Homologous equivalence study of immunogenicity after third dose of Covid-19 vaccine (recombinant) with an interval of six months after the second dose, comparing the interval of eight and 12 weeks between the first two doses

BACKGROUND In response to the coronavirus disease 2019 (Covid-19) pandemic, Brazil authorised the Astra Zeneca/Fiocruz vaccine in January 2021. As the Delta variant emerged in May 2021, interval between vaccine doses was adjusted. By September 2021, the Brazilian National Immunisation Program recommended a booster dose for individuals over 70, and later expanded the recommendation to all adults. OBJECTIVES Assess the equivalence of IgG antibody response against the Covid-19 S protein before and approximately 28 days after the third dose of a Covid-19 recombinant vaccine. Two groups received initial two doses with intervals of eight and 12 weeks. METHODS This is a phase IV clinical study, uncontrolled, non-randomised. The study proposes calculating the ratio of geometric means titres (GMT) 28 days after the third dose, with a target ratio of confidence interval (CI) between 0.77 and 1.3. FINDINGS In the primary endpoint, there was no equivalence between the eight- and 12-week intervals with a slight variation favouring the eight-week group. Post-third dose, both groups showed increases titres at 28 days, three months, six months and 12 months. Both groups responded similarly to Delta and Omicron BA.1, with a more significant increase for Delta. MAIN CONCLUSIONS The study showed strong and consistent immune response in all age groups receiving the Covid-19 recombinant vaccine. Third dose elicited an increase in GMT by at least three times aligned with Ministry of Health strategies emphasising Bio-Manguinhos crucial role in pandemic control in the country.

Equivalencia terapéutica in vitro e in vivo de rivaroxabán tabletas / In Vitro and in Vivo Therapeutic Equivalence of Rivaroxaban Tablets / Equivalência terapêutica in vitro e in vivo de comprimidos de rivaroxabana

Resumen: Se buscó analizar la equivalencia terapéutica de rivaroxabán tabletas por medio de perfiles comparativos de disolución y de un estudio in vivo comparativo de farmacocinética. Se realizaron perfiles de disolución comparativos para tabletas recubiertas de rivaroxabán de 10, 15 y 20 mg, en tres medios, que se analizaron por cromatografía líquida de alta resolución. Los resultados se compararon por pruebas de similitud (f2). Para el análisis de bioequivalencia se realizó un ensayo clínico abierto, aleatorizado, cruzado, en ayunas y posprandial en el que se compararon rivaroxabán de 20 mg fabricado por Medley Farmacéutica Ltda. (medicamento de estudio), con rivaroxabán 20 mg fabricado por Bayer Pharma A/G (Xarelto®, medicamento de referencia). La cuantificación se realizó por medio de cromatografía líquida acoplada a la espectrometría de masas en modo MS/MS, con patrón interno de rivaroxabán-d4. En análisis in vitro del perfil de disolución se determinó una similitud mayor a 50, en todos los medios, para rivaroxabán de 10, 15 y 20 mg. En el análisis in vivo se evidenció que la media de la Cmáx, ASC0-1, ASC0-inf para el rivaroxabán de estudio era equivalente al de referencia y cumplía con los criterios de bioequivalencia. Lo anterior demuestra, que, en el rango de pH fisiológico, la formulación de rivaroxabán 10 mg y 15 mg presenta una cinética de disolución similar a la formulación de rivaroxabán 20 mg, en tabletas recubiertas y el análisis de biodisponibilidad permite determinar bioequivalencia entre la formulación de referencia y la de estudio, infiriendo así un mismo efecto farmacológico y equivalencia terapéutica.

Abstract: The aim was to analyze the therapeutic equivalence of rivaroxaban tablets through comparative dissolution profiles and a comparative in vivo pharmacokinetic study. Comparative dissolution profiles were conducted for film-coated rivaroxaban tablets of 10, 15, and 20 mg in three media, analyzed by high-performance liquid chromatography. Results were compared using similarity tests (f2). For bioequivalence analysis, an open-label, randomized, crossover clinical trial was conducted, both fasting and postprandial, comparing rivaroxaban 20 mg manufactured by Medley Farmacéutica Ltda. (study drug) with rivaroxaban 20 mg manufactured by Bayer Pharma A/G (Xarelto®, reference drug). Quantification was performed using liquid chromatography coupled with tandem mass spectrometry in MS/MS mode, with rivaroxaban-d4 as the internal standard. In the in vitro dissolution profile analysis, a similarity greater than 50 was determined in all media for rivaroxaban 10, 15, and 20 mg. In the in vivo analysis of the dissolution profile, showed that the Cmáx, ASC0-1, ASC0-inf for the rivaroxaban study were equivalent to the reference and met bioequivalence criteria. Before mentioned demonstrates that, within the physiological pH range, the dissolution kinetics of rivaroxaban 10 mg and 15 mg formulations are similar to the rivaroxaban 20 mg formulation in film-coated tablets. The bioavailability analysis allows for the determination of bioequivalence between the reference and study formulations, inferring a similar pharmacological effect and therapeutic equivalence.

Resumo: Buscou-se analisar a equivalência terapêutica de comprimidos de rivaroxabana por meio de perfis comparativos de dissolução e de um estudo in vivo comparativo de farmacocinética. Foram realizados perfis de dissolução comparativos para comprimidos revestidos de rivaroxabana de 10, 15 e 20 mg, em três meios, que foram analisados por cromatografia líquida de alta resolução. Os resultados foram comparados por testes de similaridade (f2). Para a análise de bioequivalência, foi conduzido um ensaio clínico aberto, randomizado, cruzado, em jejum e pós-prandial, comparando a rivaroxabana de 20 mg fabricada pela Medley Farmacêutica Ltda. (medicamento em estudo) com a rivaroxabana de 20 mg fabricada pela Bayer Pharma A/G (Xarelto®, medicamento de referência). A quantificação foi realizada por cromatografia líquida acoplada à espectrometria de massas no modo MS/MS, com padrão interno de rivaroxabana-d4. Na análise in vitro do perfil de dissolução, foi determinada uma similaridade acima de 50, em todos os meios, para a rivaroxabana de 10, 15 e 20 mg. Na análise in vivo, observou-se que a média da Cmáx, ASC0-1, ASC0-inf para a rivaroxabana em estudo era equivalente à de referência e atendia aos critérios de bioequivalência. Isso demonstra que, no intervalo de pH fisiológico, a formulação de rivaroxabana de 10 mg e 15 mg apresenta uma cinética de dissolução semelhante à formulação de rivaroxabana de 20 mg, em comprimidos revestidos, e a análise de biodisponibilidade permite determinar a bioequivalência entre a formulação de referência e a em estudo, inferindo assim um mesmo efeito farmacológico e equivalência terapêutica.