RIFAMYCIN SV

Absorption

Rifamycin has a very poor absorption and thus, the generation of an oral modified-release formulation using the technology of the multi-matrix structure was required for the generation of the FDA approved product. This preparation allows the delivery of the active ingredient in the distal small bowel and colon without interfering with the flora in the upper gastrointestinal tract.
The multi-matrix is made by a lipophiic matrix surrounded in a hydrophilic matrix which allows for the protection of the active ingredient from dissolution in the intestinal aqueous fluids before it arrives in the cecum. All this matrix is surrounded by a gastro-resistant polymer that only desintegrate in a pH lower than 7.
All this administration-customed formulation allows for a bioavailability of <0.1% and the plasma concentrations are reported to be of <2 ng/ml in patients receiving a dose of 400 mg. This confirms that the site of action of rifamycin stays in the small intestine and colon which prevents the need for dose adjustments in special populations as well as systemic drug interactions.
The reported Cmax, tmax, AUC and mean residence time after a dosage of 250 mg of rifamycin is 36 mg/L, 5 min, 11.84 mg.h/L and 0.49 h respectively.

Toxicity

In safety studies with rifamycin, it was reported a potential of hepatotoxicity due to the depletion of glutathione and the generation of reactive oxygen species in liver microsomes. It is important to mention that this effect is mainly observed in the intravenous administration as the oral dosage does not have a significant systemic absorption.
Rifamycin is not genotoxic in bacterial mutation assays, mouse cell mutation assay or mouse bone marrow micronucleus assay. There is no current information about the effects on fertility, overdosage or carcinogenesis.

The Uses of RIFAMYCIN SV

Rifogal (Rifaximin EP Impurity C NA) is a antibacterial drug which functions by inhibiting bacterial RNA polymerase (RNAP), is an important part of the antibacteral armamentarium. Also, it is one of the few drugs in a multidrug regimens for treating lung disease (LD) due to Mycobacterium avium complex (MAC).

Indications

Rifamycin is indicated for the treatment of adult patients with travelers' diarrhea caused by noninvasive strains of E. coli. The status of the disease should not be complicated by fever or blood in the stool. To prevent drug-resistant bacteria, it is important to mention that the use of rifamycin for this indication should be only done in cases where the infection is proven or strongly suspected to be caused by bacteria.
Travallers' diarrhea is very common problem affecting 20-60% of the travellers and it is defined as an increase in frequency of bowel movements to three or more loose stools per day during a trip abroad. This condition is rarely life threatening but in severe cases it can produce dehydration and sepsis. The most common cause of travellers' diarrhea is a pathogen and from the pathogens identified, bacteria is the most common cause followed by norovirus, rotavirus and similar viruses.

Background

Rifamycin is the prime member of the rifamycin family which are represented by drugs that are a product of fermentation from the gram-positive bacterium Amycolatopsis mediterranei, also known as Streptomyces mediterranei. The parent compound of rifamycin was rifamycin B which was originally obtained as a main product in the presence of diethylbarburitic acid. Some small modifications where performed in this inactive compound and with the creation of rifamycin SV there was the first antibiotic used intravenously for the treatment of tuberculosis.
Rifamycin has had several direct derivative products such as rifamycin SV, rifaximin, rifampin and rifamycin CV. All of the derivatives have slight different physicochemical properties when compared to the parent structure.
Rifamycin was further developed by Cosmo Technologies Ltd and approved in November 16, 2018 by the FDA as a prescription drug after being granted the designation of Qualified Infectious Disease Product which allowed it to have a status a priority review. This drug was also sent for review to the EMA in 2015 by Dr. Falk Pharma Gmbh and it was granted a waiver for the tested conditions.

Definition

ChEBI: A member of the class of rifamycins that exhibits antibiotic and antitubercular properties.

Pharmaceutical Applications

The simplest rifamycin in clinical use, obtained by elimination of a glycolic moiety from rifamycin B. Formulated as sodium salt for parenteral administration. Also available for topical use. Its activity, general properties and pharmacokinetics are very similar to those of rifamide. It is orally absorbed and excreted mainly in the bile. Intramuscular doses of 250 mg produce mean plasma levels of about 2 mg/L. The plasma half-life is around 2 h.
In addition to uses similar to those of rifamide, it is administered topically in surgery and has been proposed for the treatment of synovitis by intra-articular injections. A topical preparation is used for application to wounds and bedsores. Cases of anaphylactic reactions have been reported after local administration of the drug.

Pharmacokinetics

Rifamycin is known to be effective against Gram-positive and Gram-negative pathogens and mycobacteria. It is very effective against E. coli reporting a MIC90 of 64-128 mcg/ml without showing cross-resistance with other antimicrobial agents.
The specific indication of rifamycin is extremely important as ther were previous reports that indicated a high risk factor in the generation of resistant E. coli strains in patients with inflammatory bowel disease.
In clinical trials, rifamycin was tested in a randomized clinical trial of travellers' coming from Mexico and Guatemala. In this trial, rifamycin was proven to significantly reduce the symptoms of travellers' diarrhea.

Metabolism

When absorbed, rifamycin is mainly metabolzied in hepatocytes and intestinal microsomes to a 25-deacetyl metabolite.

Purification Methods

Rifamycin SV gives yellow-orange crystals from Et2O/pet ether or aqueous EtOH, is very soluble in MeOH, EtOH, Me2CO and EtOAc, and is less soluble in Et2O and HCO3-, but slightly soluble in H2O and pet ether. Its UV has max at 223, 314 and 445nm ( 1cm 586, 322 and 204) in phosphatebuffer pH 7. [NMR: Bergamini & Fowst Arzneim.-Forsch 15 951 1965.]