Increased plasma rifabutin levels with concomitant fluconazole therapy in HIV-infected patients.
OBJECTIVE
To determine the effect of fluconazole on rifabutin pharmacokinetics.


METHODS
An open-label, crossover, phase 1 trial.


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


METHODS
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.


METHODS
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.


METHODS
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 less than or equal to 0.05) for rifabutin and 216% (959 +/- 529 ng.h/mL compared with 244 +/- 141 ng.h/mL; P less than or equal to 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.
Trapnell
C B
CB
Georgetown University Medical Center, Washington, D.C., USA.
Narang
P K
PK
Li
R
R
Lavelle
J P
JP
D017088:AIDS-Related Opportunistic Infections / Q000517:prevention & control*; D000328:Adult; D000900:Anti-Bacterial Agents / Q000009:adverse effects / Q000097:blood* / Q000627:therapeutic use; D000935:Antifungal Agents / Q000627:therapeutic use*; D000998:Antiviral Agents / Q000627:therapeutic use; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D015725:Fluconazole / Q000627:therapeutic use*; D015658:HIV Infections / Q000097:blood* / Q000188:drug therapy; D006801:Humans; D008297:Male; D017828:Rifabutin / Q000009:adverse effects / Q000097:blood* / Q000627:therapeutic use; D015215:Zidovudine / Q000627:therapeutic use
D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D000998:Antiviral Agents; D017828:Rifabutin; D015215:Zidovudine; D015725:Fluconazole