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INTRODUCTION: Metformin tablets may be challenging to swallow not only for those patients with dysphagia but also for children and the elderly. A metformin solution was developed for easier administration and flexible dose adjustment mantained with the same bioavailability of tablets. The objective of this study was to assess the single-dose oral bioavailability of metformin hydrochloride administered as an oral solution (500 mg/5 mL) compared with metformin hydrochloride 500 mg tablets in fasting Mexican healthy volunteers. METHODS: A randomized, single dose, two-period, two-sequence, crossover study design with a 7-day washout interval was conducted. Subjects were randomly assigned to receive a single dose of 500 mg metformin hydrochloride, either as an oral solution (test drug) or as a tablet (reference drug), after 10 h of fasting. Plasma samples (16) were collected over a 16-h period after drug administration. Bioequivalence was declared when the ratio for the 90% confidence intervals (CI) of the difference in the means of the log-transformed area under the concentration-time curve from time 0 to the last observed concentration time (AUC0-t), the area under the concentration-time curve extrapolated to infinite time (AUC0-∞), and the maximum plasma concentration (Cmax) of the two products were within 0.80 and 1.25 interval. Plasma concentrations were analyzed using reverse phase chromatography by tandem mass spectrometry (LC-MS/MS). Safety and tolerability of metformin were also assessed in all subjects. RESULTS: 24 subjects were enrolled and completed the study (15 female and 9 male). Test and reference metformin hydrochloride were bioequivalent during the extent of exposure since AUC0-t and Cmax 90% CIs corresponded to 89.77-101.08% and 89.63-102.48%, respectively, both being within the pre-specified acceptance range criteria (80-125%). There were two adverse events (AE) with the reference formulation that were not related to the study drug. CONCLUSIONS: Bioequivalence in healthy volunteers in fasting conditions of the two metformin hydrochloride formulations (oral solution and tablets) was established, being the difference in means of AUC0-t, AUC0-∞ and Cmax within the acceptance range (80-125%). Oral solution formulation could offer the advantages of allowing adjusted doses and easier swallowing for every patient. Plain language summary is available for this article. TRIAL REGISTRATION: National Clinical Trials Registry (RNEC by its Spanish acronym), BD METF-Sil No. 86-15. Mexican Medicine Agency (COFEPRIS) Registry: 153300410B0368. FUNDING: Laboratorios Silanes, S.A. de C.V.

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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.

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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.

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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.

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