Predictivity/Translatability of Toxicities Observed in Nonclinical Toxicology Studies to Clinical Safety Outcomes in Drug Development: Case Examples

2019 ◽  
Vol 39 (2) ◽  
pp. 141-150
Author(s):  
Nicola J. Stagg ◽  
Hanan N. Ghantous ◽  
Robert Roth ◽  
Kenneth L. Hastings
Keyword(s):  
Drug Development ◽  
Annual Meeting ◽  
Clinical Studies ◽  
Early Termination ◽  
New Drugs ◽  
Clinical Safety ◽  
Case Examples ◽  
Palm Springs ◽  
Starting Dose ◽  
Good Concordance

Nonclinical toxicology studies are conducted to characterize the potential toxicities and establish a safe starting dose for new drugs in clinical studies, but the question remains as to how predictable/translatable the nonclinical safety findings are to humans. In many cases, there is good concordance between nonclinical species and patients. However, there are cases for which there is a lack of predictivity or translatability that led to early termination of clinical studies due to unanticipated toxicities or early termination of programs before making it to the clinic due to unacceptable nonclinical toxicities assumed to be translatable. A few case examples of safety findings that are translatable versus safety findings that are not translatable and why they are not translateable were presented as a symposium at the 38th Annual Meeting of the American College of Toxicology in Palm Springs, California, and are discussed in this article.

scholarly journals Cathepsin L plays a key role in SARS-CoV-2 infection in humans and humanized mice and is a promising target for new drug development

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Miao-Miao Zhao ◽  
Wei-Li Yang ◽  
Fang-Yuan Yang ◽  
Li Zhang ◽  
Wei-Jin Huang ◽  
...  
Keyword(s):  
Drug Development ◽  
Cathepsin L ◽  
Human Cells ◽  
New Drugs ◽  
Disease Course ◽  
Promising Target ◽  
First Time

AbstractTo discover new drugs to combat COVID-19, an understanding of the molecular basis of SARS-CoV-2 infection is urgently needed. Here, for the first time, we report the crucial role of cathepsin L (CTSL) in patients with COVID-19. The circulating level of CTSL was elevated after SARS-CoV-2 infection and was positively correlated with disease course and severity. Correspondingly, SARS-CoV-2 pseudovirus infection increased CTSL expression in human cells in vitro and human ACE2 transgenic mice in vivo, while CTSL overexpression, in turn, enhanced pseudovirus infection in human cells. CTSL functionally cleaved the SARS-CoV-2 spike protein and enhanced virus entry, as evidenced by CTSL overexpression and knockdown in vitro and application of CTSL inhibitor drugs in vivo. Furthermore, amantadine, a licensed anti-influenza drug, significantly inhibited CTSL activity after SARS-CoV-2 pseudovirus infection and prevented infection both in vitro and in vivo. Therefore, CTSL is a promising target for new anti-COVID-19 drug development.

scholarly journals The Role of Network Science in Glioblastoma

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1045
Author(s):  
Marta B. Lopes ◽  
Eduarda P. Martins ◽  
Susana Vinga ◽  
Bruno M. Costa
Keyword(s):  
Personalized Medicine ◽  
Drug Development ◽  
Information Flow ◽  
Clinical Studies ◽  
Network Science ◽  
Cancer Genomics ◽  
High Dimensional ◽  
Network Discovery ◽  
Software Implementations

Network science has long been recognized as a well-established discipline across many biological domains. In the particular case of cancer genomics, network discovery is challenged by the multitude of available high-dimensional heterogeneous views of data. Glioblastoma (GBM) is an example of such a complex and heterogeneous disease that can be tackled by network science. Identifying the architecture of molecular GBM networks is essential to understanding the information flow and better informing drug development and pre-clinical studies. Here, we review network-based strategies that have been used in the study of GBM, along with the available software implementations for reproducibility and further testing on newly coming datasets. Promising results have been obtained from both bulk and single-cell GBM data, placing network discovery at the forefront of developing a molecularly-informed-based personalized medicine.

scholarly journals Lights and Shadows in Immuno-Oncology Drug Development

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 691
Author(s):  
Milana Bergamino Sirvén ◽  
Sonia Pernas ◽  
Maggie C. U. Cheang
Keyword(s):  
Drug Development ◽  
Checkpoint Inhibitors ◽  
Late Phase ◽  
New Drugs ◽  
Successful Outcome ◽  
Different Types ◽  
Cancer Types ◽  
Clinical Trial Designs ◽  
Oncology Drug Development ◽  
Critical Aspects

The rapidly evolving landscape of immuno-oncology (IO) is redefining the treatment of a number of cancer types. IO treatments are becoming increasingly complex, with different types of drugs emerging beyond checkpoint inhibitors. However, many of the new drugs either do not progress from phase I-II clinical trials or even fail in late-phase trials. We have identified at least five areas in the development of promising IO treatments that should be redefined for more efficient designs and accelerated approvals. Here we review those critical aspects of IO drug development that could be optimized for more successful outcome rates in all cancer types. It is important to focus our efforts on the mechanisms of action, types of response and adverse events of these novel agents. The use of appropriate clinical trial designs with robust biomarkers of response and surrogate endpoints will undoubtedly facilitate the development and subsequent approval of these drugs. Further research is also needed to establish biomarker-driven strategies to select which patients may benefit from immunotherapy and identify potential mechanisms of resistance.

scholarly journals Has molecular imaging delivered to drug development?

2017 ◽  
Vol 375 (2107) ◽  
pp. 20170112 ◽  
Author(s):  
Philip S. Murphy ◽  
Neel Patel ◽  
Timothy J. McCarthy
Keyword(s):  
Molecular Imaging ◽  
Drug Development ◽  
Clinical Studies ◽  
Pharmaceutical Research ◽  
Whole Body ◽  
Drug Candidate ◽  
Clinical Drug Development ◽  
Target Binding ◽  
The Brain ◽  
Clinical Drug

Pharmaceutical research and development requires a systematic interrogation of a candidate molecule through clinical studies. To ensure resources are spent on only the most promising molecules, early clinical studies must understand fundamental attributes of the drug candidate, including exposure at the target site, target binding and pharmacological response in disease. Molecular imaging has the potential to quantitatively characterize these properties in small, efficient clinical studies. Specific benefits of molecular imaging in this setting (compared to blood and tissue sampling) include non-invasiveness and the ability to survey the whole body temporally. These methods have been adopted primarily for neuroscience drug development, catalysed by the inability to access the brain compartment by other means. If we believe molecular imaging is a technology platform able to underpin clinical drug development, why is it not adopted further to enable earlier decisions? This article considers current drug development needs, progress towards integration of molecular imaging into studies, current impediments and proposed models to broaden use and increase impact. This article is part of the themed issue ‘Challenges for chemistry in molecular imaging’.

scholarly journals Characterization and applications of chimeric mice with humanized livers for preclinical drug development

2020 ◽  
Vol 36 (1) ◽  
Author(s):  
Chise Tateno ◽  
Yuha Kojima
Keyword(s):  
Liver Function ◽  
Drug Development ◽  
Mass Production ◽  
Human Hepatocytes ◽  
In Vitro Studies ◽  
New Drugs ◽  
Pharmaceutical Companies ◽  
Chimeric Mice ◽  
Preclinical Drug Development

AbstractWe have succeeded in stable mass production of chimeric PXB-mice, whose liver is repopulated by human hepatocytes at a ratio of more than 70%, and we are providing these mice to academia and pharmaceutical companies to support the development of new drugs or studies of liver function. Furthermore, we isolated human hepatocytes, called PXB-cells, from the chimeric mice, and provide them for clients weekly for in vitro studies. In this review, we summarize the existing characterizations of PXB-mice and PXB-cells and their present and future applications.

scholarly journals Estimating Drug Efficacy with a Diet-Induced NASH Model in Chimeric Mice with Humanized Livers

Biomedicines ◽  
2021 ◽  
Vol 9 (11) ◽  
pp. 1647
Author(s):  
Keishi Kisoh ◽  
Go Sugahara ◽  
Yuko Ogawa ◽  
Suzue Furukawa ◽  
Yuji Ishida ◽  
...  
Keyword(s):  
Drug Development ◽  
Drug Efficacy ◽  
Developed Countries ◽  
Liver Disorder ◽  
New Drugs ◽  
Peroxisome Proliferator ◽  
Chimeric Mice ◽  
Peroxisome Proliferator Activated Receptor ◽  
Nonalcoholic Fatty Liver ◽  
Nash Model

Nonalcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) is the most common liver disorder in developed countries. Although many new therapeutics for NASH are present in the drug development pipeline, there are still no approved drugs. One of the reasons that makes NASH drug development challenging is the lack of appropriate animal NASH models that resolve issues arising from inter-species differences between humans and rodents. In the present study, we developed a choline-deficient, L-amino-acid-defined, high-fat-diet (CDAHFD)-induced human NASH model using human liver chimeric mice. We demonstrated human hepatocyte injury by an elevation of plasma human alanine aminotransferase 1 in mice fed CDAHFD. Histological analysis showed that CDAHFD feeding induced similar histological changes to human NASH patients, including ballooning, inflammation, apoptosis, regeneration of human hepatocytes, and pericellular and perisinusoidal fibrosis. The chimeric mice fed CDAHFD were treated with a peroxisome-proliferator-activated receptor α/δ agonist, Elafibranor. Elafibranor ameliorated steatosis, ballooning of hepatocytes, and preserved fibrosis progression. We developed a novel humanized NASH model that can elucidate pathophysiological mechanisms and predict therapeutic efficacy in human NASH. This model will be useful in exploring new drugs and biomarkers in the early stages of human NASH.

scholarly journals Comparative Analysis of the QbD Approach in the Pharmaceutical Industry

2019 ◽  
Vol 8 (4) ◽  
pp. 20-26 ◽  
Author(s):  
S. A. Rozhnova ◽  
A. V. Tsypkina
Keyword(s):  
Comparative Analysis ◽  
Drug Development ◽  
Systematic Approach ◽  
New Drugs ◽  
Pharmaceutical Development ◽  
Drug Products ◽  
New Drug ◽  
Eurasian Economic Union ◽  
Pharmaceutical Manufacturers ◽  
Economic Union

Introduction. In the development and introduction of medicines into production, the aim of pharmaceutical manufacturers is to comply with the principle of «Quality-by-Design» (QbD). The International Council for Harmonisation (ICH) has created a number of GxP standards, which have become the regulatory framework for the development of documentation regulating the requirements for the development and production of drug products for countries focused on bringing their products to the world pharmaceutical market. The analysis of the system of regulation of pharmaceutical stages of development of new drugs in the territory of the Eurasian Economic Union was not considered, but for the formation of a systematic approach to the management of the process of pharmaceutical development it is necessary to describe them.Aim. To analyze the possibility of applying the QbD principle to the process of drug development at domestic pharmaceutical enterprises.Materials and methods. Content analysis of scientific publications, system and comparative analysis, sociological methods of research in the field of pharmaceutical development.Results and discussions. Regulatory state requirements to the organization and conduct of drug development procedures are analyzed and described. A number of systemic and sectoral problems typical for domestic pharmaceutical manufacturers in the organization of the development and implementation of new drug products. It is established that one of the main problems for Russian enterprises was the organization of the process as a whole and its individual procedures. To solve the problem of organization of procedures for the development and implementation of new medicines, we formed a methodological support, developed on the basis of a systematic approach and international requirements from the quality system.Conclusion. The main problem identified by the manufacturers is the lack of methodological support for the organization of the processes of pharmaceutical development and the introduction of new drugs in the part of research going to the stage of preclinical and clinical development. The decisions adopted by the Eurasian Economic Union do not affect such aspects of pharmaceutical development regulation as the organization of processes, their management and methodological support aimed at the implementation of the QbD principle. To solve this problem, we have developed guidelines for the implementation of the processes of pharmaceutical development and the introduction of new drug products, which allowed us to apply unified and formalized approaches to their organization. 

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