rifaximin was metabolized mainly by CYP3A4. Rifaximin accounted for 18% of radioactivity in plasma suggesting that the absorbed rifaximin undergoes extensive metabolism.
Excretion
In a mass balance study, after administration of 400 mg 14C-rifaximin orally to healthy volunteers, of the 96.94% total recovery, 96.62% of the administered radioactivity was recovered in feces mostly as the unchanged drug and 0.32% was recovered in urine mostly as metabolites with 0.03% as the unchanged drug.
Biliary excretion of rifaximin was suggested by a separate study in which rifaximin was detected in the bile after cholecystectomy in patients with intact gastrointestinal mucosa.
Specific Populations
Hepatic Impairment
The systemic exposure of rifaximin was markedly elevated in patients with hepatic impairment compared to healthy subjects.
The pharmacokinetics of rifaximin in patients with a history of HE was eva luated after administration of XIFAXAN 550 mg twice a day. The pharmacokinetic parameters were associated with a high variability and mean rifaximin exposure (AUCτ) in patients with a history of HE was higher compared to those in healthy subjects. The mean AUCτ in patients with hepatic impairment of Child-Pugh Class A, B, and C was 10-, 14-, and 21-fold higher, respectively, compared to that in healthy subjects (Table 3).
Table 3: Mean (± SD) Pharmacokinetic Parameters of Rifaximin at Steady-State in Patients with a History of Hepatic Encephalopathy by Child-Pugh Class*
Cross-study comparison with pharmacokinetic parameters in healthy subjects
Median (range)
Renal Impairment
The pharmacokinetics of rifaximin in patients with impaired renal function has not been studied.
Drug Interaction Studies
Effect of other drugs on rifaximin
An in vitro study suggests that rifaximin is a substrate of CYP3A4.
In vitro rifaximin is a substrate of P-glycoprotein, OATP1A2, OATP1B1, and OATP1B3. Rifaximin is not a substrate of OATP2B1.
Cyclosporine
In vitro in the presence of P-glycoprotein inhibitor, verapamil, the efflux ratio of rifaximin was reduced greater than 50%. In a clinical drug interaction study, mean Cmax for rifaximin was increased 83-fold, from 0.48 to 40.0 ng/mL; mean AUC∞ was increased 124-fold, from 2.54 to 314 ng●h/mL following co-administration of a single dose of XIFAXAN 550 mg with a single 600 mg dose of cyclosporine, an inhibitor of P-glycoprotein [see Drug Interactions (7.1)].
Cyclosporine is also an inhibitor of OATP, breast cancer resistance protein (BCRP) and a weak inhibitor of CYP3A4. The relative contribution of inhibition of each transporter by cyclosporine to the increase in rifaximin exposure is unknown.
Effect of rifaximin on other drugs
In in vitro drug interaction studies the IC50 values for rifaximin was >50 micromolar (~60 mcg) for CYP isoforms 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, and 2E1. In vitro IC50 value of rifaximin for CYP3A4 was 25 micromolar. Based on in vitro studies, clinically significant drug interaction via inhibition of 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 and 3A4 by rifaximin is not expected.
The inhibitory effect of rifaximin on P-glycoprotein transport was observed in an in vitro study. The effect of rifaximin on P-gp transporter was not eva luated in vivo.
In in vitro studies, rifaximin at 3 micromolar inhibited the uptake of estradiol glucuronide via OATP1B1 by 64% and via OATP1B3 by 70% while the uptake of estrone sulfate via OATP1A2 was inhibited by 40%. The inhibitory poten |
