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 withzidovudine. 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 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.
RCT Entities:
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 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.
Authors: R Hafner; J Bethel; M Power; B Landry; M Banach; L Mole; H C Standiford; S Follansbee; P Kumar; R Raasch; D Cohn; D Mushatt; G Drusano Journal: Antimicrob Agents Chemother Date: 1998-03 Impact factor: 5.191
Authors: R E Polk; D F Brophy; D S Israel; R Patron; B M Sadler; G E Chittick; W T Symonds; Y Lou; D Kristoff; D S Stein Journal: Antimicrob Agents Chemother Date: 2001-02 Impact factor: 5.191