Bioequivalence/bioavailability Study of a New Formulation of Imatinib Mesylate 100 mg Coated Tablets versus Glivec® in Brazilian Healthy Male Volunteers in Fed State / Estudo de Bioequivalência/Biodisponibilidade de uma Nova Formulação de Mesilato de Imatinibe versus Glivec® em Voluntários Saudáveis Brasileiros em Condições Alimentares / Estudio de Bioequivalencia/Biodisponibilidad de una Nueva Formulación de Mesilato de Imatinib versus Glivec® en Voluntarios Saludables Brasileños Bajo Condiciones Alimentarias

Introduction: Imatinib mesylate is currently the first-line oral treatment for all stages of chronic myeloid leukemia (CML) and is also used in some cases of gastrointestinal stromal tumor (GIST) and acute lymphoblastic leukemia (ALL). Objective: Investigate the bioavailability of two products containing imatinib mesylate, 100 mg coated tablet, to determine if they are bioequivalent. Method: The study was conducted using an open-label, randomized, balanced design and the formulations were administered orally in a single dose to 48 healthy adult males, in fed state, followed by sequential blood withdraws for the next 72 hours. Forty-eight male healthy volunteers were selected to participate in the study. Test formulation from Eurofarma Laboratórios S.A. Brazil was compared to from Novartis Biociências S.A. The comparative bioavailability of the formulations was assessed based on statistical comparisons of relevant pharmacokinetic parameters obtained from drug concentration data from collected blood samples measured using an analytical method based on high-performance liquid chromatography coupled to mass spectrometry. Results: The ratio of the geometric means between the test and the reference, with a 90% confidence interval, of pharmacokinetic parameters for Cmax was 102.26% (94.17-111.04%) and for AUC0-t was 101.24% (95.19-107.68%). Conclusion: Imatinib mesylate 100 mg (test product) from Eurofarma Laboratórios S.A. was considered bioequivalent to the reference Glivec® 100 mg manufactured by Novartis Biociências S.A, and the test product can be interchangeable with the reference, based on their pharmacokinetic performance

Introdução: O mesilato de imatinibe é atualmente o tratamento oral de primeira linha para todos os estágios de leucemia mieloide crônica (LMC) e é usado também em alguns casos de tumores gastrointestinais (GIST) e na leucemia linfoide aguda (LLA). Objetivo: Investigar a biodisponibilidade de dois produtos contendo mesilato de imatinibe de 100 mg em comprimidos revestidos para determinar se são bioequivalentes. Método: Estudo conduzido usando um desenho aberto, randomizado e balanceado. As formulações foram administradas de forma oral em única dose a 48 participantes saudáveis do sexo masculino após alimentação, seguido de coletas de sangue por 72 horas. Quarenta e oito participantes saudáveis foram selecionados para participar do estudo. A formulação teste da Eurofarma Laboratórios S.A. foi comparada com a formulação referência da Novartis Biociências S.A. A biodisponibilidade relativa das formulações foi avaliada em comparações estatísticas dos parâmetros farmacocinéticos relevantes obtidos de concentrações de droga das amostras coletadas mediante a utilização de um método analítico baseado em cromatografia líquida de alta performance acoplada à espectrometria de massas. Resultados: A razão das médias geométricas entre teste e referência com intervalo de confiança 90% dos parâmetros farmacocinéticos para Cmáx foi de 102,26% (94,17-111,04%) e para ASC0-t foi de 101,24% (95,19-107,68). Conclusão: Mesilato de imatinib 100 mg (produto teste) da Eurofarma Laboratórios S.A. foi considerado bioequivalente ao Glivec® 100 mg produzido por Novartis Biociências S.A., e o produto teste pode ser intercambiável como referência com base em seu desempenho farmacocinético

Introducción: El mesilato de imatinibe es actualmente el tratamiento oral de primera línea para todos los estadios de leucemia mieloide crónica (LMC) y es usado también en algunos casos de tumores gastrointestinales (GIST) y leucemia linfoide aguda (LLA). Objetivo: Investigar la biodisponibilidad de dos productos de mesilato de imatinibe de 100 mg en comprimidos revestidos para determinar si son bioequivalentes. Método: Estudio ejecutado usando un diseño abierto, aleatorizado y balanceado. Las formulaciones fueron administradas de forma oral en dosis única a 48 participantes saludables de sexo masculino en condiciones de alimentación, seguidas de muestras de sangre por 72 horas. Cuarenta y ocho participantes saludables fueron seleccionados para participar del estudio. La formulación de prueba de Eurofarma Laboratórios S.A. fue comparada con la formulación referencia de Novartis Biociências S.A. La biodisponibilidad relativa de las formulaciones fue evaluada mediante comparaciones estadísticas de los parámetros farmacocinéticos relevantes obtenidos de concentraciones del fármaco de muestras recolectadas con la utilización de un método analítico basado en cromatografía de alto rendimiento acoplada a espectrometría de masas. Resultados: La relación de las medias geométricas entre la prueba y la referencia con un intervalo de confianza del 90% de los parámetros farmacocinéticos para Cmax fue 102,26% (94,17-111,04%) y para AUC0-t fue 101,24% (95,19-107,68). Conclusión: El mesilato de imatinib 100 mg (producto de prueba) de Eurofarma Laboratórios S.A. fue considerado bioequivalente al Glivec® 100 mg producido por Novartis Biociências S.A. y el producto de prueba puede ser intercambiable con el de referencia en función de su desempeño farmacocinético

Elaboration of guideline for monitoring in relative bioavailability / pharmaceutical bioequivalence study by the sponsor / Elaboração de diretriz para monitoramento em biodisponibilidade relativa / estudo de bioequivalência farmacêutica pelo patrocinador / Elaboración de la directriz para el seguimiento en la biodisponibilidad relativa / estudio de bioequivalencia farmacéutica por parte del promotor

For registration of generic and similar drugs, it is necessary to carry out pharmaceutical equivalence (PE) tests and pharmaceutical bioequivalence (PB). To carry out these tests, duly qualified research centers are contracted, which need to be monitored by the sponsor who is legally responsible for the activities. To this end, it is the recommendation of the Document of the Americas, periodic monitoring to verify compliance with quality requirements, Standard Operating Procedures, Good Clinical Practices (GCP), Good Laboratory Practices (GLP), of the applicable regulatory framework, as well as of compliance with the study protocol. Thus, monitoring is a methodical and documented process to evaluate the degree of adhesion of the center to the planned design for the evaluation of the formulations. To this end, the implementation of a standardized and easily completed guideline is a very important tool to guarantee a consistent evaluation and maintain the organizational memory of the evaluated items by monitors designated by the sponsor, contributing to the constant improvement of the contracted centers and supporting traceability of the studies. This work provided a systemic view of the evidence process related mainly to pharmaceutical bioequivalence, with the monitoring guideline summarizing the items of greatest relevance to be verified.

Para registro de medicamentos genéricos e similares, é necessária a realização de testes de equivalência farmacêutica (EF) e bioequivalência farmacêutica (BF). Para a realização desses testes, são contratados centros de pesquisa devidamente habilitados, que precisam ser monitorados pelo patrocinador legalmente responsável pelas atividades. Há também a recomendação do Documento das Américas de realizar monitoramentos periódicos para verificar o cumprimento dos requisitos de qualidade, Procedimentos Operacionais Padrão, Boas Práticas Clínicas (BPC), Boas Práticas de Laboratório (BPL), de marco regulatório aplicável, bem como de cumprimento do protocolo do estudo. Assim, o monitoramento é um processo metódico e documentado para avaliar o grau de adesão do centro ao desenho planejado para a avaliação das formulações. Para tanto, a implantação de uma diretriz padronizada e de fácil preenchimento é uma ferramenta muito importante para garantir uma avaliação consistente e manter a memória organizacional dos itens avaliados por monitores designados pelo patrocinador, contribuindo para a melhoria constante dos centros contratados e apoiando rastreabilidade dos estudos. Este artigo forneceu uma visão sistêmica do processo de evidência relacionado principalmente à bioequivalência farmacêutica, com a diretriz de monitoramento resumindo os itens de maior relevância a serem verificados.

Para el registro de medicamentos genéricos y similares, es necesario realizar pruebas de equivalencia farmacéutica (EP) y de bioequivalencia farmacéutica (PB). Para llevar a cabo estas pruebas se contratan centros de investigación debidamente cualificados, que deben ser supervisados por el promotor, que es el responsable legal de las actividades. Para ello, es la recomendación del Documento de las Américas, el monitoreo periódico para verificar el cumplimiento de los requisitos de calidad, los Procedimientos Operativos Estándar, las Buenas Prácticas Clínicas (BPC), las Buenas Prácticas de Laboratorio (BPL), del marco regulatorio aplicable, así como del cumplimiento del protocolo del estudio. Así, la monitorización es un proceso metódico y documentado para evaluar el grado de adhesión del centro al diseño previsto para la evaluación de las formulaciones. Para ello, la implantación de una pauta estandarizada y de fácil cumplimentación es una herramienta muy importante para garantizar una evaluación consistente y mantener la memoria organizativa de los elementos evaluados por parte de los monitores designados por el promotor, contribuyendo a la mejora constante de los centros contratados y apoyando la trazabilidad de los estudios. Este trabajo proporcionó una visión sistémica del proceso de evidencia relacionado principalmente con la bioequivalencia farmacéutica, con la pauta de monitoreo que resume los ítems de mayor relevancia a ser verificados.

Avaliação da bioequivalência entre duas formulações de rivaroxabana ­ 20 mg comprimido revestido ­ administradas em jejum e pós-prandial em voluntários sadios / Evaluation of bioequivalence between two rivaroxaban formulations ­ coated tablet 20 mg ­ administered under fasting and fed conditions in healthy volunteers

Objetivo: O objetivo deste trabalho foi avaliar a bioequivalência entre duas formulações de rivaroxabana 20 mg comprimido revestido, sendo a formulação teste produzida por Sanofi Medley, Brasil e a formulação referência (Xarelto®) comercializada por Bayer S/A. Métodos: Os estudos foram conduzidos em voluntários sadios de ambos os sexos e as formulações foram administradas em dose única, sob o estado de jejum e pós-prandial. Cada estudo foi conduzido de maneira independente, sendo ambos do tipo aberto, randomizado e com intervalo (washout) de sete dias entre os períodos. O estudo em jejum foi realizado em quatro períodos, com 48 voluntários, enquanto o pós-prandial foi realizado em dois períodos, com 36 voluntários. Resultados: Na administração em jejum, a razão entre a média geométrica da formulação teste e referência (T/R) de Cmáx foi de 100,77%, com intervalo de confiança de 90% (IC 90%) de 94,24% a 107,76%. Para ASC0-t, a razão T/R foi de 100,65%, com IC 90% de 96,13% a 105,39%. Na administração pós-prandial, a razão T/R de Cmáx foi de 110,63%, com IC 90% de 102,39% a 119,54%. Para ASC0-t, a razão T/R foi de 104,65%, com IC 90% de 98,44% a 109,12%. Conclusões: As formulações teste e referência foram consideradas estatisticamente bioequivalentes em ambas as condições de administração, de acordo com os critérios exigidos pela Agência Nacional de Vigilância Sanitária (Anvisa). A formulação teste foi registrada na Anvisa e disponibilizada para comercialização, contribuindo, assim, para a ampliação da disponibilidade do tratamento para doenças tromboembólicas e para a redução de custos ao paciente e ao Sistema Único de Saúde.

Objective: The objective of the present study was to evaluate the bioequivalence between two formulations of rivaroxaban 20 mg coated tablet, the test formulation being manufactured by Sanofi Medley, Brazil and the reference formulation (Xarelto® ) commercialized by Bayer S/A. Methods: The studies were conducted in healthy volunteers of both sexes and the formulations were administered in a single dose, under fasting and fed conditions. Each study was conducted independently, both being open-label, randomized and with a seven-day interval (washout) between periods. The fasting study was carried out in four periods, with 48 volunteers, while the fed study was carried out in two periods, with 36 volunteers. Results: In the fasting administration, the ratio between.

Use of biorelevant dissolution media in dissolution tests as a predictive method of oral bioavailability

Abstract Dissolution is a key step in the uptake of oral drugs. In order to compare the behaviour of the dissolution of two formulations, the dissolution profile test was used. This assay must be discriminative and should mimic in vivo conditions. Many dissolution media described in pharmacopoeias are not predictive of bioavailability. Due to this, biorelevant media are used as an alternative to solve this problem. The objective of this work is to evaluate the relevance of biorelevant dissolution media to predict in vivo drug dissolution. For this, a bibliographic search was carried out in scientific databases. The search was first performed for articles verifying the physicochemical properties of human gastrointestinal fluids. Subsequently, a comparison was made between the properties of gastrointestinal fluids and those of biorelevant and pharmacopoeial media. Finally, the results of bioequivalence studies and dissolution profile tests in biorelevant media described in the literature were compared. The results revealed that there are a few publications that have analysed some physicochemical properties of gastrointestinal fluids. In addition, high variability was observed for some properties. Regarding the comparison of these properties with pharmacopoeial media and biorelevant media, the analysis showed that the biorelevant media are more similar to gastrointestinal fluids than the pharmacopoeial media. Finally, the in vitro dissolution profile results were similar to the results obtained in vivo. Thus, biorelevant media may be useful for analysing dissolution profiles.

Mupirocin ointments: In vitro x In vivo bioequivalence evaluation

Abstract Bioequivalence (BE) assessment of topical drug products is a long-standing challenge. Agencies such as the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have published several drafts in recent years suggesting different approaches as alternative to evaluate the BE. A proposed Topical Classification System (TCS) has even been discussed. Given the above, the objective of this research was to use in vitro and in vivo BE approaches to evaluate Brazilian marketed mupirocin (MPC) ointments, previously classified as TCS class The in vitro permeation test (IVPT) was performed by applying formulations to pig skin by Franz cells. The in vivo methodology was dermatopharmacokinetic (DPK). These approaches (in vivo tape stripping and IVPT) demonstrated capability of distinguishing among different formulations, thus making them useful methodologies for BE evaluation.

Dissolution test for oral suspension: an overview about use and importance

Abstract This work aims to ascertain the comprehensiveness of dissolution tests for oral suspensions registered in Brazil and the USA. After consulting literature since 1994, a paucity of information about dissolution methods for suspensions was detected. It makes it difficult to establish the most appropriate test parameters. In January, 2019, there were 46 drugs registered in Anvisa (Brazil) as oral suspension, being 47 reference, 173 generic and 114 interchangeable similar (IS) medicines; while in the USA, 90 drugs were registered as oral suspension by FDA, 235 Abreviatted New Drug Application and 111 New Drug Application medicines. Out of 46 and 90, only six and 15 drugs as oral suspension had a pharmacopeial dissolution test, corresponding to 70 (20.9%) and 82 (23.7%) products in Brazil and the USA, respectively. Dissolution studies were found for 17 drugs as oral suspension in the non-compendial literature. Dissolution test conditions were established to few marketable oral suspension drugs, most of which are BCS class II or IV. Thus, investing in dissolution studies could subsidize the registration of these products by regulators, especially for generic and IS drugs, by comparing dissolution profiles, and predicting their in vivo behavior to avoid exposure of healthy individuals to clinical research.

Estudio comparativo de la calidad biofarmacéutica de Alprazolam 0, 5 mg comercializadas en el mercado peruano / Comparative study of the biopharmaceutical quality of Alprazolam 0. 5 mg commercialized in the Peruvian market

El Alprazolam pertenece a las benzodiazepinas. Sus efectos se atribuyen a que actúa sobre receptores de membrana específicos, lo cual facilita la acción inhibitoria presináptica y postsináptica del ácido γ-aminobutírico (GABA), especialmente en la formación reticular ascendente. Se utiliza para el tratamiento de los estados de ansiedad, crisis de angustia, ataques de pánico y estrés intenso. Este estudio se realizó para analizar los parámetros comparativos de control de calidad in vitro mediante la evaluación de la variación de peso, friabilidad, dureza, tiempo de desintegración, perfil y eficiencia de disolución entre el medicamento innovador (Xanax®) y multifuentes que son comercializados en el mercado peruano. Para realizarlo, se seleccionaron tabletas de Alprazolam 0,5 mg multifuente de diferentes laboratorios comparándolos con el medicamento innovador y se evaluaron las características fisicoquímicas y biofarmacéuticas. Los ensayos farmacopeicos se evaluaron según lo establecido en la USP 42. Los resultados de las pruebas fisicoquímicas indicaron que las muestras analizadas no tenían diferencia significativa y estaban dentro de lo establecido en la farmacopea, así mismo el perfil y eficiencia de disolución permitieron establecer que el comportamiento biofarmacéutico de las mismas era muy similar para ambos tipos de molécula. Se estableció que las tabletas multifuentes de Alprazolam 0,5 mg de esta investigación son bioequivalentes con el innovador, por lo que permite proponer a la comunidad científica la determinación de la equivalencia biofarmacéutica como elemento de apoyo en la toma de decisiones de compra en el servicio farmacéutico

Alprazolam belongs to benzodiazepines. Its effects are attributed to the fact that it acts on specific membrane receptors, which facilitates the presynaptic and postsynaptic inhibitory action of γ-aminobutyric acid (GABA), especially in the ascending reticular formation. It is used to treat anxiety states, panic attacks, and intense stress. This study was carried out to analyze comparative parameters of in vitro quality control by evaluating the variation in weight, friability, hardness, disintegration time, profile and dissolution efficiency between the innovative drug (Xanax®) and multi-sources tablets that are marketed in the Peruvian market. To perform this, Alprazolam 0.5 mg multi-source tablets were selected from different laboratories comparing them with the innovative medicine and the physicochemical and biopharmaceutical characteristics were evaluated. Pharmacopoeial trials were evaluated as established in USP 42. The results of physicochemical tests indicated that analyzed samples did not have a significant difference and were within the established in the pharmacopoeia, as well as the profile and dissolution efficiency allowed to establish that their biopharmaceutical behavior was very similar for both types of molecules. It was established that Alprazolam 0.5 mg multi-source tablets from this research are bioequivalent with innovator, which makes it possible to propose to scientific community determination of biopharmaceutical equivalency as a support element in decision-making process for purchasing services pharmacist

Comparación de la equivalencia terapéutica de dos productos de bisoprolol - hidroclorotiazida en pacientes con hipertensión arterial / Comparison of two products containing bisoprolol - hydrochlorothiazide therapeutic equivalence in patients with arterial hypertension

Resumen Objetivo: Evaluar la equivalencia terapéutica de dos marcas comerciales de bisoprolol -hidroclorotiazida como terapia antihipertensiva. Método: Estudio prospectivo, doble ciego, doble falso, aleatorizado, de grupos paralelos, en el que se evaluó el efecto antihipertensivo de la combinación de bisoprolol-hidroclorotiazida 2,5-6,25 y 5-6,25 mg (comprimidos BHL, formulación test) y bisoprolol-hidroclorotiazida 2,5-6,25 y 5-6,25 mg tabletas (BHM, formulación de referencia), administrados en pacientes con hipertensión arterial. Variables de efectividad: Presiones arteriales medidas mediante mediante esfigmomanómetro de mercurio al inicio y después del período placebo, a las 4 y 8 semanas del inicio del tratamiento; cambios horarios de la presión arterial durante 24 horas, mediante monitorización ambulatoria de la presión arterial. Resultados: El control de los valores de presión arterial se logró en ambas formulaciones, principalmente a partir de la cuarta semana de tratamiento. Los pacientes del grupo test ingresaron con presiones arteriales sistólicas más elevadas. Después del tratamiento no hubo diferencias entre los grupos, a ninguno de los tiempos. La relación V/P del grupo test fue 0,5-1. Los índices de suavidad de ambos fueron mayores a 1,75. Conclusiones: La formulación test de la combinación de bisoprolol-hidroclotiazida demostró acción antihipertensiva similar al compararla con la formulación de referencia.

Abstract Objective: To evaluate the therapeutic equivalence of two commercial brands of bisoprolol -hydrochlorothiazide as antihypertensive therapy. Method: A prospective, double blind, double placebo, randomised, parallel group study was conducted, in which the antihypertensive effect of the bisoprolol -hydrochlorothiazide 2.5 - 6.25 mg and 5 - 6.25 mg (tablets BHL, test formula) and bisoprolol -hydrochlorothiazide 2.5 - 6.25 mg and 5 - 6.25 mg tablets (BHM, reference formula), was compared by administering it to patients with arterial hypertension given to patients with arterial hypertension. Effectivity variables: blood pressures measured using a mercury sphygmomanometer at the beginning and after the placebo period, at 4 weeks and 8 weeks from the start of the treatment; blood pressure hours change during 24 hours using an ambulatory blood pressure monitoring device. Results: Control of the blood pressure values was achieved with both formulas, mainly from the fourth week of treatment. The patients of the test group were admitted with higher systolic blood pressures. After the treatment, there were no differences between the groups at any of the times. The V/P ratio of the test group was 0.5 - 1. The smoothness index in both groups was greater than 1.75 of fit of both was greater than 1.75. Conclusions: The test formula of the bisoprolol-hydrochlorothiazide demonstrated an antihypertensive action similar to that achieved with the reference formula.

Conceptos fundamentales de bioequivalencia y biosimilitud en la normativa chilena y controversias sobre intercambiabilidad / Chilean legislation on bioequivalence and biosimilarity and current controversies related to drug interchangeability

Los medicamentos constituyen un bien económico que forma parte del gasto público y privado y de la toma de decisiones en salud. El aseguramiento de su calidad, eficacia y seguridad resulta fundamental. Sin embargo, la variada oferta disponible en el mercado chileno, donde se reconocen productos innovadores y genéricos, constituye un escenario confuso para consumidores y proveedores en salud. En esta revisión pretendemos aclarar los conceptos de fármacos bioequivalentes (aplicable a compuestos de tamaño molecular pequeño) y fármacos biosimilares (para compuestos biológicos de mayor complejidad molecular). En ambos casos, el comportamiento en el organismo del principio activo debe ser demostrado mediante estudios realizados para este fin. Una aplicación directa del concepto de bioequivalencia es la intercambiabilidad, definida como la posibilidad de utilizar un producto de un mismo principio activo, mientras la forma farmacéutica y esquema de dosificación sean iguales. Las normas relativas a esta materia y los organismos públicos encargados, no solo debieran garantizar la seguridad y la eficacia en el intercambio entre productos, sino también aspectos relacionados con el costo, la accesibilidad a los fármacos y la implementación de una guía de homogeneización de conceptos y criterios de intercambiabilidad basados en la evidencia, lo cual impactaría en una mejor educación para los usuarios, reduciendo la asimetría de información entre el usuario y la industria. La importancia de la intercambiabilidad destaca en Chile en el contexto del Plan de Garantías Explícitas en Salud (GES) y la Ley de Protección Financiera para Diagnósticos y Tratamientos de Alto Costo en Salud (Ley Ricarte Soto). Sin embargo, no es posible garantizar que todos los productos alternativos al innovador presentes en el mercado chileno son bioequivalentes. El conocimiento disponible en esta temática puede impactar y contribuir a la toma de decisiones en los prescriptores y usuarios, así como en la elaboración de políticas públicas en torno a los productos farmacéuticos bioequivalentes y biosimilares en nuestro país.

Medicines are an economic good and a fundamental component of public and private health spending and decision-making. Assurance of their quality, efficiency, and safety is essential. In Chile, the wide variety of available drugs, including innovator products, and generics­some of which are certified as bioequivalent, while others are not­creates a potentially confusing scenario for both consumers and health providers. In this review, we intend to shed light on the concepts of bioequivalency (the standard permitting interchangeability for small-molecule drugs) and biosimilarity (the standard permitting interchangeability for biological compounds of greater molecular complexity). In both cases, how the active substance interacts with the host organism must be demonstrated by studies designed and carried out for this purpose. Interchangeability is defined as the possibility of using a product of the same active principle, as long as the pharmaceutical form and dosage scheme are the same. Regulations related to bioequivalence and biosimilarity must not only guarantee safety and efficacy when products are interchanged but also facilitate cost savings and access to medicines. Implementation of evidence-based guidelines that standardize concepts of interchangeability could lead to more educated usage and reduced information asymmetry between patients (users) and industry. Drug interchangeability is particularly relevant in two government health initiatives in Chile: the Explicit Guarantees in Health Care (GES) plan, and the Law on Financial Protection for High-Cost Diagnostics and Treatment in Health Care (also known as the "Ricarte Soto Law"). Nonetheless, it is not possible to guarantee that all alternative drug products on the Chilean market are bioequivalents of the reference product. Synthesis of the available knowledge on bioequivalent and biosimilar pharmaceutical products in Chile could facilitate and contribute to stakeholder decision-making and the development of better health policies.

Equivalencia terapéutica evaluada mediante estudios in vitro de medicamentos multifuentes: estudio de casos de amoxicilina, doxiciclina y fluconazol en Lima, Perú / Therapeutic equivalence evaluated by in vitro studies of multisource pharmaceutical products: case studies of amoxicillin, doxycycline and fluconazole in Lima, Peru

RESUMEN El objetivo del estudio fue determinar la equivalencia terapéutica evaluada mediante estudios in vitro de cuatro marcas de medicamentos conteniendo amoxicilina, doxiciclina y fluconazol adquiridos en establecimientos farmacéuticos de Lima Metropolitana y establecer su intercambiabilidad con un producto de referencia (PR). Se empleó un método validado de espectrofotometría ultravioleta visible para determinar el perfil de disolución. El factor de similitud (f2) se utilizó para establecer la equivalencia terapéutica, considerándose equivalentes si los valores de f2 se encontraban entre 50 y 100. Para doxiciclina los cuatro medicamentos fueron equivalentes in vitro al PR, para amoxicilina sólo dos medicamentos fueron equivalentes in vitro al PR y para fluconazol ninguno fue equivalente in vitro al PR. Se concluye que algunos medicamentos de amoxicilina y fluconazol que circulan en el mercado nacional no cumplen con la equivalencia terapéutica evaluada mediante estudios in vitro; es decir, no son intercambiables.

ABSTRACT The objective of the study was to determine the therapeutic equivalence evaluated through in vitro studies of four brands of drugs containing amoxicillin, doxycycline, and fluconazole purchased at pharmaceutical facilities in Metropolitan Lima, and to establish their interchangeability with a reference product (RP). A validated method of visible ultraviolet spectrophotometry was used to determine the dissolution profile. The similarity factor (f2) was used to establish the therapeutic equivalence, being considered equivalent if the values of f2 were between 50 and 100. For doxycycline, the four drugs were equivalent in vitro to the RP; for amoxicillin, only two drugs were equivalent in vitro to the RP; and for fluconazole, none was equivalent in vitro to the RP. It is concluded that some amoxicillin and fluconazole drugs circulating in the national market do not meet the therapeutic equivalence assessed by in vitro studies; in other words, they are not interchangeable.

Intercambialidade de produtos biológicos no Sistema Único de Saúde (SUS): principais desafios regulatórios / Interchangeability of biological products in the Brazilian Unified National Health System (SUS): the main regulatory challenges / Intercambiabilidad de productos biológicos en el Sistema Único de Salud (SUS): principales desafíos regulatorios

Resumo: Produtos biológicos revolucionaram a terapêutica mundial. O alto custo desses medicamentos, no entanto, ameaça a sustentabilidade dos sistemas de saúde. O desenvolvimento de cópias é tido como uma alternativa econômica, mas devido à complexidade desses produtos, muitos conceitos utilizados para os medicamentos genéricos não se aplicam. A intercambialidade entre produtos biológicos representa um desafio regulatório a ser superado. Este ensaio discute os principais desafios regulatórios relacionados ao estabelecimento de critérios para intercambialidade entre produtos biológicos novos e suas cópias no âmbito do Sistema Único de Saúde (SUS), considerando as diretrizes adotadas pelas principais agências reguladoras de medicamentos do mundo sobre a intercambialidade e o arcabouço regulatório vigente no Brasil para esta questão. Preocupações relacionadas à intercambialidade de produtos biológicos incluem substituição automática, nomenclatura, farmacovigilância, imunogenicidade e extrapolação das indicações terapêuticas e dos dados clínicos de produtos biológicos novos para suas cópias. Embora o sucesso clínico e os benefícios econômicos da alternância entre alguns produtos biológicos novos e seus biossimilares já tenham sido observados, a heterogeneidade das barreiras regulatórias para aprovação das cópias de produtos biológicos entre diferentes países deve ser considerada para a regulamentação da intercambialidade de produtos biológicos no Brasil.

Abstract: Biological products have sparked a worldwide therapeutic revolution. However, the high cost of these products threatens health systems' sustainability. The development of copies is considered an economic alternative, but due to the products' complexity, many concepts used in generic drugs do not apply. Interchangeability between biologicals poses a regulatory challenge. This essay discusses the main regulatory challenges for establishing criteria for interchangeability between new biologicals and their copies in the scope of the Brazilian Unified National Health System (SUS), considering the guidelines adopted by the world's main drug regulatory agencies concerning interchangeability and the prevailing Brazilian regulatory framework on this issue. Concerns related to the interchangeability of biologicals include automatic substitution, nomenclature, pharmacovigilance, immunogenicity, and extrapolation of therapeutic indications and clinical data from new biologicals to their copies. While the clinical success and economic benefits of switching from new biologicals to their biosimilars have already been observed, the heterogeneity between countries in the regulatory barriers to the approval of copies of biologicals should be taken into consideration during the regulation of interchangeability of biologicals in Brazil.

Resumen: Los productos biológicos revolucionaron la terapéutica mundial. El alto coste de estos medicamentos, no obstante, amenaza la sostenibilidad de los sistemas de salud. El desarrollo de copias se considera como una alternativa económica, pero debido a la complejidad de estos productos, muchos conceptos utilizados para los medicamentos genéricos no se aplican a los mismos. La intercambiabilidad entre productos biológicos representa un desafío regulatorio que se debe superar. Este trabajo discute los principales desafíos regulatorios, relacionados con el establecimiento de criterios para la intercambiabilidad entre productos biológicos nuevos y sus copias en el ámbito del Sistema Único de Salud (SUS), considerando las directrices adoptadas por las principales agencias regulatorias de medicamentos del mundo sobre la intercambiabilidad y el armazón regulatorio vigente en Brasil para esta cuestión. Las preocupaciones relacionadas con la intercambiabilidad de productos biológicos incluyen la sustitución automática, nomenclatura, farmacovigilancia, inmunogenicidad y extrapolación de las indicaciones terapéuticas, así como de los datos clínicos de productos biológicos nuevos para sus copias. A pesar de que el éxito clínico y los beneficios económicos de la alternancia entre algunos productos biológicos nuevos y sus biosimilares, ya se han observados, la heterogeneidad de las barreras regulatorias para la aprobación de las copias de productos biológicos entre los diferentes países debe ser considerada para la regulación de la intercambiabilidad de productos biológicos en Brasil.

Brand innovator versus multisource cefpodoxime in respiratory tract infections: A comparative study

Purpose: In everyday practice clinicians are overwhelmed by claims from the pharmaceutical industry and, due to marketing efforts, they often view generic multisource products with scepticism despite proof and registration by regulatory authorities of bioequivalence. The primary aim of this study was exploratory and aimed to compare the acceptability of generic cefpodoxime (Cepodem®) versus the innovator brand product (Orelox®) in terms of effectiveness, safety and tolerability in a general private setting in South Africa in the treatment of upper and lower respiratory tract infections.Methods and patients: Ninety patients were recruited and randomised to receive either product for 10 days after clinical diagnoses of either tonsillo-pharyngitis or rhino-sinusitis or pneumonia.Results: It was demonstrated that both products resulted in similar clinical and bacteriological cure rates with also no difference in tolerability profiles. Conclusion: These findings support the bioequivalence data as submitted for regulatory approval, of the generic Cepodem® translating into clinical effectiveness and argues against the need for a clinical non-inferiority study to demonstrate sameness

Pharmacokinetic comparison between fixed-dose combination of fimasartan/amlodipine 60/10 mg and the corresponding loose combination through partial replicated crossover study in healthy subjects

Combination therapies of antihypertensive drugs are recommended in cases where hypertension is not controlled by monotherapy. This study aimed to compare the pharmacokinetics (PKs) between fixed-dose combination (FDC) of fimasartan/amlodipine 60/10 mg and the corresponding loose combination. Because of the high intra-subject variability for maximum plasma concentration (C(max)) of fimasartan, a randomized, open-label, 3×3 partial replicated crossover design was adopted. Subjects received a single dose of FDC of fimasartan/amlodipine 60/10 mg or the corresponding loose combination in each period. Blood samples for PK analysis were collected up to 48 hours for fimasartan and 144 hours for amlodipine, respectively. Geometric mean ratios (GMRs) and its 90% confidence intervals (CIs) of the FDC to the loose combination for C(max) and area under the concentration-time curve from time 0 to the last quantifiable time point (AUC(last)) were calculated. Sixty healthy subjects were randomized, and 57 subjects completed the study. The concentration-time profiles of fimasartan and amlodipine were similar between the FDC and loose combination. The GMRs (90% CIs) of the FDC to the loose combination for C(max) and AUC(last) were 1.0440 (0.9202–1.1844) and 1.0412 (0.9775–1.1090) for fimasartan, and 1.0430 (1.0156–1.0711) and 1.0339 (1.0055–1.0631) for amlodipine, respectively. The GMRs and its 90% CIs for C(max) and AUC(last) of fimasartan and amlodipine were included not only in the scaled bioequivalence criteria but also in the conventional bioequivalence criteria. In conclusion, FDC of fimasartan/amlodipine 60/10 mg showed comparable PK profiles with the corresponding loose combination, which suggests their bioequivalence.

Power Analysis and Sample Size Determination for Crossover Trials with Application to Bioequivalence Assessment of Topical Ophthalmic Drugs Using Serial Sampling Pharmacokinetic Data / 生物医学与环境科学（英文）

OBJECTIVE@#To develop methods for determining a suitable sample size for bioequivalence assessment of generic topical ophthalmic drugs using crossover design with serial sampling schemes.@*METHODS@#The power functions of the Fieller-type confidence interval and the asymptotic confidence interval in crossover designs with serial-sampling data are here derived. Simulation studies were conducted to evaluate the derived power functions.@*RESULTS@#Simulation studies show that two power functions can provide precise power estimates when normality assumptions are satisfied and yield conservative estimates of power in cases when data are log-normally distributed. The intra-correlation showed a positive correlation with the power of the bioequivalence test. When the expected ratio of the AUCs was less than or equal to 1, the power of the Fieller-type confidence interval was larger than the asymptotic confidence interval. If the expected ratio of the AUCs was larger than 1, the asymptotic confidence interval had greater power. Sample size can be calculated through numerical iteration with the derived power functions.@*CONCLUSION@#The Fieller-type power function and the asymptotic power function can be used to determine sample sizes of crossover trials for bioequivalence assessment of topical ophthalmic drugs.

Comparison of pharmacokinetic characteristics of two Tegoprazan (CJ-12420) formulations in healthy male subjects

Proton-pump inhibitors (PPIs) are effectively used to treat acid-related diseases, including gastroesophageal reflux disease (GERD); however, many unmet medical needs still exist. As a new treatment option, potassium-competitive acid blockers (P-CABs), such as tegoprazan, have been developed. This study was performed to compare the pharmacokinetics (PKs) between two formulations (test and reference drugs) of tegoprazan 100 mg tablets. A randomized, single oral dose, two-treatment, two-period, two-sequence study was conducted with 12 healthy subjects. Each subject received the test drug or reference drug in the first period and the alternative treatment in the second period. For PK evaluation, blood samples were collected up to 48 hours post-dose in each period. The plasma concentrations of tegoprazan and its active metabolite (M1) were measured by liquid chromatography-tandem mass spectrometry. PK parameters, including maximum plasma concentration (C(max)) and area under the concentration-time curve from zero to the last measurable time (AUC(last)), were estimated using a non-compartmental method. The plasma concentration-time profiles of the two formulations were comparable. The geometric mean ratios [90% confidence intervals (CIs)] of the test drug to the reference drug for C(max) and AUC(last) were 0.98 (0.85–1.12) and 1.03 (0.93–1.13), respectively. The corresponding values of M1 were 0.99 (0.89–1.11) and 1.01 (0.93–1.09), respectively. The two formulations of tegoprazan exhibited comparable PK profiles, fulfilling the regulatory criteria for bioequivalence.

Equivalencia terapéutica y tiempo de administración de los esteroides sistémicos en la exacerbación del asma / Therapeutic equivalence and time of administration of systemic steroids in the exacerbation of asthma

Introduction. The early use of systemic steroids has been associated with a decrease in the rate of hospitalizations in pediatric patients with asthma exacerbation. The objective was to compare the equivalence of two forms of administration, as well as to determine the optimal time for its indication. Material and methods: Observational, randomized, open study of equivalence, comparing oral versus parenteral steroids. The primary outcomes were changes in the severity scale and the rate of hospitalizations. The secondary result was the time until improvement was reached. ANOVA and Chi square tests were used to determine the statistical significance; it was considered significant when p <0,05. Results: In both groups both the severity scale and the hospitalization rate were considerably modified with early administration. At 30 minutes after using hydrocortisone (p<0,05). The greatest variation in the severity scale was observed. Conclusion: both routes of administration proved to be effective and should be used early.

Introducción: El uso precoz de los esteroides sistémicos ha sido asociado con disminución de la tasa de hospitalizaciones en los pacientes pediátricos con exacerbación asmática. El objetivo de este estudio es comparar la equivalencia de dos formas de administración, así como determinar el tiempo óptimo para su indicación. Material y métodos: Estudio observacional, aleatorizado, abierto de equivalencia, comparando esteroides por via oral contra parenteral. Los outcomes primarios fueron los cambios en la escala de gravedad y la tasa de hospitalizaciones y el secundario fue el tiempo en alcanzar la mejoría. Se utilizó ANOVA, prueba Chi cuadrado para determinar las significaciones estadísticas, se consideró significancia p<0,05. Resultados: En ambos grupos tanto la escala de gravedad como la tasa de mortalidad se modificaron de forma importante con la administración precoz. A los 30 minutos de administrar hidrocortisona (p<0,05) se observó la mayor variación en la escala de gravedad. Conclusión: ambas vías de administración demostraron ser efectivas y deben ser usadas de forma precoz.

Determination of Gemifloxacin in human plasma by high performance liquid chromatography using Ultra Violet detector and its application to a bioequivalence study

A liquid chromatography method was developed and validated for the determination of gemifloxacin in human plasma using chloramphenicol as internal standard to achieve lower quantification limit. Acetonitrile was used to precipitated and extracted analyte and internal standard from plasma by Protein Precipitation. Analysis was performed isocratically on C18 column using 25% acetonitrile and 75% 0.02 M phosphate buffer as mobile phase. The method was demonstrated to be linear from 0.003 µg/mL to 5 µg/mL with the lower limit of quantitation of 0.003 µg/mL. The method was successfully applied for the bioequivalence study of gemifloxacin after a single oral administration of 320 mg gemifloxacin mesylate tablets to 12 healthy volunteers.

Pharmacokinetics comparison of solifenacin tartrate and solifenacin succinate: a randomized, open-label, single-dose, 2-way crossover study in healthy male volunteers

Solifenacin is a muscarinic antagonist indicated for the treatment of overactive bladder with symptoms. Solifenacin tartrate is a newly developed salt formulation of solifenacin. This study compared the pharmacokinetic and safety properties after single-dose administration of solifenacin tartrate (test formulation) and solifenacin succinate (reference formulation) in healthy male volunteers. A total of 36 subjects were enrolled in this randomized, open-label, single-dose, two-way crossover study. During each treatment period, subjects received the test formulation or reference formulation. Plasma samples were collected at pre-dose and at 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48 and 72 hours post-dose. Safety was assessed by adverse events, physical examinations, laboratory assessments, 12-lead electrocardiograms, and vital signs. Thirty-three subjects completed the study and were included in the pharmacokinetic analysis. The mean (standard deviation) values of AUC(last) for the test and reference formulations were 486.98 (138.47) and 469.07 (128.29) h·ng/mL, respectively. The mean (standard deviation) values of C(max) for the test and reference formulations were 14.66 (3.85) and 14.10 (3.37) ng/mL, respectively. The 90% confidence intervals for AUC(last) and C(max) were 0.9702 to 1.1097 and 0.9779 to 1.0993, respectively. All adverse events were mild or moderate, and there were no serious adverse events. The pharmacokinetic properties of solifenacin tartrate were similar to those of solifenacin succinate and met the acceptance criteria for bioequivalence. Both formulations were safe, and no significant difference was observed in the safety assessments of the formulations.

A post hoc analysis of intra-subject coefficients of variation in pharmacokinetic measures to calculate optimal sample sizes for bioequivalence studies

Because bioequivalence studies are performed using a crossover design, information on the intra-subject coefficient of variation (intra-CV) for pharmacokinetic measures is needed when determining the sample size. However, calculated intra-CVs based on bioequivalence results of identical generic drugs produce different estimates. In this study, we collected bioequivalence results using public resources from the Ministry of Food and Drug Safety (MFDS) and calculated the intra-CVs of various generics. For the generics with multiple bioequivalence results, pooled intra-CVs were calculated. The estimated intra-CVs of 142 bioequivalence studies were 14.7±8.2% for AUC and 21.7±8.8% for Cmax. Intra-CVs of Cmax were larger than those of area under the concentration-time curve (AUC) in 129 studies (90.8%). For the 26 generics with multiple bioequivalence results, the coefficients of variation of intra-CVs between identical generics (mean±sd (min ~ max)) were 38.0±24.4% (1.9 ~ 105.3%) for AUC and 27.9±18.2% (4.0 ~ 70.1%) for Cmax. These results suggest that substantial variation exists among the bioequivalence results of identical generics. In this study, we presented the intra-CVs of various generics with their pooled intra-CVs. The estimated intra-CVs calculated in this study will provide useful information for planning future bioequivalence studies. (This is republication of the article 'Transl Clin Pharmacol 2017;25:179-182' retracted from critical typographic errors. See the 'Retraction and Republication section of this issue for further information)