Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

Mechanism of action
Rifaximin (polymorphic form α) is an antibacterial drug of the rifamycin class that irreversibly binds the beta sub-unit of the bacterial enzyme DNA-dependent RNA polymerase and consequently inhibits bacterial RNA synthesis.
Rifaximin (polymorphic form α) has a broad antimicrobial spectrum against most of the gram- positive and-negative, aerobic and anaerobic bacteria responsible for intestinal infections.
Due to the very low absorption from the gastro-intestinal tract Rifaximin (polymorphic form α) in its polymorph form is locally acting in the intestinal lumen and clinically not effective against invasive pathogens, even though these bacteria are susceptible in vitro.

Resistance Development
The development of resistance to Rifaximin (polymorphic form α) is primarily a reversible chromosomal one-step alteration in the rpoB gene encoding the bacterial RNA-polymerase. The incidence of resistant subpopulations among bacteria isolated from patients with travellers’ diarrhoea was very low.
Clinical studies that investigated changes in the susceptibility of intestinal flora of subjects affected by travellers’ diarrhoea, failed to detect the emergence of drug resistant gram-positive (e.g.
enterococci) and gram-negative (E. coli) organisms during a three-day course of treatment with rifaximin (polymorphic form α).
Development of resistance in the normal intestinal bacterial flora was investigated with repeated, high doses of rifaximin (polymorphic form α) in healthy volunteers and Inflammatory Bowel Disease patients. Strains resistant to rifaximin (polymorphic form α) developed but were unstable and did not colonise the gastrointestinal tract or replace rifaximin-sensitive strains. When treatment was discontinued resistant strains disappeared rapidly.

Experimental and clinical data suggest that the treatment of travellers’ diarrhoea with rifaximin (polymorphic form α) of patients harbouring strains of Mycobacterium tuberculosis or Neisseria meningitides will not select for rifampicin resistance.

In general, the prevalence of acquired resistance may vary geographically and with time for selected species. Therefore, local information about on resistance is desirable, especially when treating severe infections. As with all antibiotics an expert should be consulted as necessary if the local tolerance is such that utility of Rifaximin (polymorphic form α) in at least some types of infections is questionable.

Susceptibility
Rifaximin (polymorphic form α) is a non-absorbed antibacterial agent. In vitro susceptibility testing cannot be used to reliably establish susceptibility or resistance of bacteria to rifaximin (polymorphic form α). There are currently insufficient data available to support the setting of a clinical breakpoint for susceptibility testing.
Rifaximin (polymorphic form α) has been evaluated in vitro on pathogens causing travellers’ diarrhoea in four different areas of the world. These pathogens were: ETEC (Enterotoxigenic E.
coli), EAEC (Enteroaggregative E. coli), Salmonella spp., Shigella spp., Non-V cholerae vibrios, Plesiomonas spp., Aeromonas spp., Campylobacter spp. The MIC90, for the bacterial isolates tested, was 32 μg/ml, which can easily be achieved in the intestinal lumen due to high faecal concentrations of rifaximin (polymorphic form α). Due to the very low absorption from the gastro- intestinal tract rifaximin (polymorphic form α) is not clinically effective against invasive pathogens, even though these bacteria are susceptible in vitro.

Topical Efficacy
The absorption of orally administered Rifaximin (polymorphic form α) by the gastrointestinal tract is negligible (less than 0.4 %). Therefore, the Rifaximin (polymorphic form α) is only locally active in the intestinal tract, where at the intake of the usual dosages, very high concentrations can be attained, which are significantly higher than the MICs (minimal inhibitors concentrations) for the tested enteropathogens (after 3 days of therapy with a daily dose of 800 mg, faecal concentrations of 4000-8000 µg/g faeces are attained).
Rifaximin (polymorphic form α) is thus able to efficiently combat the pathogen species existing in the gut.

Paediatric Use
The efficacy, posology and safety of Rifaximin (polymorphic form α) in paediatric patients younger than 12 years of age have not been established.
Literature review identified 9 efficacy studies in the paediatric population which have included 371 children, 233 having received Rifaximin (polymorphic form α). The large majority of enrolled children aged nore than 2 years. The characteristic which was present in all studies was diarrhoea of bacterial origin (proven before, during or after the treatment).
The data (the studies per se and a meta-analysis) show that there is a positive trend to demonstrate efficacy of Rifaximin (polymorphic form α) in a special condition (acute diarrhoeas (mainly recurrent or relapsing) which are known or supposed to be caused by non- invasive Rifaximin (polymorphic form α) sensitive bacteria such as Escherichia coli).
The mostly used dosage in children from 2 - 12 years in these limited studies with few patients was in the range of 20-30 mg/kg/d in 2 to 4 administrations (see also Section 4.2).

Others
The broad antibacterial spectrum of Rifaximin (polymorphic form α) enables the efficient reduction of large amounts of gut bacteria. Because of this, also the bacterial production of ammonia and of other toxic substances involved in the pathogenesis and symptomatology of hepatoportal encephalopathy is reduced.
There are no indices for the induction of a necrotizing enterocolitis. Even if Mycobacterium tuberculosis is in-vitro sensitive against Rifaximin (polymorphic form α) after oral treatment, Rifaximin (polymorphic form α) has in-vivo practically no effect in the treatment of tuberculosis because of its missing systemic availability. For the same reason, the risk of the induction of a cross- resistance to Rifampicin is assessed as extremely low.

Pharmacokinetic Properties