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


METHODS
Prospective, randomized, open-label, two-period, crossover study.


METHODS
Clinical research center.


METHODS
Twenty-seven healthy adult volunteers.


METHODS
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.


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.


CONCLUSIONS
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.
Pentikis
Helen S
HS
ICON Development Solutions, Ellicott City, Maryland, USA.
Connolly
Margaret
M
Trapnell
Carol B
CB
Forbes
William P
WP
Bettenhausen
Doug K
DK
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D001682:Biological Availability; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D006970:Disorders of Excessive Somnolence / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D007422:Intestines / Q000187:drug effects / Q000201:enzymology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics*; D008875:Middle Aged; D012294:Rifamycins / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000078262:Rifaximin
D014151:Anti-Anxiety Agents; D000890:Anti-Infective Agents; D012294:Rifamycins; C040081:1-hydroxymethylmidazolam; D051544:Cytochrome P-450 CYP3A; D000078262:Rifaximin; D008874:Midazolam