Estudios de bioequivalencia in vivopara demostrar la intercambiabilidadde medicamentos / In vivo bioequivalence studies to prove drug interchangeability

Introducción: la exigencia de demostración de la intercambiabilidadde medicamentos genéricos en relación con los innovadores comenzó en el mundo desarrollado en la década de 1970. Objetivo: en el presente artículo se hace una breve reseña histórica señalando los medicamentos con los cuales y por primera vez se constataron problemas de bioequivalencia. Resultados: se señala que la implementación de la intercambiabilidaden América Latina comienza a principios de la primera década de este siglo, impulsado por un grupo de trabajo de la Organización Panamericana de la Salud (OPS), y que Uruguay comenzó a legislar en la materia en enero de 2007.Se definen los conceptos de bioequivalencia y de intercambiabilidadde medicamentos y se aclara cuáles son los medicamentos que deberían cumplir con esta exigencia en nuestro país. Se examinan los criterios para diseñar un listado de prioridades para exigir la bioequivalencia y se hace una revisióndel marco regulatorio que nuestro país se ha dado desde el año 2007. Se hace referencia a diseños específicos de estosestudios cuyo objetivo es evaluar la interacción de las nuevas formulaciones ôretardõ con la comida o minimizar el efecto de la variabilidad intraindividual sobre la potencia estadística de los estudios. Conclusiones: se comentan algunos detalles mejorables de la normativa y el impacto de los estudios de bioequivalencia sobre los hábitos de prescripción, el mercado farmacéutico enUruguay y la accesibilidad a medicamentos eficaces y seguros.

Introduction: the demand to prove the interchangeability of generic drugs with innovative medicines originatedin 1970, in the developed world.Objective: the present article comprises a brief historical summary, pointing out the first drugs that caused bioequivalence problems. Results: the study states the implementation of interchangeability in Latin America started the first decade of the current century, encouraged by a working teamof the PAHO, and in January, 2007, Uruguay passed the first laws on this matter. The concepts of drug bioequivalence and interchangeabilityare defined and the drugs that should observe this regulation are mentioned. The criteria for the design of a priorities list for the demand of bioequivalence areexamined, and a review of the regulatory framework inour country since 2007 is also included in the present study.Reference to specific designs of these studies is made, aiming to assess the interaction of the new retard formulations with food or to minimize the effects of intra-individual variability on the statistical value of the studies.Conclusions: a few improvable details in terms of regulation and the impact of bioequivalence studies on prescription habits, the pharmaceutical market in Uruguay and accessibility to effective and safe drugs are commented upon.

Introdução: a exigência da demonstração da intercambiabilidadede medicamentos genéricos em relação aos medicamentos de referência começou no mundo desenvolvidona década de 70. Objetivo: neste artigo faz-se uma breve resenha históricaindicando os medicamentos com os quais se constataram problemas de bioequivalência pela primeiravez. Resultados: a implementação da intercambiabilidade na América Latina começou nos primeiros anos desteséculo, impulsada por um grupo de trabalho da Organização Panamericana da Saúde (OPAS); o Uruguai começoua legislar sobre esse tema em janeiro de 2007. Definem-se os conceitos de bioequivalência e de intercambiabilidadede medicamentos e se especificaquais são os medicamentos que deveriam cumprir com esta exigência no nosso país. Faz-se uma análise dos critérios utilizados para definir uma lista de prioridades para exigir a bioequivalência e uma revisão do quadro regulatório vigente no Uruguai desde 2007. Faz-se referencia aos protocolos específicos dos estudoscujo objetivo é avaliar a interação das novas formulações ôretardõ com os alimentos ou minimizar o efeito da variabilidade intraindividual sobre a potencia estatística dos estudos.Conclusões: discutem-se alguns detalhes da legislação que podem ser melhorados e o impacto dos estudosde bioequivalência sobre os hábitos de prescrição de medicamentos, o mercado farmacêutico no Uruguai e o acesso a medicamentos eficazes e seguros.

Single-dose relative bioavailability of a new quetiapine fumarate extended-release formulation: a postprandial, randomized, open-label, two-period crossover study in healthy Uruguayan volunteers.

BACKGROUND: Quetiapine is a dibenzothiazepine derivative that has been established as an effective therapy for schizophrenia and bipolar disorder. A new extended-release (XR) solid formulation of quetiapine was developed in the United Kingdom and a Uruguayan company has developed a branded generic version of the innovator. OBJECTIVE: The goal of the present study was to assess the relative bioavailability of a new XR formulation of quetiapine 300 mg versus the XR reference product after the administration of a high-fat breakfast as required to assume bioequivalence according to the Uruguayan regulatory authority. METHODS: This was a randomized-sequence, open-label, 2-period crossover study performed in healthy Uruguayan volunteers with a washout period of 7 days. One tablet of quetiapine XR 300 mg (test and reference formulations) was administered as a single oral dose, and blood samples were collected over 36 hours. Plasma quetiapine concentration was measured by using HPLC. Plasma concentration-time curves were plotted for each volunteer, and AUC from 0 to 36 hours (AUC(0-36)), AUC(0-∞), C(max), and T(max) were calculated. A priori bioequivalence requirements were set to require a 90% CI of the test/reference ratios for AUC and C(max) values that were between 0.80 and 1.25. Adverse events were determined using clinical assessment, laboratory test results, and monitoring of vital signs throughout the study. Study subjects were asked to report any adverse events at any time during the study. RESULTS: Twenty-four healthy volunteers (12 men, 12 women) were enrolled and completed the study (mean [SD] age, 31 [6.5] years; weight, 68 [12] kg; height, 1.69 [0.09] m; body mass index, 23.7 [3.2] kg/m(2)). Arithmetic mean (SD) of AUC(0-36), AUC(0-∞), C(max), and T(max) were 3279 (1169) ng/mL/h, 3731 (1332) ng/mL/h, 341.5 (108.3) ng/mL, and (median [range]) 5.0 (1.5-12.0) hours, respectively, for the test formulation and 3528 (1308) ng/mL/h, 3546 (1350) ng/mL/h, 365.9 (136.4) ng/mL, and (median [range]) 5.0 (2.5-10.0) hours, respectively, for the reference formulation. The geometric mean (90% CI) for the test/reference ratio of the log-transformed AUC(0-36), AUC(0-∞), and C(max) values were: 0.99 (0.91-1.07), 1.06 (0.95-1.18), and 0.94 (0.84-1.05), respectively. The frequency of reported adverse events was: hypotension (27%), dry mouth (27%), dizziness (10%), headache (7%), and nausea (7%). The difference between formulations was not statistically significant (P > 0.05). CONCLUSIONS: This single-dose study found that the test and reference formulations of quetiapine met the regulatory criteria for bioequivalence among healthy male and female volunteers who took the medicines after a high-fat breakfast. Both products were generally well tolerated.

Enzyme polymorphism on the metabolic-demethylation of dextromethorphan in a Southamerican population

The polymorphic oxidative metabolism of debrisoquine and sparteine were discovered in the seventies by Mahgoub and Eichelbaum. Since then, many other therapeutic substances were added and one of these drugs is dextromethorphan. The object of this investigation was to ascertain the distribution of the oxidative phenotype of dextromethorphan in the Uruguayan population. The drug and its metabolite, dextrorphan, were quantified in the urine of 165 healthy volunteers by a modificacion of an HPLC method by Chen et al. The metabolic ratio was calculated and frequency distribution histograms were drawn. By inspection of the histogram two antimodes can be assigned which determine three sub-populations: on one side the fast extensive metabolizers (n = 30, 18.2 per cent), in the middle the extensive metabolizers (n = 123, 74.5 per cent) and on the other extreme of the histogram the slow metabolizers (n = 12, 7.3 per cent). No other studies have confirmed thus far this trimodal distribution. This research will be continued by genotyping the populations studied in order to confirm these findings and to elucidate the underlying genetic mechanisms of the polymorphism.

Enzyme polymorphism on the metabolic-demethylation of dextromethorphan in a Southamerican population

The polymorphic oxidative metabolism of debrisoquine and sparteine were discovered in the seventies by Mahgoub and Eichelbaum. Since then, many other therapeutic substances were added and one of these drugs is dextromethorphan. The object of this investigation was to ascertain the distribution of the oxidative phenotype of dextromethorphan in the Uruguayan population. The drug and its metabolite, dextrorphan, were quantified in the urine of 165 healthy volunteers by a modificacion of an HPLC method by Chen et al. The metabolic ratio was calculated and frequency distribution histograms were drawn. By inspection of the histogram two antimodes can be assigned which determine three sub-populations: on one side the fast extensive metabolizers (n = 30, 18.2 per cent), in the middle the extensive metabolizers (n = 123, 74.5 per cent) and on the other extreme of the histogram the slow metabolizers (n = 12, 7.3 per cent). No other studies have confirmed thus far this trimodal distribution. This research will be continued by genotyping the populations studied in order to confirm these findings and to elucidate the underlying genetic mechanisms of the polymorphism. (AU)