with early symptomatic HIV infection.
- Oral rifabutin administered at doses of 300, 600, 900, and 1,200 mg/day.
- Intravenous administration of radiolabeled [14C]rifabutin in 12 studies.
- Blood and urine sample collection for 72 hours post-dose (day 1 and day 28).
- Analysis using high-pressure liquid chromatography (HPLC).
Main Results:
- Rifabutin exhibited rapid oral absorption, with peak plasma concentrations reached in 2-3 hours.
- The terminal half-life was determined to be approximately 36 hours, best described by a two-compartment open model.
- Oral bioavailability ranged from 12% to 20%, with moderate plasma protein binding (29% free fraction).
- Total body clearance was estimated between 10-18 L/h, and renal clearance was 1.5 L/h, with about 10% of the intravenous dose excreted unchanged in urine.
- A large volume of distribution (8-9 L/kg) indicated extensive tissue distribution.
- The area under the curve (AUC) was lower for the last dose compared to the first, suggesting possible induction of drug-metabolizing enzymes.
Conclusions:
- Rifabutin demonstrates predictable pharmacokinetic properties in HIV-infected patients, characterized by rapid absorption and extensive distribution.
- The observed decrease in AUC with repeated dosing suggests rifabutin may induce its own metabolism, a factor to consider in long-term therapy.
- These findings contribute to the understanding of rifabutin's behavior in HIV patients, informing dosage adjustments and potential drug-drug interactions.