RESUMO
Rifaximin is an antibiotic, locally acting in the gastrointestinal tract, which may exist in different crystal as well as amorphous forms. The branded rifaximin formulation contains the polymorph rifaximin-α, whose systemic bioavailability is very limited. This study was performed to compare the pharmacokinetics of this formulation with that of a generic product, whose composition in terms of solid state forms of the active pharmaceutical ingredient was found to be different. Two tablets (2×200mg) of branded and generic formulations were given to 24 healthy volunteers of either sex, according to a single-blind, randomized, two-treatment, single-dose, two-period, cross-over design. Plasma and urinary samples were collected at preset times (for 24h or 48h, respectively) after dosing, and assayed for rifaximin concentrations by high-performance liquid chromatography-mass spectrometry. Rifaximin plasma and urine concentration-time profiles showed relevant differences when generic and branded rifaximin were compared. Most pharmacokinetic parameters were significantly higher after administration of generic rifaximin than after rifaximin-α. In particular, the differences for Cmax, AUC and cumulative urinary excretion between the generic formulation and the branded product ranged from 165% to 345%. The few adverse events recorded were not serious and not related to study medications. The results of the present investigation demonstrate different systemic bioavailability of generic and branded formulations of rifaximin. As a consequence, the therapeutic results obtained with rifaximin-α should not be translated sic et simpliciter to the generic formulations of rifaximin, which do not claim containing only rifaximin-α and will display significantly higher systemic absorption in both health and disease.
Assuntos
Antibacterianos/farmacocinética , Medicamentos Genéricos/farmacocinética , Rifamicinas/farmacocinética , Adolescente , Adulto , Antibacterianos/sangue , Antibacterianos/urina , Disponibilidade Biológica , Estudos Cross-Over , Feminino , Voluntários Saudáveis , Humanos , Absorção Intestinal , Masculino , Pessoa de Meia-Idade , Rifamicinas/sangue , Rifamicinas/urina , Rifaximina , Método Simples-Cego , Adulto JovemRESUMO
BACKGROUND: Rifaximin is an antibiotic, acting locally in the gastrointestinal tract, which may exist in different crystal as well as amorphous forms. The current marketed rifaximin formulation contains polymorph alpha, the systemic bioavailability of which is very limited. This study compared the pharmacokinetics of this formulation with those of the amorphous form. METHODS: Amorphous rifaximin was specifically prepared for the study and formulated as the marketed product. Two doses (200 mg and 400 mg) of both formulations were given to two groups of 12 healthy volunteers of either sex according to a single-blind, randomized, two-treatment, single-dose, two-period, cross-over design. Plasma and urine samples were collected at preset times (for 24 hours or 48 hours, respectively) after dosing, and assayed for rifaximin concentrations by high-performance liquid chromatography-mass spectrometry. RESULTS: For both dose levels, peak plasma concentration, area under the concentration-time curve, and cumulative urinary excretion were significantly higher after administration of amorphous rifaximin than rifaximin-α. Ninety percent confidence intervals for peak plasma concentration, area under the concentration-time curve, and urinary excretion ratios were largely outside the upper limit of the accepted (0.80-1.25) range, indicating higher systemic bioavailability of the amorphous rifaximin. The few adverse events recorded were not serious and not related to the study medications. CONCLUSION: Rifaximin-α, a crystal polymorph, does differ from the amorphous form, the latter being systemically more bioavailable. In this regard, care must be taken when using - as a medicinal product - a formulation containing even small amounts of amorphous form, which may alter the peculiar pharmacologic properties of this poorly absorbed antibiotic.
Assuntos
Antibacterianos/química , Antibacterianos/farmacocinética , Trato Gastrointestinal/efeitos dos fármacos , Rifamicinas/farmacologia , Rifamicinas/farmacocinética , Adolescente , Adulto , Antibacterianos/análise , Antibacterianos/farmacologia , Disponibilidade Biológica , Cromatografia Líquida de Alta Pressão , Estudos Cross-Over , Cristalização , Relação Dose-Resposta a Droga , Feminino , Voluntários Saudáveis , Humanos , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Distribuição Aleatória , Rifamicinas/análise , Rifamicinas/química , Rifaximina , Adulto JovemRESUMO
Rifaximin is a non-systemic oral antibiotic derived from rifampin and characterized by a broad spectrum of antibacterial activity against Gram-positive and -negative, aerobic and anaerobic bacteria. Rifaximin was first approved in Italy in 1987 and afterwards in many other worldwide countries for the treatment of several gastrointestinal diseases. This review updates the pharmacology and pharmacodynamics of rifaximin highlighting the different actions, beyond its antibacterial activity, such as alteration of virulence, prevention of gut mucosal adherence and bacterial translocation. Moreover, rifaximin exerts some anti-inflammatory effects with only a minimal effect on the overall composition of the gut microbiota. All these properties make rifaximin a good candidate to treat various gastrointestinal diseases.
Assuntos
Antibacterianos/farmacologia , Infecções Bacterianas/tratamento farmacológico , Rifamicinas/farmacologia , Animais , Bactérias/efeitos dos fármacos , Bactérias/patogenicidade , Infecções Bacterianas/microbiologia , Fármacos Gastrointestinais/farmacologia , Gastroenteropatias/tratamento farmacológico , Trato Gastrointestinal/microbiologia , Humanos , RifaximinaRESUMO
Resumen: ANTECEDENTES: Los fármacos que tienen polimorfismo, como la rifaximina, pueden tener diferencias farmacocinéticas según el polimorfo. La rifaximina polimorfa-α (alfa) es un antibiótico no absorbible. OBJETIVO: Investigar si la farmacocinética de la rifaximina de referencia (α) es distinta de la de una rifaximina genérica en el mercado mexicano. MATERIAL Y MÉTODO: Estudio prospectivo experimental del polimorfo con difracción de rayos X, su perfil de solubilidad y la farmacocinética de una dosis única de 100 mg/ kg de cada rifaximina administrada por vía oral en perros Beagle. RESULTADOS: La rifaximina de referencia fue polimorfo-α (alfa) y la rifaximina genérica resultó polimorfo-к (kappa). El perfil de solubilidad fue diferente porque el polimorfo-к fue más soluble que el α. La concentración plasmática máxima (Cmáx), la concentración durante 24 horas (AUC0-t) y la biodisponibilidad relativa fueron 8 a 10 veces mayores con rifaximina genérica (к) que con la de referencia (α). CONCLUSIÓN: La rifaximina genérica estudiada tiene farmacocinética distinta del producto de referencia y no puede considerarse del todo un antibiótico no absorbible. Se discuten las posibles implicaciones terapéuticas, especialmente en la seguridad.
Abstract: BACKGROUND: Drugs with polimorphism, as rifaximin, may have different pharmacokinetic depending on the polymorph. Rifaximin polymorph-α (alfa) is a non-absorbable antibiotic. OBJECTIVE: To investigate if pharmacokinetic of reference rifaximin (α) is different from a generic rifaximin of the Mexican market. MATERIAL AND METHOD: A prospective experimental study was done assessing polymorphism with X-ray diffraction, solubility test and pharmacokinetics in Beagle dogs after unique oral dose of 100 mg/kg of each rifaximin. RESULTS: Reference rifaximin was a polymorph-α (alfa), while generic rifaximin resulted a polymorph-к (kappa). Solubility profile of both was different, solubility of generic was major than reference rifaximin. Plasma peak concentration (Cmax), area under curve (AUC0-t) and relative bioavailability were 8 to 10 folds higher with generic rifaximin (к) than reference drug (α). CONCLUSION: Generic rifaximin has a different pharmacokinetic from the reference rifaximin and the former cannot be considered a non-absorbable antibiotic.
RESUMO
HBV vaccine needs 3 injections over 6 months to induce immunity. Thus, the use of adjuvants capable of inducing earlier immune protection would be highly desirable. Most adjuvants may act by inducing cytokines, and among them, type I interferons (IFNs), deserve a special attention in view of the potent immunomostimulatory activity observed in mouse models and on dendritic cell functions. The aim of the present trial was to evaluate the effects of IFN-alpha administered as an adjuvant of HBV vaccine in healthy unvaccinated individuals. No significant enhancing effect on the antibody response was observed, in spite of an early and transient upregulation of costimulatory molecule expression on peripheral blood mononuclear cells, which may be suggestive of an IFN-mediated activation of antigen presenting cells. We conclude that, under the conditions used in this trial, natural IFN-alpha does not act as an adjuvant of the HBV vaccine in healthy unvaccinated individuals.