Efecto sobre los niveles de moléculas de adhesión endotelial (sVCAM-1, sICAM-1 y sE-selectina) después del tratamiento con filgrastim o molgramostim en pacientes con neutropenia posquimioterapia o radioterapia.

Objetivo: Determinar los niveles séricos de sVCAM-1, sICAM-1 y sE-selectina como marcadores biológicos a partir de la administración de factores estimulantes de colonias de granulocitos o macrófagos, o ambos (FEC-G o FEC-GM), así como valorar la seguridad de éstos en el manejo de la neutropenia relacionada con el tratamiento antineoplásico. Pacientes y métodos: Estudio prospectivo, longitudinal y comparativo que incluyó a 32 pacientes menores de 70 años con neutropenia después de recibir quimioterapia o radioterapia. Todos los pacientes signaron el consentimiento informado antes de cualquier otro procedimiento. Se evaluó el efecto de tres distintos FEC-G o FEC-GM (1) sobre las moléculas de adhesión endotelial (sVCAM-1, sICAM-1 y sE-selectina). Los pacientes se asignaron de manera aleatoria para recibir cualquiera de los factores estimulantes de colonias (FEC), los cuales se administraron diariamente hasta alcanzar una cifra de neutrófilos absolutos ≥ 1500 cel/mm3 por tres días consecutivos. Los niveles séricos de las moléculas de adhesión se determinaron antes y durante el tratamiento con los FEC. La condición clínica de los sujetos se valoró mediante la historia clínica y exámenes de laboratorio. Los eventos adversos atribuidos al empleo de los FEC y la medicación concomitante se registraron en el formato de reporte de caso. Resultados: En los tres grupos de estudio se observó un incremento en los niveles séricos de los tres marcadores biológicos (sE-selectina, sICAM-1, sVCAM-1, p ≤ 0.05) entre la visita basal y el día 5 de tratamiento con FEC-G o FEC-GM. Al quinto día de tratamiento con FEC, la cuenta absoluta de neutrófilos alcanzó niveles superiores a 1 500 cel/mm3 en 90% de los pacientes incluidos. Los eventos adversos fueron similares en los tres grupos de tratamiento. El perfil de seguridad y el efecto sobre las moléculas de adhesión fue semejante en todos los grupos; no se encontraron diferencias en relación con género, edad ni estado basal y final. Conclusiones: En este grupo de pacientes el efecto biológico ejercido por los FEC pudo observarse por el incremento en los niveles séricos de las moléculas de adhesión sin considerar el tipo de producto

Pharmacokinetic Comparability of a Biosimilar Trastuzumab Anticipated from Its Physicochemical and Biological Characterization

Comparability between a biosimilar and its reference product requires the evaluation of critical quality attributes that may impact on its pharmacological response. Herein we present a physicochemical characterization of a biosimilar trastuzumab focused on the attributes related to the pharmacokinetic response. Capillary isoelectrofocusing (cIEF) and cation exchange chromatography (CEX) were used to evaluate charge heterogeneity; glycosylation profiles were assessed through hydrophilic interaction liquid chromatography (HILIC); aggregates content was evaluated through size exclusion chromatography (SEC) while binding affinity to FcRn was evaluated using isothermal titration calorimetry (ITC). The biosimilar trastuzumab and its reference product exhibited a high degree of similarity for the evaluated attributes. In regard to the pharmacokinetic parameters, randomized, double blind, and two-arm parallel and prospective study was employed after the administration of a single intravenous dose in healthy volunteers. No significant differences were found between the pharmacokinetic profiles of both products. Our results confirm that similarity of the critical quality attributes between a biosimilar product, obtained from a different manufacturing process, and the reference product resulted in comparable pharmacokinetic profiles, diminishing the uncertainty related to the biosimilar's safety and efficacy

Assessment of Physicochemical Properties of Rituximab Related to Its Immunomodulatory Activity

Rituximab is a chimeric monoclonal antibody employed for the treatment of CD20-positive B-cell non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis. It binds specifically to the CD20 antigen expressed on pre-B and consequently on mature B-lymphocytes of both normal and malignant cells, inhibiting their proliferation through apoptosis, CDC, and ADCC mechanisms. The immunomodulatory activity of rituximab is closely related to critical quality attributes that characterize its chemical composition and spatial configuration, which determine the recognition of CD20 and the binding to receptors or factors involved in its effector functions, while regulating the potential immunogenic response. Herein, we present a physicochemical and biological characterization followed by a pharmacodynamics and immunogenicity study to demonstrate comparability between two products containing rituximab. The physicochemical and biological characterization revealed that both products fit within the same response intervals exhibiting the same degree of variability. With regard to clinical response, both products depleted CD20+ B-cells until posttreatment recovery and no meaningful differences were found in their pharmacodynamic profiles. The evaluation of anti-chimeric antibodies did not show differential immunogenicity among products. Overall, these data confirm that similarity of critical quality attributes results in a comparable immunomodulatory activity

Assessment of Physicochemical Properties of Rituximab Related to Its Immunomodulatory Activity

Rituximab is a chimeric monoclonal antibody employed for the treatment of CD20-positive B-cell non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis. It binds specifically to the CD20 antigen expressed on pre-B and consequently on mature B-lymphocytes of both normal and malignant cells, inhibiting their proliferation through apoptosis, CDC, and ADCC mechanisms. The immunomodulatory activity of rituximab is closely related to critical quality attributes that characterize its chemical composition and spatial configuration, which determine the recognition of CD20 and the binding to receptors or factors involved in its effector functions, while regulating the potential immunogenic response. Herein, we present a physicochemical and biological characterization followed by a pharmacodynamics and immunogenicity study to demonstrate comparability between two products containing rituximab. The physicochemical and biological characterization revealed that both products fit within the same response intervals exhibiting the same degree of variability. With regard to clinical response, both products depleted CD20+ B-cells until posttreatment recovery and no meaningful differences were found in their pharmacodynamic profiles. The evaluation of anti-chimeric antibodies did not show differential immunogenicity among products. Overall, these data confirm that similarity of critical quality attributes results in a comparable immunomodulatory activity

New Alternatives for Autoimmune Disease Treatments: Physicochemical and Clinical Comparability of Biosimilar Etanercept

Etanercept is a recombinant fusion protein approved for the treatment of TNF-α mediated diseases such as rheumatoid arthritis (RA), psoriasis, psoriatic arthritis, and ankylosing spondylitis. Herein, we present an evaluation of the physicochemical and biological properties of a biosimilar etanercept and its reference product followed by a clinical study in patients diagnosed with RA intended to demonstrate comparability of their immunomodulatory activity. Identity analyses showed a total correspondence of the primary and higher-order structure between the two products. In regard to intrinsic heterogeneity, both products showed to be highly heterogenous; however the biosimilar etanercept exhibited similar charge and glycan heterogeneity intervals compared to the reference product. Apoptosis inhibition assay also showed that, despite the high degree of heterogeneity exhibited by both products, no significant differences exist in their in vitro activity. Finally, the clinical assessment conducted in RA-diagnosed patients did not show significant differences in the evaluated pharmacodynamic markers of both products. Collectively, the results from the comparability exercise provide convincing evidence that the evaluated biosimilar etanercept can be considered an effective alternative for the treatment of RA

Pharmacokinetic Comparability of a Biosimilar Trastuzumab Anticipated from Its Physicochemical and Biological Characterization

Comparability between a biosimilar and its reference product requires the evaluation of critical quality attributes that may impact on its pharmacological response. Herein we present a physicochemical characterization of a biosimilar trastuzumab focused on the attributes related to the pharmacokinetic response. Capillary isoelectrofocusing (cIEF) and cation exchange chromatography (CEX) were used to evaluate charge heterogeneity; glycosylation profiles were assessed through hydrophilic interaction liquid chromatography (HILIC); aggregates content was evaluated through size exclusion chromatography (SEC) while binding affinity to FcRn was evaluated using isothermal titration calorimetry (ITC). The biosimilar trastuzumab and its reference product exhibited a high degree of similarity for the evaluated attributes. In regard to the pharmacokinetic parameters, randomized, double blind, and two-arm parallel and prospective study was employed after the administration of a single intravenous dose in healthy volunteers. No significant differences were found between the pharmacokinetic profiles of both products. Our results confirm that similarity of the critical quality attributes between a biosimilar product, obtained from a different manufacturing process, and the reference product resulted in comparable pharmacokinetic profiles, diminishing the uncertainty related to the biosimilar’s safety and efficacy