The effect of multiple-dose, oral rifaximin on the pharmacokinetics of intravenous and oral midazolam in healthy volunteers.

STUDY OBJECTIVE: To evaluate the potential of rifaximin, an oral nonabsorbed (< 0.4%) structural analog of rifampin, to induce human hepatic and/or intestinal cytochrome P450 (CYP) 3A enzymes, with use of a known CYP3A probe, midazolam. DESIGN: Prospective, randomized, open-label, two-period, crossover study. SETTING: Clinical research center. SUBJECTS: Twenty-seven healthy adult volunteers. INTERVENTION: During the first treatment period, subjects received a single dose of either intravenous midazolam 2 mg over 30 minutes or oral midazolam 6 mg on day 0. From days 3-10, they received rifaximin 200 mg every 8 hours. On days 6 (after the 9th dose of rifaximin) and 10 (after the 21st dose of rifaximin), subjects received a concomitant single dose of intravenous or oral midazolam. After a 15-day washout period, subjects were crossed over to the other formulation of midazolam, and the treatment schedule was repeated, with the second treatment period starting on day 26 and single-dose administration of midazolam on days 26, 32, and 36. Serial plasma samples were collected for pharmacokinetic analyses. MEASUREMENTS AND MAIN RESULTS: The pharmacokinetic parameters of single-dose intravenous or oral midazolam were determined alone and after coadministration of rifaximin for 3 and 7 days. Rifaximin coadministration did not alter the measured pharmacokinetic parameters for midazolam or its major metabolite, 1'-hydroxymidazolam. The 90% confidence intervals for the maximum concentration and area under the concentration-time curve from time zero extrapolated to infinity (bioavailability) were all within 80-125% for intravenous and oral midazolam. Therefore, no drug interaction was observed between rifaximin and midazolam. Coadministration of midazolam and rifaximin was well tolerated. CONCLUSION: Overall, 3-7 days of rifaximin 200 mg 3 times/day did not alter single-dose midazolam pharmacokinetics. Rifaximin also does not appear to induce intestinal or hepatic CYP3A activity.

The effect of clarithromycin, fluconazole, and rifabutin on dapsone hydroxylamine formation in individuals with human immunodeficiency virus infection (AACTG 283).

BACKGROUND: Dapsone hydroxylamine formation is thought to be the cause of the high rates of adverse reactions to dapsone in human immunodeficiency virus (HIV)-infected individuals. Therefore we studied the effect of the commonly coadministered drugs fluconazole, clarithromycin, and rifabutin on hydroxylamine formation in individuals with HIV infection. METHODS: HIV-infected subjects (CD4 + > or =200 cells/mm 3 ) were enrolled in a 2-part (A or B) open-label drug interaction study. In part A, subjects (n = 12) received dapsone (100-mg tablet once daily) alone for 2 weeks and then, in a randomly assigned order, received dapsone and either fluconazole (200 mg daily), rifabutin (300 mg daily), or fluconazole plus rifabutin, each for a 2-week period. Part B (n = 11) was identical to part A except that clarithromycin (500 mg twice daily) was substituted for rifabutin. On the last study day of each 2-week period, plasma and urine were collected over ascorbic acid for 24 hours. RESULTS: In part A, fluconazole decreased the area under the plasma concentration-time curve, percent of dose excreted in 24-hour urine, and formation clearance of the hydroxylamine by 49%, 53%, and 55% (n = 12, P < .05), respectively. This inhibition of in vivo hydroxylamine formation was quantitatively consistent with that predicted from human liver microsomal experiments. Rifabutin had no effect on hydroxylamine area under the plasma concentration-time curve or percent excreted in 24-hour urine but increased formation clearance of the hydroxylamine by 92% (n = 12, P < .05). Dapsone clearance was increased by rifabutin or rifabutin plus fluconazole (67% and 38%, respectively) (n = 12, P < .05) but was unaffected by fluconazole or clarithromycin. In part B, hydroxylamine production was unaffected by clarithromycin but was affected by fluconazole in a manner identical to that in part A. CONCLUSIONS: On the basis of these data and with the assumption that the exposure to the hydroxylamine is a determinant of dapsone toxicity, we predict that coadministration of fluconazole should decrease the rate of adverse reactions to dapsone in persons with HIV infection but that rifabutin and clarithromycin will have no effect. When dapsone is given in combination with rifabutin, dapsone dosage adjustment may be necessary in light of the increase in dapsone clearance.

The effect of clarithromycin, fluconazole, and rifabutin on sulfamethoxazole hydroxylamine formation in individuals with human immunodeficiency virus infection (AACTG 283).

BACKGROUND: Sulfamethoxazole hydroxylamine formation, in combination with long-term oxidative stress, is thought to be the cause of high rates of adverse drug reactions to sulfamethoxazole in human immunodeficiency virus (HIV)-infected subjects. Therefore the goal of this study was to determine the effect of fluconazole, clarithromycin, and rifabutin on sulfamethoxazole hydroxylamine formation in individuals with HIV-1 infection. METHODS: HIV-1-infected subjects (CD4 + count >/=200 cells/mm 3 ) were enrolled in a 2-part (A and B), open-label drug interaction study (Adult AIDS Clinical Trial Group [AACTG] 283). In part A (n = 9), subjects received cotrimoxazole (1 tablet of 800 mg sulfamethoxazole/160 mg trimethoprim daily) alone for 2 weeks and then, in a randomly assigned order, cotrimoxazole plus either fluconazole (200 mg daily), rifabutin (300 mg daily), or fluconazole plus rifabutin, each for a 2-week period. Part B (n = 12) was identical to part A except that clarithromycin (500 mg twice daily) was substituted for rifabutin. RESULTS: In part A, fluconazole decreased the area under the plasma concentration-time curve (AUC), percent of dose excreted in 24-hour urine, and formation clearance (CL f ) of the hydroxylamine by 37%, 53%, and 61%, respectively (paired t test, P < .05). Rifabutin increased the AUC, percent excreted, and CL f of the hydroxylamine by 55%, 45%, and 53%, respectively ( P < .05). Fluconazole plus rifabutin decreased the AUC, percent excreted, and CL f of the hydroxylamine by 21%, 37%, and 46%, respectively ( P < .05). In part B the fluconazole data were similar to those of part A. Overall, clarithromycin had no effect on hydroxylamine production. CONCLUSIONS: If the exposure (AUC) to sulfamethoxazole hydroxylamine is predictive of sulfamethoxazole toxicity, then rifabutin will increase and clarithromycin plus fluconazole or rifabutin plus fluconazole will decrease the rates of adverse reactions to sulfamethoxazole in HIV-infected subjects.