INCREASED PLASMA RIFABUTIN LEVELS WITH CONCOMITANT FLUCONAZOLE THERAPY IN HIV-INFECTED PATIENTS

Objective: To determine the effect of fluconazole on rifabutin pharmac okinetics. Design: An open-label, crossover, phase 1 trial. Setting: O utpatient clinical research center at a university medical center in W ashington, D.C. Patients: 12 persons with human immunodeficiency virus (HIV) infection whose CD4 lymphocyte counts were between 200 and 500 cells/mm(3) 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 th en rifabutin, 300 mg/d, for the final 2 weeks of the study. Measuremen ts: Blood and urine samples were obtained at regular intervals for 24 hours at the end of each 2-week dosing period to ascertain concentrati ons of fluconazole and rifabutin and the 25-desacetyl metabolite of ri fabutin, LM565. Results: Fluconazole significantly increased the plasm a concentrations of both rifabutin and LM565. Mean increases in the ar ea under the plasma concentration curve compared with the time curve o ver a 24-hour dosing interval were 82% (5442 +/- 2404 ng . h/mL compar ed with 3025 +/- 1117 ng . h/mL; P less than or equal to 0.05) for rif abutin 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: Fluconazol e significantly increases the systemic exposure of both rifabutin and LM565. This pharmacokinetic interaction offers a mechanism that may ex plain the changes reported in both the efficacy and toxicity of rifabu tin with concomitant fluconazole therapy.