The effect of rifaximin on the pharmacokinetics (PK) of single doses of intravenous (IV) and oral (PO) midazolam in healthy volunteers

Abstract

Introduction Rifaximin (RFX) is a broad-spectrum, poorly absorbed, rifamycin S derived antibiotic being developed to treat traveler's diarrhea. Objective: To evaluate the effect of RFX on the PK of IV and PO midazolam (MDZ), a CYP 3A probe. Methods: An open label, randomized, crossover study to determine the effect of RFX 200 mg PO administered Q8 hr for 3 days and Q8 hrs for 7 days on the PK of single doses of MDZ 2 mg IV or MDZ 6 mg PO. Subjects were randomly assigned as to the order of PO and IV MDZ. Plasma samples were harvested at specified intervals to characterize the plasma concentration-time profiles of RFX, and of MDZ and 1'-hydroxymidazolam (OHM) with the 9th or 21st dose of RFX. Results: No significant differences were observed in metrics of systemic exposure of IV or PO midazolam (see table) or its major metabolite, with MDZ alone or for MDZ with RFX. All drugs were well tolerated. Conclusion: RFX does not significantly affect intestinal or hepatic CYP 3A activity. Clinical Pharmacology & Therapeutics (2004) 75, P66–P66; doi: 10.1016/j.clpt.2003.11.246 PK (Mean + SD) MDZ alone MDZ +9th dose RFX MDZ +21st dose RFX IV MDZ Cmax (ng/mL) 45.68 ± 11.49 44.62 ± 10.96 48.84 ± 9.06 AUC0-last (ng.h/mL) 81.68 ± 23.08 76.99 ± 19.21 78.76 ± 16.45 Clearance (L/h) 24.86 ± 6.06 25.62 ± 6.91 24.71 ± 4.93 PO MDZ Cmax (ng/mL) 32.40 ± 15.54 29.12 ± 8.79 31.87 ± 12.00 AUC0-last (ng.h/mL) 72.91 ± 32.20 66.47 ± 25.59 68.70 ± 24.43 Bioavailability 0.29 ± 0.07 0.28 ± 0.07 0.27 ± 0.05 Clearance (L/h) 24.78 ± 5.95 24.87 ± 6.00 25.24 ± 4.50