Comparison of biodisponibility between test-formulation and reference-formulation of propafenone (Ritmonorm®) in phenotipically selected healthy volunteers of both sexes

Orientador: Gilberto de NucciTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências MédicasResumo: O cloridrato de propafenona é um fármaco antiarrítmico da classe 1C, que exerce efeito estabilizador de membrana na célula miocárdica. Possui propriedades bloqueadoras de canais de sódio nas fibras ventriculares e de Purkinje, além de leve ação betabloqueadora, cerca de 1/50 da potência do propranolol, e fraca atividade bloqueadora de canais de cálcio. É metabolizada primariamente no fígado pelo citocromo P-450 2D6, mas a ocorrência de hepatoxicidade é rara, sendo reportado na literatura científica até o ano de 2013, apenas 8 casos clínicos. O presente trabalho teve como objetivo comparar a biodisponibilidade de duas formulações pelo método de cromatografia líquida de alta eficiência acoplada a espectrometria de massas em tandem (LC-MS/MS): formulação referência (Ritmonorm® ¿ propafenona comprimido 300 mg ¿ Abbott Laboratórios do Brasil Ltda.) e formulação teste (propafenona comprimido 300 mg ¿ Biolab Sanus Farmacêutica Ltda.), em voluntários sadios de ambos os sexos, selecionados fenotipicamente com base na atividade para a enzima CYP2D6. A debrisoquina 2.5 mg foi utilizada para a fenotipagem de voluntários, quantificando-se na urina as concentrações de 4-hidroxidebrisoquina, que corresponde à debrisoquina biotransformada primariamente pela CYP2D6, e debrisoquina excretada de forma inalterada, após 5 horas da administração do medicamento. Os metabolizadores extensivos para a debrisoquina foram selecionados para participar da avaliação de bioequivalência entre formulações de propafenona, princípio ativo este que também é primariamente metabolizado pela CYP2D6. Os resultados das etapas clínicas e analíticas mostraram que as duas formulações foram consideradas bioequivalentes para velocidade e extensão de absorção, além de serem seguras e bem toleradas. Dois métodos analíticos foram desenvolvidos e validados, com seletividade satisfatória e com tempos de corrida curtosAbstract: Propafenone hydrochloride is a 1C class of antiarrhythmic drug, which exerts a membrane stabilizing effect on the myocardial cell. It has sodium channel blocking properties in the ventricular and Purkinje fibers, as well as a weak beta blocker action, about 1/50 of the potency of propranolol, and a calcium channel blocker. Propafenone is metabolized primarily in the liver by cytochrome P-450 2D6, but occurrence of hepatotoxicity is rare with only 8 clinical cases reported in the scientific literature until 2013. The objective of the present study was to compare the bioavailability of two formulations by high performance liquid chromatography coupled to tandem mass spectrometry method: reference formulation (Ritmonorm® - propafenone tablet 300 mg - Abbott Laboratories do Brasil Ltda.) and test formulation (300 mg Biolab Sanus Pharmaceuticals Ltda.), in healthy volunteers of both sexes, phenotypically selected based on activity for CYP2D6 enzyme. Debrisoquine 2.5 mg was administered for phenotyping purpose by quantifying urine concentrations of 4hydroxydebisoquine, which corresponds to the biotransformed debrisoquine primarily by CYP2D6, and debrisoquine excreted unaltered, after 5 hours of administration of drug. Extensive metabolizers of debrisoquine were selected to participate in the bioequivalence study between propafenone formulations, which is also primarily metabolized by CYP2D6. The results of the clinical and analytical stages showed that the two formulations were considered bioequivalent for speed and extent of absorption, being also safe and well tolerated. Two analytical methods were developed and validated, with satisfactory selectivity and presenting short run timesDoutoradoFarmacologiaDoutor em Farmacologia01-P-3371/2017CAPE

Propafenone quantification in human plasma by high-performance liquid chromatography coupled with electrospray tandem mass spectrometry in a bioequivalence study

Propafenone is an antiarrhythmic drug applied to ventricular arrhythmias, initially recognized as a sodium channel blocker. This study aims to evaluate the bioequivalence of two propafenone formulations (300 mg tablet) in healthy subjects under non-fasting conditions. The study was conducted as an open, randomized, 2-period design with a 2-sequence (RT, TR) with a 1-week washout interval. The subjects were selected for the study after having their health status previously assessed by a clinical evaluation and laboratory tests (biochemical and hematological parameters, and urinalysis). Debrisoquine phenotype of healthy subjects was determined by analysis of urinary excretion of debrisoquine and its major metabolite, 4-hydroxydebrisoquine. A single propafenone tablet (300 mg) was given in each occasion. Plasma propafenone concentrations were analyzed by liquid chromatography coupled to tandem mass spectrometry (HPLC/MS/MS) with positive ion electrospray ionization using multiple reactions monitoring (MRM). The geometric mean and 90% confidence intervals (CI) of propafenone/Ritmonorm® (T/R) percent ratio were 100.44% (88.39 - 114.13%) for AUClast, 99.84% (90.31 - 110.36%) for AUCinf, and 99.30% (90.08 - 109.47%) for Cmax. Since the 90% CI for Cmax, AUClast, and AUCinf ratios were all inside the 80 - 125% interval proposed by the US Food and Drug Administration Agency, it was concluded that the propafenone formulation elaborated by Biolab Sanus Farmacêutica Ltda. is bioequivalent to Ritmonorm® formulation for both the rate and the extent of absorption. The drug was well tolerated by the subjects, indicating that it is safe to perform propafenone bioequivalence studies in healthy subjects with intermediate/extensive metabolism