Biopharmaceuticals have the potential to raise an immunogenic response in treated individuals, which may impact the efficacy and safety profile of these drugs. As a result, it is essential to evaluate immunogenicity throughout the different phases of the clinical development of a biopharmaceutical, including post-marketing surveillance. Although rigorous evaluation of biopharmaceutical immunogenicity is required by regulatory authorities, there is a lack of uniform standards for the type, quantity, and quality of evidence, and for guidance on experimental design for immunogenicity assays or criteria to compare immunogenicity of biopharmaceuticals. Moreover, substantial technological advances in methods to assess immune responses have yielded higher immunogenicity rates with modern assays, and limit comparison of immunogenicity of biopharmaceuticals outside of head-to-head clinical trials. Accordingly, research programs, regulatory agencies, and clinicians need to keep pace with continuously evolving analyses of immunogenicity. Here, we review factors associated with immunogenicity of biopharmaceuticals, potential clinical ramifications, and current regulatory guidance for evaluating immunogenicity, and discuss methods to assess immunogenicity in non-clinical and clinical studies. We also describe special considerations for evaluating the immunogenicity of biosimilar candidates.
This study aimed (1) to develop a semimechanistic pharmacokinetic (PK) model for nimotuzumab in patients with advanced breast cancer and (2) to identify demographic, biochemical, and clinical predictive factors of the PK variability. Data from a phase 1 study were analyzed using the nonlinear mixed-effects approach (NONMEM). A target-mediated disposition model that included 2 open PK compartments, the monoclonal antibody (mAb)-target binding, and target and mAb-target complex turnovers best described the linear and nonlinear PK. Covariates had no influence on the PK parameters. The final parameter estimates were 19.93 L (steady-state volume), 0.0045-0.0172 L/h (range of total clearance values), 6.96 μg/mL (steady-state binding constant), 5.50 h(-1) (target degradation rate constant), 1.43 (μg/mL) · h(-1) (complex formation rate), and 0.148 h(-1) (complex internalization rate constant). The model described the effect of the mAb-target binding, and target and mAb-target complex turnovers on nimotuzumab PK. Simulations showed that doses above 200 mg maintained the 50% target occupancy during all of the treatment. This model can be very useful for knowing the dosing schedules required for efficacy and supports further investigation of the pharmacokinetic/pharmacodynamic relationships of nimotuzumab to improve its therapeutic use.
BackgroundThe term “intended copy” (IC) is used to describe biotherapeutic medicinal products that have not been approved via a regulatory pathway aligned with WHO's Similar Biotherapeutic Product (SBP) guidelines to ensure quality, safety and efficacy. In some countries, the WHO SBP guidelines are not being consistently adopted or implemented and ICs of etanercept (ETN), originally developed by Pfizer (Wyeth), are being marketed as biosimilar versions, although rigorous regulatory criteria for analytical testing and clinical demonstration of biosimilarity may not have been fully assessed.ObjectivesPfizer conducted an analytical assessment of multiple lots of 4 ICs, and a single lot of 1 IC of ETN that have received marketing approval in various global markets. The results for critical quality attributes are compared with the licensed specifications of ETN.MethodsICs of ETN manufactured by Shanghai CP Guojian (China), Lafrancol (Colombia), Cipla (India), Probiomed (Mexico) and AryoGen (Iran) were assessed. Analyses included a subset of the release tests for ETN, together with evaluation by additional characterization methods to provide appropriate comparative detail on biochemical composition. Results for each product were evaluated against licensed specifications and historical ranges for ETN and ETN reference standard for the additional characterization test results.ResultsNone of the ICs met all of the individual product quality criteria that Pfizer apply for analytical comparability, although each product met some of the requirements. Principal differences were observed during assessments of identity (as measured by tryptic peptide map high-performance liquid chromatography [HPLC]), purity (as measured by hydrophobic interaction chromatography [HIC]), degree of aggregation (size exclusion [SE] HPLC), distribution of charged species (isoelectric focusing [IEF]/anion exchange [AEX] chromatography) and carbohydrate profile (N-linked oligosaccharide map). These are shown in the table.Key structural differences*IC ManufacturerShanghai CP GuojianLafrancolCiplaProbiomedAryoGenIdentity (tryptic peptide map HPLC): AtypicalYAggregation (SE HPLC): above specification limitYYYCharged species (IEF/AEX chromatography): Differences in distribution vs ETNYYYYPurity (HIC): Atypical profileYYYCarbohydrate profile (N-linked oligosaccharide map): Atypical (additional species not in ETN profile)YY*Relative to ETN release specifications and additional characterization historical data. Y, yes.ConclusionsWhile a degree of structural similarity with ETN was observed for each of the ICs analyzed, a number of significant structural and biochemical differences were noted. None of the products analyzed meet the combination of release specification and additional characterization criteria Pfizer typically apply to support a comparability assessment with ETN.Disclosure of InterestM. Scheinberg Consultant for: Pfizer Boehringer Mannenheim, Genzyme, Orygen, GSK, G. Castaneda Hernandez Consultant for: Abbvie, Bayer, Boehringer-Ingelheim, Eli-L...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.