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.