Biostatistics
Arkadiy Pitman, Oleksandr Sverdlov, L. Bruce Pearce in Mathematical and Statistical Skills in the Biopharmaceutical Industry, 2019
Bioassay is a collection of methods for estimating dose–response relationships using generalized linear models, such as logistic and probit regression models. One of the central problems in bioassay is estimation of various quantiles of the dose-response curve, such as median effective dose (ED50), which is the dose for which probability of response is 50%. Applications of bioassay in the pharmaceutical industry are numerous: toxicology studies, relative potency analysis (to provide a comparison between two substances), animal carcinogenicity studies, etc. One important application of bioassay is in clinical oncology phase I trials to estimate the maximum tolerated dose (MTD). The MTD is often defined as a quantile of a monotone dose–toxicity probability curve, which is to be estimated sequentially, by using adaptive dose escalation designs. A proper application of bioassay methodologies can help an investigator to estimate the dose–toxicity relationship, the toxicity probabilities at the study doses, the MTD and other parameters of interest. This information is used for calibrating dose range for subsequent (phase II) studies.
Characterization of Uncertainty
Samuel C. Morris in Cancer Risk Assessment, 2020
Wong (1984) explored the question of using the dose extrapolation model to design the experiment so as to provide more precise results. The uncertainty in the final risk estimate is composed of model uncertainties and sampling uncertainties. The sampling uncertainty can be reduced by using more animals in each dose group in the bioassay, while the model uncertainty can be reduced by using more experimental doses. If the bioassay is done with the aim of supplying data to an extrapolation model and finally to estimate the risk at low dose, these design aspects should be examined jointly. An important factor is the length of extrapolation necessary. Uncertainty generally increases the further one extrapolates from the experimental data. Larger samples reduce uncertainty associated with shorter extrapolations, but their effect decreases with distance; long extrapolations may be insensitive to larger sample sizes. Model uncertainty remains a limit, however. As sample size increases, total uncertainty approaches model uncertainty. The rate of convergence depends on the design. If convergence is fast, a large increase in sample size may have little effect, the limit being essentially reached with a small increase in sample size.
Interactions of Sleep Substances
Shojiro Inoué in Biology of Sleep Substances, 2020
However, as far as experimental studies are concerned, no systematic approach had been made to analyze interactions occurring among coexisting sleep substances before our attempt since 1985. In most studies on sleep factors, analyses have been individually performed on each substance which was singly administered. Hence, synergistic or antagonistic interactions, if any, among several substances could hardly be detected. Moreover, bioassay techniques were originally developed by different researchers using different recipient animals, different timings and routes of administration, different dosage, different recording durations, and so on. Thus, comparison of experimental results from different laboratories are extremely difficult.
Establishment of an anti-inflammation-based bioassay for the quality control of the 13-component TCM formula (Lianhua Qingwen)
Published in Pharmaceutical Biology, 2021
Shuaishuai Chen, Xiaojuan Yang, Ziying Wei, Yanru Zhang, Ying Huang, Zhuo Shi, Ziteng Zhang, Jiabo Wang, Haizhu Zhang, Jianli Ma, Xiaohe Xiao, Ming Niu
Bioassay is a type of quality control method commonly used in biological preparations, including in complex components like TCM. Some scholars have proposed to utilise bioassays in quality control of TCM (Xiao et al. 2010). Theoretically, bioassays can profile the overall efficacy of chemicals in TCM preparations if a reasonable assay model has been chosen (Xiao et al. 2018). Most recently, network pharmacology has been used to screen and enrich potential targets and pathways by computing all the known components with the biological target network (Hopkins 2007, 2008; Li and Zhang 2013). This seems promising and enables network pharmacology and bioassays to be utilised in establishing a new quality control method for TCM preparations. In this study, we considered LHQW as an example to explore a bioassay method for the quality control of TCM.
Analytical comparability study of recombinant monoclonal antibody therapeutics
Published in mAbs, 2018
Alexandre Ambrogelly, Stephen Gozo, Amit Katiyar, Shara Dellatore, Yune Kune, Ram Bhat, Joanne Sun, Ning Li, Dongdong Wang, Christine Nowak, Alyssa Neill, Gomathinayagam Ponniah, Cory King, Bruce Mason, Alain Beck, Hongcheng Liu
Bioassay, typically included in the release assay panel, is specifically mentioned in several ICH, FDA and EMA guidance documents,5–8,243 because it serves a variety of purposes. First, the bioassay measures the activity of the product, which is an important quality attribute. Second, the bioassay ensures the integrity of the mAb with respect to its higher order structure, especially when the direct assessment of the structure is challenging. Third, the bioassay serves as “a link to clinical activity.”8 The bioassay can also provide other useful information, for example “when a drug substance has more than one form and a manufacturing change shifts the distribution of forms, determination of the bioactivity of the various forms may be of value in assessing the impact of the change.”5 Of particular interest is the guidance from ICH Q5E,7 which states that “when changes are made to a product with multiple biological activities, manufacturers should consider performing a set of relevant functional assays designed to evaluate the range of activities.” This is especially true for a mAb that targets a cell surface antigen and requires the engagement of a Fcγ receptor or complement proteins as part of the MOA.98 In such a case, ADCC or CDC activity may need to be evaluated.
The impact of proline isomerization on antigen binding and the analytical profile of a trispecific anti-HIV antibody
Published in mAbs, 2020
Alessandro Masiero, Lechat Nelly, Gentric Marianne, Sourrouille Christophe, Laville Florian, Crépin Ronan, Borel Claire, Ziegler Cornelia, Bisch Grégoire, Leclerc Eric, Laurent Ludovic, Brault Dominique, Alexandre Sylvie, Gagnaire Marie, Duffieux Francis, Soubrier Fabienne, Capdevila Cécile, Arnould Isabelle, Dumas Jacques, Dabin Jérôme, Genet Bruno, Radošević Katarina, Menet Jean-Michel, Prades Catherine
The GP41 MPER antigen was coated on 96-well plate overnight at +2/+8°C the day before. After a blocking step, with Tris-Buffered Saline (TBS)–bovine serum albumin 1% two preparations of the SAR441236 antibody concentrations from approximately 125 μg/mL to 0.002 μg/mL were applied in triplicate and incubated 1 h at 22°C on every plate. After a wash step with TBS-Tween 0.1%, a goat anti-human IgG (H + L) conjugated to horseradish peroxidase was added into the plates and incubated 1 h at 22°C. After a wash step with TBS-Tween 0.1%, the 3,3ʹ,5,5ʹ-tétraméthylbenzidine substrate was finally added into the plates and incubated for 7 min. The peroxidase catalyzes a chemical reaction resulting in a colorimetric change. This colorimetric reaction was stopped using the STOP solution and the optical densities (OD) were measured at a wavelength of 450 nm using a spectrophotometer. The dose–response curves were generated with an internal application (Biost@t-Bioassay), using a 4-parameter model (OD versus antibody concentration in μg/mL). The effective concentration for which 50% of the maximum response is measured (EC50 in µg/mL) was determined by the application.
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