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Increased Plasma Rifabutin Levels with Concomitant Fluconazole Therapy in HIV-Infected Patients

Carol Braun Trapnell, MD; Prem K. Narang, PhD; Ronald Li, PhD; and James P. Lavelle, MD
[+] Article, Author, and Disclosure Information

From the Georgetown University Medical Center, Washington, D.C.; Food and Drug Administration, Rockville, Maryland; and Pharmacia, Inc., Columbus, Ohio. Acknowledgments: The authors thank Catherine O'Leary, RN, Mr. David James, and Mr. David Colborn for technical support and Darrell Abernethy, MD, PhD, Jerry Collins, PhD, and Charles W. Flexner, MD, for manuscript review. Grant Support: In part by Pharmacia, Inc., Columbus, Ohio. Requests for Reprints: Carol Braun Trapnell, MD, Food and Drug Administration, Center for Drug Evaluation and Research, 5600 Fishers Lane, HFD-900, Room 13B-16, Rockville, MD 20857. Current Author Addresses: Dr. Trapnell: Food and Drug Administration, Center for Drug Evaluation and Research, 5600 Fishers Lane, HFD-900, Room 13B-16, Rockville, MD 20857.

Copyright ©2004 by the American College of Physicians

Ann Intern Med. 1996;124(6):573-576. doi:10.7326/0003-4819-124-6-199603150-00006
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Objective: To determine the effect of fluconazole on rifabutin pharmacokinetics.

Design: An open-label, crossover, phase 1 trial.

Setting: Outpatient clinical research center at a university medical center in Washington, D.C.

Patients: 12 persons with human immunodeficiency virus (HIV) infection whose CD4 lymphocyte counts were between 200 and 500 cells/mm3 and who were receiving maintenance therapy with zidovudine.

Intervention: Fluconazole, 200 mg/d for 2 weeks; then a combination of fluconazole, 200 mg/d, and rifabutin, 300 mg/d, for 2 weeks; and then rifabutin, 300 mg/d, for the final 2 weeks of the study.

Measurements: Blood and urine samples were obtained at regular intervals for 24 hours at the end of each 2-week dosing period to ascertain concentrations of fluconazole and rifabutin and the 25-desacetyl metabolite of rifabutin, LM565.

Results: Fluconazole significantly increased the plasma concentrations of both rifabutin and LM565. Mean increases in the area under the plasma concentration curve compared with the time curve over a 24-hour dosing interval were 82% (5442 ± 2404 ng · h/mL compared with 3025 ± 1117 ng · h/mL; P ≤ 0.05) for rifabutin and 216% (959 ± 529 ng · h/mL compared with 244 ± 141 ng · h/mL; P ≤ 0.05) for LM565.

Conclusions: Fluconazole significantly increases the systemic exposure of both rifabutin and LM565. This pharmacokinetic interaction offers a mechanism that may explain the changes reported in both the efficacy and toxicity of rifabutin with concomitant fluconazole therapy.


Grahic Jump Location
Figure 1.
Steady-state concentration compared with time curves of the plasma concentrations (mean ±SD) of rifabutin and its 25-desacetyl metabolite, LM565, over one dosing interval.

The dashed line indicates rifabutin alone; the solid line indicates rifabutin plus fluconazole.

Grahic Jump Location
Grahic Jump Location
Figure 2.
Area under the plasma concentration-time curve for rifabutin and its 25-desacetyl metabolite, LM565, when rifabutin is administered alone and in combination with fluconazole.

Bars and error bars represent mean ±SD. Data on individual participants are joined by a solid line.

Grahic Jump Location




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