ABSTRACT
Title
Rifaximin, a GI Selective Antibiotic: Current Status & Future Development
Authors
C. Scarpignato
Laboratory of Clinical Pharmacology, Division of Gastroenterology, Department of Clinical Sciences, University of Parma, Italy
Laboratory of Clinical Pharmacology, Division of Gastroenterology, Department of Clinical Sciences, University of Parma, Italy
Abstract
Rifaximin is a synthetic antibiotic designed to modify the parent compound, rifamycin, in order to achieve low gastrointestinal (GI) absorption while retaining good antibacterial activity. Both experimental and clinical pharmacology clearly show that this compound is a non systemic antibiotic with a broad spectrum of antibacterial activity covering Gram-positive and Gram-negative organisms, both aerobes and anaerobes. Being virtually non absorbed, its bioavailability within the GI tract is rather high with intraluminal and fecal drug concentrations that largely exceed the minimal inhibitory concentration values observed in vitro against a wide range of pathogenic organisms. The GI tract represents, therefore, the primary therapeutic target and GI infections the main indication. The appreciation of the pathogenic role of gut bacteria in several organic and functional GI diseases has increasingly broadened its clinical use, which is now extended to hepatic encephalopathy, small intestine bacterial overgrowth, irritable bowel syndrome and colonic diverticular disease. Potential indications include also inflammatory bowel disease, chronic constipation, Clostridium difficile infection and bowel preparation before colorectal surgery. Oral administration of this drug, by getting rid of enteric bacteria, could also be employed to achieve selective bowel decontamination in acute pancreatitis, liver cirrhosis (thus preventing spontaneous bacterial peritonitis) and nonsteroidal anti-inflammatory drug (NSAID) use (lessening in that way NSAID-enteropathy). This antibiotic has, therefore, little value outside the enteric area and this will minimize both antimicrobial resistance and systemic adverse events. Indeed, the drug proved to be safe in all patient populations, including young children.
Although rifaximin has stood the test of time, it still attracts the attention of both basic scientists and clinicians. As a matter of fact, novel indications and new drug regimens are being explored. Besides widening the clinical use, the research on rifaximin is also focused on the synthesis of new derivatives and on the development of original formulations designed to expand the spectrum of its clinical use. In addition, it was recently discovered that rifaximin can be either crystalline or amorphous. The crystal structure can display polymorphism, which depends on how molecules are arranged in the solid state. Five polymorphic forms of rifaximin have been identified, i.e. rifaximin-α, -β, -γ, -δ, -ε. The currently available formulation of rifaximin, employed in more than 400 clinical studies, contains rifaximin-α. Different polymorphic forms can have different chemical and physical properties, including stability and chemical reactivity, dissolution rate and solubility, which can all affect bioavailability, PK (and, as a consequence, PD). And indeed, animal and human studies have shown that the different polymorphs as well as the amorphous form display different absorption and PK profiles, with the γ polymorph exhibiting the largest systemic bioavailability. These data suggest that the results obtained with the polymorph α cannot be translated sic et simpliciter to the other solid state forms or mixtures of them, which can display an erratic systemic absorption and be no longer considered poorly absorbable antibiotics.
C. Scarpignato, I. Pelosini (2005) Rifaximin, a poorly absorbed antibiotic: pharmacology and clinical potential. Chemotherapy 51 (Suppl 1): 36-66.
G.C. Viscomi (2008) Crystal forms of rifaximin and their effect on pharmaceutical properties. CrystEngComm 10: 1074-1081.
A. Marzo, S.A. Ismaili (2010) randomized, crossover study to evacuate the safety and the pharmacokinetic profiles of a single oral dose (400 mg) of amorphous rifaximin in comparison with a single oral dose (400 mg) of Normix® (rifaximin polymorph-α) in healthy volunteers. Dig Liver Dis 42 (Suppl 2): S191-S192.
Although rifaximin has stood the test of time, it still attracts the attention of both basic scientists and clinicians. As a matter of fact, novel indications and new drug regimens are being explored. Besides widening the clinical use, the research on rifaximin is also focused on the synthesis of new derivatives and on the development of original formulations designed to expand the spectrum of its clinical use. In addition, it was recently discovered that rifaximin can be either crystalline or amorphous. The crystal structure can display polymorphism, which depends on how molecules are arranged in the solid state. Five polymorphic forms of rifaximin have been identified, i.e. rifaximin-α, -β, -γ, -δ, -ε. The currently available formulation of rifaximin, employed in more than 400 clinical studies, contains rifaximin-α. Different polymorphic forms can have different chemical and physical properties, including stability and chemical reactivity, dissolution rate and solubility, which can all affect bioavailability, PK (and, as a consequence, PD). And indeed, animal and human studies have shown that the different polymorphs as well as the amorphous form display different absorption and PK profiles, with the γ polymorph exhibiting the largest systemic bioavailability. These data suggest that the results obtained with the polymorph α cannot be translated sic et simpliciter to the other solid state forms or mixtures of them, which can display an erratic systemic absorption and be no longer considered poorly absorbable antibiotics.
C. Scarpignato, I. Pelosini (2005) Rifaximin, a poorly absorbed antibiotic: pharmacology and clinical potential. Chemotherapy 51 (Suppl 1): 36-66.
G.C. Viscomi (2008) Crystal forms of rifaximin and their effect on pharmaceutical properties. CrystEngComm 10: 1074-1081.
A. Marzo, S.A. Ismaili (2010) randomized, crossover study to evacuate the safety and the pharmacokinetic profiles of a single oral dose (400 mg) of amorphous rifaximin in comparison with a single oral dose (400 mg) of Normix® (rifaximin polymorph-α) in healthy volunteers. Dig Liver Dis 42 (Suppl 2): S191-S192.