ro.
Excretion
After a single oral dose of 400 mg AEMCOLO (388 mg rifamycin base) in fasting healthy adults, fecalexcretion of rifamycin was on average 86% of the nominal dose.
Specific Populations
The pharmacokinetics of rifamycin (taken as AEMCOLO) in patients with impaired renal or hepaticfunction have not been studied.
Drug Interaction Studies
Clinical drug-drug interaction studies of rifamycin (taken as AEMCOLO) have not been conducted.
In Vitro Transporter Studies where Drug Interaction Potential Was Not Further eva luated ClinicallyRifamycin is a substrate of P-glycoprotein (P-gp) and anticipated to be an inhibitor of P-gp and breast
cancer resistant protein (BCRP) in the gut.
Rifamycin is an inhibitor of renal transporters organic anion transporter (OAT) 3, multidrug and toxin
extrusion (MATE) 1, and MATE2-K transporters in vitro, however, based on systemic concentrations of rifamycin observed after administration of the recommended dose, clinically relevant inhibition ofthese transporters in vivo is unlikely.
In Vitro Cytochrome P450 (CYP) Studies where Drug Interaction Potential Was Not Further eva luatedClinicallyRifamycin is an inhibitor of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4/5 in vitro, however, basedon systemic concentrations of rifamycin observed after administration of the recommended doseclinically relevant inhibition of these enzymes in vivo is unlikely.
Rifamycin is an inducer of CYP3A4 and CYP2B6 but not CYP1A2 in vitro, however, based onsystemic concentrations of rifamycin observed after administration of the recommended dose,clinically relevant induction of these enzymes in vivo is unlikely.
Rifamycin is not a substrate of CYPs 1A2, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4/5.
12.4 Microbiology
Mechanism of Action
Rifamycin belongs to the ansamycin class of antibacterial drugs and acts by inhibiting the betasubunitof the bacterial DNA-dependent RNA polymerase, blocking one of the steps in DNAtranscription. This results in inhibition of bacterial synthesis and consequently growth of bacteria.
Resistance
Resistance to rifamycin is associated with mutations in the RNA polymerase beta subunit. Among E.
coli strains, the spontaneous mutation frequency rate of rifamycin ranged from 10-6 to 10-10 at 4x –16x MIC; the mutation frequency was independent of rifamycin concentration. Increases in theminimum inhibitory concentrations were observed both in vitro and while on treatment followingexposure to rifamycin. Cross-resistance between rifamycin and other ansamycins have beenobserved.
Antibacterial Activity
Rifamycin has been shown to be active against most isolates of the following pathogen both in vitroand in clinical studies of travelers’ diarrhea:
Escherichia coli (enterotoxigenic and enteroaggregative isolates)
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
No carcinogenicity studies have been conducted in animals with rifamycin.
Mutagenesis
Rifamycin was not genotoxic in the bacterial reverse mutation assays, mouse lymphoma cell mutationassay, or mouse bone marrow micronucleus assay.
Impairment of Fertility
No fertility studies have been conducted in animals with rifamycin.
14 CLINICAL STUDIES
14.1 Travelers’ Diarrhea
The efficacy of AEMCOLO given as 388 mg orally, taken two times a day, for 3 days was eva luated inone multi-center, randomized, double-blind, placebo |
