A survey of pharmacokinetic bioanalytical methods in biosimilar biological license applications (BLAs) for the assessment of target and antidrug antibodies effects

Bioanalysis ◽  
2021 ◽  
Author(s):  
Dana T Hackel ◽  
Theingi M Thway ◽  
Shiew Mei Huang ◽  
Yow-Ming C Wang
Keyword(s):  
Bioanalytical Methods ◽  
Experimental Testing ◽  
Biologically Active ◽  
Bioanalytical Method ◽  
Exposure Response ◽  
Antidrug Antibody ◽  
Clinical Responses ◽  
Survey Results ◽  
Antidrug Antibodies ◽  
Target Effects

The presence of circulating targets and antidrug antibodies can influence the ability of a bioanalytical method to measure therapeutic protein (TP) concentration relevant to exposure-response evaluations. This project surveyed biosimilar submissions for their bioanalytical methods. Survey results revealed that 97% of pharmacokinetic methods designed to measure theoretically free or partial-free TPs with respect to target indeed measured free or partial-free TPs when considering experimental testing results for target effects. Antidrug antibody effect is less often evaluated. The observed trend of measuring biologically active forms of TP is consistent with the scientific understanding that pharmacokinetics of biologically active forms is more likely to be relevant to the clinical responses and evaluation of clinically meaningful differences to contribute to biosimilarity assessments.

scholarly journals CETSA MS Profiling for a Comparative Assessment of FDA-Approved Antivirals Repurposed for COVID-19 Therapy Identifies TRIP13 as a Remdesivir Off-Target

2020 ◽  
pp. 247255522097359
Author(s):  
Tomas Friman ◽  
Alexey Chernobrovkin ◽  
Daniel Martinez Molina ◽  
Laurence Arnold
Keyword(s):  
Small Molecules ◽  
Antiviral Drugs ◽  
Biologically Active ◽  
Target Engagement ◽  
Intact Cells ◽  
Protein Targets ◽  
Antiviral Compounds ◽  
Binding Partners ◽  
Cellular Thermal Shift Assay ◽  
Target Effects

The reuse of preexisting small molecules for a novel emerging disease threat is a rapid measure to discover unknown applications for previously validated therapies. A pertinent and recent example where such a strategy could be employed is in the fight against coronavirus disease 2019 (COVID-19). Therapies designed or discovered to target viral proteins also have off-target effects on the host proteome when employed in a complex physiological environment. This study aims to assess these host cell targets for a panel of FDA-approved antiviral compounds including remdesivir, using the cellular thermal shift assay (CETSA) coupled with mass spectrometry (CETSA MS) in noninfected cells. CETSA MS is a powerful method to delineate direct and indirect interactions between small molecules and protein targets in intact cells. Biologically active compounds can induce changes in thermal stability, in their primary binding partners, and in proteins that in turn interact with the direct targets. Such engagement of host targets by antiviral drugs may contribute to the clinical effect against the virus but can also constitute a liability. We present here a comparative study of CETSA molecular target engagement fingerprints of antiviral drugs to better understand the link between off-targets and efficacy.

scholarly journals EBF recommendation on practical management of critical reagents for antidrug antibody ligand-binding assays

Bioanalysis ◽  
2019 ◽  
Vol 11 (19) ◽  
pp. 1787-1798 ◽  
Author(s):  
Susanne Pihl ◽  
Barry WA van der Strate ◽  
Michaela Golob ◽  
Janka Ryding ◽  
Laurent Vermet ◽  
...  
Keyword(s):  
Life Cycle ◽  
Ligand Binding ◽  
Crucial Role ◽  
Binding Assays ◽  
Antidrug Antibody ◽  
Regulatory Guidelines ◽  
Minimum Requirements ◽  
Antidrug Antibodies ◽  
Immunogenicity Assays

Immunogenicity (ISI) assays are required to measure antidrug antibodies that are generated against biotherapeutic modalities. As for any ligand-binding assays, critical reagents (CR) play a crucial role in immunogenicity assays, as the robustness and reliability of an assay are defined by the quality and long-term availability of these reagents. The current regulatory guidelines do not provide clear directions on how to implement and verify lot-to-lot changes of CR during an assay life cycle, or the acceptance criteria that should be used when implementing new lots of CR. These aspects were extensively discussed within the European Bioanalysis Forum community. In this paper, CR for immunogenicity assays are identified and the minimum requirements for introducing new lots of CR in immunogenicity assays are described.

scholarly journals Exposure-Response Analyses of Tigecycline Efficacy in Patients with Complicated Skin and Skin-Structure Infections

2007 ◽  
Vol 51 (6) ◽  
pp. 1939-1945 ◽  
Author(s):  
A. K. Meagher ◽  
J. A. Passarell ◽  
B. B. Cirincione ◽  
S. A. Van Wart ◽  
K. Liolios ◽  
...  
Keyword(s):  
Sample Size ◽  
Regression Tree ◽  
Classification And Regression Tree ◽  
Loading Dose ◽  
Time Curve ◽  
Skin Structure ◽  
Exposure Response ◽  
Concentration Time ◽  
Complicated Skin ◽  
Clinical Responses

ABSTRACT Exposure-response analyses were performed for the microbiological and clinical efficacy of tigecycline in the treatment of complicated skin and skin-structure infections, where Staphylococcus aureus and streptococci are the predominant pathogens. A prospective method was developed to create homogeneous patient populations for PK-PD analyses. Evaluable patients from three clinical trials were pooled for analysis. Patients received a tigecycline 100-mg loading dose/50 mg every 12 h or a 50-mg loading dose/25 mg every 12 h. At the test-of-cure visit, microbiologic and clinical responses were evaluated. Patients were prospectively evaluated and classified into cohorts based on baseline pathogens: S. aureus only (cohort 1), monomicrobial S. aureus or streptococci (cohort 2), two gram-positive pathogens (cohort 3), polymicrobial (cohort 4), or other monomicrobial infections (cohort 5). A prospective procedure for combining cohorts was used to increase the sample size. Logistic regression evaluated steady-state 24-h area under the concentration-time curve (AUC24)/MIC ratio as a predictor of response, and classification and regression tree (CART) analyses were utilized to determine AUC/MIC breakpoints. Analysis began with pooled cohorts 2 and 3, the focus of these analyses, and included 35 patients with 40 S. aureus and/or streptococcal pathogens. CART analyses identified a significant AUC/MIC breakpoint of 17.9 (P = 0.0001 for microbiological response and P = 0.0376 for clinical response). The continuous AUC/MIC ratio was predictive of microbiological response based on sample size (P = 0.0563). Analysis of all pathogens combined decreased the ability to detect exposure-response relationships. The prospective approach of creating homogeneous populations based on S. aureus and streptococci pathogens was critical for identifying exposure-response relationships.

scholarly journals Development of Fish Products Technology with Using Food Supplements from Fish Remaining Feedstock

2020 ◽  
Author(s):  
Inna Brazhnaia ◽  
Alina Tifanyuk ◽  
Olga Kulik ◽  
Svetlana Sudak
Keyword(s):  
Mathematical Modeling ◽  
Raw Materials ◽  
Food Additives ◽  
Biologically Active ◽  
Fish Products ◽  
Blue Whiting ◽  
Daily Diet ◽  
City Population ◽  
Mineral Components ◽  
Survey Results

The article describes the technology for the production of chopped fish products from blue whiting with the use of food additives from secondary fish raw materials. The sociological survey results and analysis of Murmansk city population nutritional structure are presented and the main factors that affect the choice of fortified foods are identified. The basic formulation of chopped fish products with the introduction of biologically active mineral components is developed and its optimization is carried out by computer simulation. To search close to optimal for a mineral composition that, taking into account the high organoleptic and rheological characteristics, a high orthogonal rototable by mathematical modeling method. The results were processed Datafit 9.0 computer program by generally accepted statistical methods. The experimental results of the chemical composition of chopped fish products and their caloric value are presented. As a result of the studies, a technological scheme and recipe for chopped fish products from Northern Basin underutilized raw materials such as blue whiting with the secondary fish raw materials additives was developed. Experimentally was obtained, that the using a cutlet portion with the 15% addition from its net weight exceeds the daily share of calcium intake, which is unacceptable due to the presence of other food products containing it in the consumers daily diet. The previously developed optimization recipe for chopped blue whiting products with the fish bones flour addition based on organoleptic and structural-mechanical indicators obtained by mathematical modeling methods allowed us to establish the optimal ratio of the introduced components.

scholarly journals Estimating Real-World Emissions of PHEVs in Norway by Combining Laboratory Measurement with User Surveys

2018 ◽  
Vol 9 (2) ◽  
pp. 31 ◽  
Author(s):  
Erik Figenbaum ◽  
Christian Weber
Keyword(s):  
Co2 Emission ◽  
Online Survey ◽  
Experimental Testing ◽  
Hybrid Vehicles ◽  
Exhaust Emission ◽  
Co2 Emission Reduction ◽  
Emission Testing ◽  
Survey Results ◽  
Reduction Of Co2 ◽  
Electric Mode

The paper presents the results of experimental testing of the exhaust emission and energy consumption of two gasoline plug-in hybrid vehicles in an emission testing laboratory with different drive cycles and drive modes and at summer and winter temperatures. One was a compact vehicle with a type approval electric mode range of 50 km, the other a mid-sized vehicle with an electric mode range of 31 km. Additionally, an online survey of 2065 private plug-in hybrid vehicles (PHEV) owners investigated the usage pattern of the vehicles. Combining the laboratory tests with the user survey results provided an estimate for the reduction of CO2-emission of PHEVs in use in Norway. The main conclusion is that the PHEV is a vehicle type that needs to match well with the use pattern to produce low CO2- and local emissions. The achievable CO2-emission reduction was proportional to the range in electric drive-mode (E-mode), i.e., 50 km range resulted in about 50% reduction.

scholarly journals Exposure-Response Analyses of Tigecycline Efficacy in Patients with Complicated Intra-Abdominal Infections

2007 ◽  
Vol 52 (1) ◽  
pp. 204-210 ◽  
Author(s):  
J. A. Passarell ◽  
A. K. Meagher ◽  
K. Liolios ◽  
B. B. Cirincione ◽  
S. A. Van Wart ◽  
...  
Keyword(s):  
Sample Size ◽  
Small Sample Size ◽  
Small Sample ◽  
Classification And Regression Tree ◽  
Loading Dose ◽  
Time Curve ◽  
E Coli ◽  
Exposure Response ◽  
Clinical Responses ◽  
Abdominal Infections

ABSTRACT Exposure-response analyses were performed to test the microbiological and clinical efficacies of tigecycline in complicated intra-abdominal infections where Escherichia coli and Bacteroides fragilis are the predominant pathogens. Data from evaluable patients enrolled in three clinical trials were pooled. Patients received intravenous tigecycline (100-mg loading dose followed by 50 mg every 12 h or 50-mg loading dose followed by 25 mg every 12 h). At the test-of-cure visit, microbiological and clinical responses were evaluated. Patients were prospectively classified into cohorts based on infection with a baseline pathogen(s): E. coli only (cohort 1), other mono- or polymicrobial Enterobacteriaceae (cohort 2), at least one Enterobacteriaceae pathogen plus an anaerobe(s) (cohort 3), at least one Enterobacteriaceae pathogen plus a gram-positive pathogen(s) (cohort 4), and all other pathogens (cohort 5). The cohorts were prospectively combined to increase sample size. Logistic regression was used to evaluate ratio of steady-state 24-hour area under the concentration-time curve (AUC) to MIC as a response predictor, and classification-and-regression-tree (CART) analyses were utilized to determine AUC/MIC breakpoints. Analysis began with cohorts 1, 2, and 3 pooled, which included 71 patients, with 106 pathogens. The small sample size precluded evaluation of cohorts 1 (34 patients, 35 E. coli pathogens) and 2 (16 patients, 24 Enterobacteriaceae). CART analyses identified a significant AUC/MIC breakpoint of 6.96 for microbiological and clinical responses (P values of 0.0004 and 0.399, respectively). The continuous AUC/MIC ratio was also borderline predictive of microbiological response (P = 0.0568). Cohort 4 (21 patients, 50 pathogens) was evaluated separately; however, an exposure-response relationship was not detected; cohort 5 (31 patients, 60 pathogens) was not evaluated. The prospective approach of creating homogenous populations of pathogens was critical for identifying exposure-response relationships in complicated intra-abdominal infections.

scholarly journals CETSA® MS profiling for a comparative assessment of FDA approved antivirals repurposed for COVID-19 therapy identifies Trip13 as a Remdesivir off-target

2020 ◽  
Author(s):  
Tomas Friman ◽  
Alexey Chernobrovkin ◽  
Daniel Martinez Molina ◽  
Laurence Arnold
Keyword(s):  
Small Molecules ◽  
Antiviral Drugs ◽  
Biologically Active ◽  
Intact Cells ◽  
Protein Targets ◽  
Antiviral Compounds ◽  
Binding Partners ◽  
Infected Cells ◽  
Cellular Thermal Shift Assay ◽  
Target Effects

AbstractThe reuse of pre-existing small molecules for a novel emerging disease threat is a rapid measure to discover unknown applications for previously validated therapies. A pertinent and recent example where such strategy could be employed is in the fight against COVID-19. Therapies designed or discovered to target viral proteins also have off-target effects on the host proteome when employed in a complex physiological environment. This study aims to assess these host cell targets for a panel of FDA approved antiviral compounds including Remdesivir, using the cellular thermal shift assay (CETSA®) coupled to mass spectrometry (CETSA MS) in non-infected cells. CETSA MS is a powerful method to delineate direct and indirect interactions between small molecules and protein targets in intact cells. Biologically active compounds can induce changes in thermal stability, in their primary binding partners as well as in proteins that in turn interact with the direct targets. Such engagement of host targets by antiviral drugs may contribute to the clinical effect against the virus but can also constitute a liability. We present here a comparative study of CETSA molecular target engagement fingerprints of antiviral drugs to better understand the link between off-targets and efficacy.

scholarly journals Assessment of immunogenicity from galcanezumab phase 3 trials in patients with episodic or chronic migraine

Cephalalgia ◽  
2020 ◽  
Vol 40 (9) ◽  
pp. 978-989 ◽  
Author(s):  
James M Martinez ◽  
Nada Hindiyeh ◽  
Greg Anglin ◽  
Kavita Kalidas ◽  
Michael E Hodsdon ◽  
...  
Keyword(s):  
Adverse Events ◽  
Chronic Migraine ◽  
Antibody Titer ◽  
Episodic Migraine ◽  
Calcitonin Gene Related Peptide ◽  
Phase 3 ◽  
Related Peptide ◽  
Antidrug Antibody ◽  
Calcitonin Gene ◽  
Antidrug Antibodies

Background This analysis characterizes the immunogenicity profile of galcanezumab, a humanized monoclonal antibody that selectively binds calcitonin gene-related peptide and inhibits its activity, in phase 3 migraine trials. Methods Immunogenicity data were analyzed from baseline and double-blind, placebo-controlled phases of the 3-month chronic migraine study REGAIN, the 6-month episodic migraine studies EVOLVE-1 and EVOLVE-2, and from baseline and open-label phases of the 12-month chronic and episodic migraine Study CGAJ. The incidence of baseline antidrug antibodies, treatment-emergent antidrug antibodies, neutralizing antidrug antibodies, and the effect of antidrug antibody titer on pharmacokinetics and pharmacodynamics were assessed. The relationship between antidrug antibody status and efficacy was explored using average change in monthly migraine headache days. Safety analyses assessed the potential relationship between treatment-emergent antidrug antibodies and hypersensitivity events or adverse events related to injection sites. Findings Across studies, 5.9–11.2% of patients had baseline antidrug antibodies. The incidence of treatment-emergent antidrug antibodies was 2.6–12.4% in the galcanezumab group and 0.5–1.7% in the placebo group. The majority of treatment-emergent antidrug antibodies were detected approximately 3–6 months after first study drug dose. Overall, the observed antidrug antibody titer did not impact galcanezumab concentrations, calcitonin gene-related peptide concentrations, or galcanezumab efficacy. There was no evidence that hypersensitivity events or adverse events related to injection sites were mediated by treatment-emergent antidrug antibodies. Interpretation These data showed that immunogenicity did not impact galcanezumab concentrations, calcitonin gene-related peptide concentrations, or the efficacy and hypersensitivity profile of galcanezumab in patients with migraine.

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