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.

Antibiotic-loaded Bone Cement as Prophylaxis in Total Joint Replacement.

One of its most serious complications associated with arthroplasty is the development of infections. Although its prevalence is only between 0.5% and 3%, in some cases it can lead to death. Therefore, an important challenge in joint surgery is the prevention of infections when an arthroplasty is performed. The use of antibiotic-loaded cements could be a suitable tool due to numerous advantages. The main advantage of the use of antibiotic loading into bone cement derives directly from antibiotic release in the effect site, allowing achievement of high concentrations at the site of action, and minimal or no systemic toxicity. This route of administration was first described by Buchholz and Engelbrecht. In the case of infection treatment, this is an established method and its good results have been confirmed. However, its role in infection prevention, and, therefore, the use of these systems in clinical practice, has proved controversial because of the uncertainty about the development of possible antibiotic resistance after prolonged exposure time, their effectiveness, the cost of the systems, toxicity and loosening of mechanical properties. This review discusses all these topics, focusing on effectiveness and safety, antibiotic decisions, cement type, mixing method, release kinetics and future perspectives. The final objective is to provide the orthopaedic surgeons the right information in their clinical practice based on current evidence.

Evaluación de la bioactividad de ciprofloxacino y vancomicina incorporados en cementos óseos poliacrílicos / Evaluation of ciprofloxacin and vancomycin bioactivity loaded in bone cements

La inclusión de antibióticos en el cemento óseo destinado a la fijación mecánica de las prótesis constituye un sistema de liberación local de antibiótico que permite minimizar la prevalencia y la gravedad de las reacciones adversas que pueden desencadenar los fármacos cuando éstos se administran por vía sistémica. El objetivo del trabajo es estudiar el mecanismo y cinética de liberación in vitro de ciprofloxacino y vancomicina incorporados en diferentes cementos óseos comerciales y evaluar la bioactividad mediante un ejercicio de simulación farmacocinética. Se prepararon mezclas de los cementos de estudio con ciprofloxacino clorhidrato y vancomicina (40:0,5:0,5). Los estudios de liberación se realizaron en agitación continua en solución salina de tampón fosfatos, pH = 7,4, durante dos meses a 37ºC. El análisis estadístico de las cantidades de antibiótico liberadas acumuladas y las velocidades de elución se realizó mediante ANOVA. Con el fin estudiar la bioactividad, se realizó una simulación de Monte Carlo. La cantidad total liberada de ciprofloxacino en un periodo de 8 semanas fue de 0,29 ± 0,06 mg desde los cementos Palacos(R), 0,44 ± 0,06mg LimaCMT1(R) y 0,18 ± 0,04 mg Simplex(R). La cantidad total de vancomicina liberada en 24 horas fue de 0,34 ± 0,17mg desde el cemento Palacos(R), 0,68 ± 0,16 mg LimaCMT1(R) y 0,17 ± 0,02 mg Simplex(R). Transcurrido este tiempo la liberación cesó. El estudio de simulación, muestra que durante las primeras 72 horas, la cobertura antibiótica dependería tanto del cemento elegido como de la sensibilidad del microorganismo y el tiempo postquirúrgico. En tiempos posteriores, es de prever que la bioactividad local aumente

Antibiotic loaded bone cement used in prosthesis fixing, is a local release form that minimizes the prevalence and the complications that the antibiotics would unleash when administered intravenously. The aim of this work is to study in vitro release kinetics of ciprofloxacin and vancomycin loaded in different commercial cements and evaluate the bioactivity through a simulation exercise pharmacokinetics. Samples were prepared with commercial bone cement and ciprofloxacin and vancomycin hydrochloride (40:0,5:0,5). Release study were carried out under stirring in phosphate buffer, pH=7,4, for two months at 37ºC. The antibiotic amount and elution rate, were compared using ANOVA. In order to study the bioactivity, Monte Carlo simulation was performed. The ciprofloxacin released from samples for 8 weeks was 0.29 ± 0.06 mg from the Palacos(R) cements, 0.44 ± 0.06 mg from LimaCMT1® and 0.18 ± 0.04 mg from Simplex(R). The vancomycin released for 24 hours was 0.34 ± 0.17 mg from Palacos(R) cement, 0.68 ± 0.16 mg from LimaCMT1(R) and 0.17 ± 0.02 mg from Simplex(R). After this time the release stopped. The simulation study shows that during the first 72 hours, the antibiotic coverage would depends on the bone cement, the sensitivity of the microorganism and postoperative day. At subsequence times, it is expected that local bioactivity increases

Study of the Influence of Bone Cement Type and Mixing Method on the Bioactivity and the Elution Kinetics of Ciprofloxacin.

The objectives of this study were to examine ciprofloxacin release from three trademarks of bone cements (Simplex®, Lima® and Palacos®) and its bioactivity using as variables, the mixing method, the chemical form of the antibiotic and the antibiotic combination. The antibiotic amount released in base form represents 35% of antibiotic amount released when hydrochloride form is incorporated. Moreover, the combination (vancomycin and ciprofloxacin) shows a stronger release (132%) than hydrochloride ciprofloxacin alone. Three cements show equal drug release profile (P > 0.05). A bioactivity simulation exercise showed that until 72 hours post-surgery, ciprofloxacin concentrations in the implant would be higher than 0.1 µg/mL in 100% of the patients. After drain removal, it is expected that bioactivity would increase since drug clearance from implant would decrease.