Farmacocinética de eculizumab en pacientes adultos y pediátricos con síndrome hemolítico urémico atípico y glomerulopatía C3 / Pharmacokinetics of eculizumab in adult and pediatric patients with atypical hemolytic uremic syndrome and C3 glomerulopathy

Objetivo analizar y describir las concentraciones de eculizumab y el bloqueo del complemento en los pacientes con síndrome hemolítico urémico atípico (SHUa) y glomerulopatía C3, y definir un margen terapéutico donde se alcance una alta probabilidad de conseguir eficacia terapéutica. Métodos estudio observacional, ambispectivo y multicéntrico que incluyó pacientes adultos y pediátricos diagnosticados de SHUa y glomerulopatía C3 desde septiembre de 2020 hasta octubre de 2022 en 5 hospitales de España. Eculizumab se administró a las dosis recomendadas por la ficha técnica. Se determinaron las concentraciones pre y posdosis de eculizumab, así como del bloqueo de la vía clásica del complemento (CH50). Se recogieron variables sociodemográficas, analíticas y clínicas, y se calcularon los parámetros farmacocinéticos. Para establecer el punto de corte de las concentraciones de eculizumab que predecían el bloqueo del complemento se realizó un análisis de curvas ROC (Receiver Operating Characteristic). Se utilizó el test de Kruskal-Wallis para contrastar las diferencias en distintos parámetros según las concentraciones de eculizumab. Resultados se incluyeron 25 pacientes, 19 adultos (76,0%) y 6 pediátricos (24,0%), con edades medianas de 43,4 (RIC 35,7-48,8) y 10,1 (RIC 9,6-11,3) años, respectivamente. De ellos, 22 (88,0%) pacientes fueron diagnosticados con SHUa y 3 (12,0%) con glomerulopatía C3. Se determinaron un total de 111 concentraciones de eculizumab. Las concentraciones predosis y posdosis medias detectadas durante la fase de mantenimiento fueron 243,8 (SD 240,6) μg/ml y 747,4 (SD 444,3) μg/ml, respectivamente (AU)

Objective The objective of the study was to analyze and describe the concentrations of eculizumab and the complement blockade in patients with atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy, and to define a therapeutic margin where there is a high probability of achieving therapeutic efficacy. Methods Observational, ambispective and multicenter study that included adult and pediatric patients diagnosed with aHUS and C3 glomerulopathy from September 2020 to October 2022 in five hospitals in Spain. Eculizumab was administered at the doses recommended by the data sheet according to the European Medicines Agency (EMA). Pre-dose and post-dose concentrations of eculizumab were determined, as well as blockade of the classical complement pathway (CH50). Sociodemographic and clinical data were collected, and pharmacokinetic parameters were calculated. To establish the cut-off point for eculizumab concentrations that predicted complement blockade, Receiver Operating Characteristic (ROC) curve analysis was performed. Lastly, the Kruskal-Wallis test was used to contrast the differences in different parameters according to eculizumab concentrations. Results Twenty-five patients were included, 19 adults (76.0%) and 6 pediatrics (24.0%), with median ages of 43.4 (IQR 35.7-48.8) and 10.1 (IQR 9.6-11.3) years, respectively. Of these, 22 (88.0%) patients were diagnosed with aHUS and 3 (12.0%) with C3 glomerulopathy. A total of 111 eculizumab concentrations were determined (AU)

Pharmacokinetics of eculizumab in adult and pediatric patients with atypical hemolytic uremic syndrome and C3 glomerulopathy. / Farmacocinética de eculizumab en pacientes adultos y pediátricos con síndrome hemolítico urémico atípico y glomerulopatía C3.

OBJECTIVE: The objective of the study was to analyze and describe the concentrations of eculizumab and the complement blockade in patients with atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy, and to define a therapeutic margin where there is a high probability of achieving therapeutic efficacy. METHODS: Observational, ambispective and multicenter study that included adult and pediatric patients diagnosed with aHUS and C3 glomerulopathy from September 2020 to October 2022 in five hospitals in Spain. Eculizumab was administered at the doses recommended by the data sheet according to the European Medicines Agency (EMA). Pre-dose and post-dose concentrations of eculizumab were determined, as well as blockade of the classical complement pathway (CH50). Sociodemographic and clinical data were collected, and pharmacokinetic parameters were calculated. To establish the cut-off point for eculizumab concentrations that predicted complement blockade, Receiver Operating Characteristic (ROC) curve analysis was performed. Lastly, the Kruskal-Wallis test was used to contrast the differences in different parameters according to eculizumab concentrations. RESULTS: Twenty-five patients were included, 19 adults (76.0%) and 6 pediatrics (24.0%), with median ages of 43.4 (IQR 35.7-48.8) and 10.1 (IQR 9.6-11.3) years, respectively. Of these, 22 (88.0%) patients were diagnosed with aHUS and 3 (12.0%) with C3 glomerulopathy. A total of 111 eculizumab concentrations were determined. Mean pre-dose and post-dose concentration values detected during the maintenance phase were 243.8 (SD 240.6) µg/mL and 747.4 (SD 444.3) µg/mL, respectively. Increased complement blockade was observed at higher pre-dose concentrations (p=0.002) and decreased serum creatinine at both higher pre- and post-dose concentrations (p=0.001 and p=0.017, respectively). Using ROC curves, it was determined that a pre-dose concentration >149.0 µg/mL was optimal to achieve complement blockade, with an AUC of 0.87 (0.78-0.95). Finally, high inter-individual (48.9% CV) with low intra-individual variabilities (11.9% CV) in eculizumab clearance were observed. CONCLUSIONS: The present study reports supratherapeutic concentrations of eculizumab in patients with aHUS, and defines higher concentrations than those described in the data sheet to achieve blockade, thus encouraging the personalization of treatment with eculizumab.

[Translated article] Pharmacokinetics of eculizumab in adult and pediatric patients with atypical hemolytic uremic syndrome and C3 glomerulopathy.

OBJECTIVE: The objective of the study was to analyze and describe the concentrations of eculizumab and the complement blockade in patients with atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy, and to define a therapeutic margin where there is a high probability of achieving therapeutic efficacy. METHODS: Observational, ambispective, and multicenter study that included adult and pediatric patients diagnosed with aHUS and C3 glomerulopathy from September 2020 to October 2022 in 5 hospitals in Spain. Eculizumab was administered at the doses recommended by the data sheet according to the European Medicines Agency (EMA). Pre- and post-dose concentrations of eculizumab were determined, as well as blockade of the classical complement pathway (CH50). Sociodemographic and clinical data were collected, and pharmacokinetic parameters were calculated. To establish the cut-off point for eculizumab concentrations that predicted complement blockade, Receiver Operating Characteristic (ROC) curve analysis was performed. Lastly, the Kruskal-Wallis test was used to contrast the differences in different parameters according to eculizumab concentrations. RESULTS: Twenty-five patients were included, 19 adults (76.0%) and 6 pediatrics (24.0%), with median ages of 43.4 (interquartile range (IQR) 35.7-48.8) and 10.1 (IQR 9.6-11.3) years, respectively. Of these, 22 (88.0%) patients were diagnosed with aHUS and 3 (12.0%) with C3 glomerulopathy. A total of 111 eculizumab concentrations were determined. Mean pre- and post-dose concentration values detected during the maintenance phase were 243.8 (SD 240.6) µg/mL and 747.4 (standard deviation (SD) 444.3) µg/mL, respectively. Increased complement blockade was observed at higher pre-dose concentrations (P = .002) and decreased serum creatinine at both higher pre- and post-dose concentrations (P = .001 and P = .017, respectively). Using ROC curves, it was determined that a pre-dose concentration >149.0 µg/mL was optimal to achieve complement blockade, with an AUC of 0.87 (0.78-0.95). Finally, high inter-individual (48.9% variation coefficient (CV)) with low intra-individual variabilities (11.9% CV) in eculizumab clearance were observed. CONCLUSIONS: The present study reports supratherapeutic concentrations of eculizumab in patients with aHUS, and defines higher concentrations than those described in the data sheet to achieve blockade, thus encouraging the personalization of treatment with eculizumab.

Evidentia praxis: nirsevimab y prevención de bronquiolitis en lactantes nacidos a término / Evidentia praxis: Nirsevimab and bronchiolitis prevention in term-born infants

Analizamos la evidencia publicada sobre la eficacia y seguridad de nirsevimab, un anticuerpo monoclonal, empleado para prevenir las infecciones de vías respiratorias bajas (IVRB) por virus respiratorio sincitial (VRS) en el lactante a término. Encontramos un ensayo clínico aleatorizado controlado con placebo doble ciego que incluyó 3012 lactantes, nacidos a término o pretérmino tardío, menores de un año con un seguimiento de al menos 150 días. La calidad de la evidencia se clasificó como baja para IVRB muy grave y moderada para IVRB que precisara asistencia o ingreso. La evidencia se sustenta sobre un escaso número de eventos (para ingresos hospitalarios sólo 29 casos, para IVRB con atención médica 78), por lo que cualquier estimación debe considerarse imprecisa. La eficacia, estimada como reducción relativa del riesgo (RRR) fue del 76,4% (intervalo de confianza del 95% [IC 95]: 62,3 a 85,2) para IVRB por VRS y del 76,8% (IC 95: 49,4 a 89,4%) para ingreso. No se encontraron diferencias en cuanto a seguridad. Existen dudas sobre la importancia clínica, por los criterios de gravedad empleados, y sobre su impacto, con un número necesario a tratar para evitar una IVRB con ingreso de 63 y que requiera asistencia médica de 24. Por la información disponible parece una intervención segura, de la que no esperamos efectos adversos comunes, pero no podemos descartar efectos de baja frecuencia. Asimismo, esperamos contar pronto con estimaciones más precisas de eficacia y seguridad (AU)

We reviewed the published evidence on the efficacy and safety of nirsevimab, a monoclonal antibody, used to prevent respiratory syncytial virus (RSV) associated lower respiratory tract infections (LRTI) in term infants. We have found a randomized double-blind placebo-controlled clinical trial that included 3012 infants, born at term or late preterm, less than one year of age with a follow-up of at least 150 days. The quality of the evidence was classified as low for very severe LRTI and moderate for LRTI requiring medical care or admission. The evidence is based on a small number of events (only 29 cases for hospital admissions, 78 for IVRB with medical care), so any estimate must be considered imprecise. Efficacy, estimated as relative risk reduction (RRR) was 76.4% (95% confidence interval [95 CI]: 62.3 to 85.2) for RSV associated LRTI that required medical care and 76.8% (CI 95: 49.4 to 89.4%) for hospital admission. No differences were found in terms of safety. There are doubts about the clinical importance, due to the severity criteria used, and about its impact, with a number needed to treat of 63 to avoid a LRTI with hospital admission and of 24 to avoid LRTI requiring medical care. Based on the available information, it seems a safe intervention, from which we do not expect common adverse effects, but we cannot rule out low-frequency effects. We also expect to have more precise estimates of efficacy and safety soon. (AU)

Relación entre las concentraciones séricas devedolizumab en fase de inducción y respuesta temprana y mantenida en el primer año de tratamiento en pacientes con colitis ulcerosa / Relationship between vedolizumab serum concentrations in the induction phase and early and sustained response in the first year of treatment in patients with ulcerative colitis

Objetivo: La evidencia sobre la utilidad de la monitorización proactiva delas concentraciones séricas de vedolizumab en la fase de inducción del tratamiento es limitada. El objetivo del estudio ha sido evaluar la capacidad delas concentraciones séricas de vedolizumab determinadas en esta fase parapredecir la respuesta al tratamiento en pacientes con colitis ulcerosa, con el finde establecer si los pacientes se beneficiarían clínicamente de una monitorización precoz.Método: Estudio descriptivo, prospectivo, realizado en tres hospitalesgenerales públicos. Incluyó a los pacientes adultos con colitis ulcerosa, queiniciaron tratamiento con vedolizumab en los centros participantes desdejunio de 2019 a junio de 2020. Se determinaron las concentraciones séricas de vedolizumab en las semanas 6 y 14 de tratamiento. La respuestabioquímica, clínica y endoscópica se evaluó en las semanas 6, 14 y 52.Se estudió la relación de las concentraciones séricas de vedolizumab determinadas en la semana 6 con la respuesta temprana al tratamiento, asícomo la relación de las concentraciones séricas de vedolizumab en lassemanas 6 y 14 con la persistencia de respuesta al año de tratamiento. (AU)

Objective: Evidence on the usefulness of proactive monitoring of vedolizumab serum concentrations during the induction phase of treatment islimited. The objective of our study was to evaluate the effectiveness ofmeasuring such concentrations during this phase in predicting responseto treatment in patients with ulcerative colitis with a view to determiningwhether patients would benefit from early monitoring of vedolizumabserum concentrations.Method: This was a prospective descriptive study carried out at threepublic general hospitals. It included adult patients with ulcerative colitiswho were initiated on vedolizumab at the participating hospitals from June2019 to June 2020. Vedolizumab serum concentrations were determined at weeks 6 and 14. Response to treatment was biologically, clinically,and endoscopically evaluated at weeks 6, 14, and 52. An analysis wasmade of the relationship between vedolizumab serum concentrations atweek 6 and early response to treatment, and of the relationship betweenthe vedolizumab serum concentrations at weeks 6 and 14 and persistentresponse at one year. (AU)