It addresses body fluid dynamics, describes the scientific processes necessary to understand the various aspects of the physico-chemical issues relating to vascular infusion delivery, and discusses vascular infusion dynamics. It also considers all the essential elements of the preparation of a formulation intended for vascular delivery as well as assessment of compatibility of the formulation with the dosing apparatus.
Volume II: The Techniques builds upon the highly praised Handbook of Pre-Clinical Continuous Intravenous Infusion and provides a current account of the techniques and equipment involved in all the major laboratory animal species for conducting successful vascular infusion studies with xenobiotics. It is organized by species, including all those commonly used in pre-clinical studies: rat, mouse, dog, minipig, large primate, and marmoset.
There are also chapters on juvenile studies and reproductive toxicity studies. Each section addresses the selection of the best model, surgical and non-surgical best practices, practical techniques, equipment selection, and commonly encountered background pathologies. Systems pharmacology describes an approach that links systems biology, pharmacology, medicinal chemistry and bioinformatics, and enables the development of models that predict and explain how drugs interact with biologic components. Modeling approaches are highly specific for the system s they describe and the questions being asked, thus, although they have shown value in defining potential on-target toxicities of new molecular entities, there is currently limited experience with using such approaches in the development of biologics.
The assertion by van Meer et al. One of the criticisms of publications reviewing current practice in how mAbs are developed is that they are often based solely on drugs that have been through regulatory review. Often, this approach is taken because regulatory dossiers e. However, this leads to bias because conclusions are based on a limited sub-set of drugs, without representation of drugs that are terminated during development due to identified safety and toxicity issues. The drugs that are accepted for first-in-human FIH clinical studies are believed to be relatively safe drugs, as safety concerns such as severe toxicity would have been assessed non-clinically.
To address this gap in available information, unpublished and published industry case-studies were gathered and analyzed to determine whether emerging technologies could have been used to predict nonclinical or clinical outcomes. Several case-studies were selected for discussion at the workshop to enable a variety of targets and challenges to be debated in breakout groups.
Not all questions were relevant for all case studies and only relevant questions were answered in each breakout group. It is an aggrecanase that degrades the aggrecan component of articular cartilage, making it an attractive target for osteoarthritis. The expression pattern of ADAMTS-5 shows that it is expressed in articular cartilage and surrounding joint tissues, but also many other tissues including arterial smooth muscle cells, mesothelium lining the peritoneal, pericardial and pleural cavities, smooth muscle cells in bronchi and pancreatic ducts, glomerular mesangial cells in the kidney, dorsal root ganglia, and Schwann cells.
Pre-existing knowledge of the target i. Furthermore, in vitro assays, such as the rabbit cardiac wedge assay and human CV ion channel assays did not detect the risk. There were no cardiovascular changes detected in the rat. The consensus of the breakout group was that the cardiovascular effects observed in the nonclinical studies were not predictable based on the mechanism of action of anti-ADAMTS Due to the target expression in the cardiovascular tissue, the heart was identified as a potential target organ; however, the observed effects hemorrhage in the initial non-GLP study, acute arrhythmias, persistent ST segment elevations and dose-dependent delayed onset increase in blood pressure could not have been predicted.
The only adverse effect that could possibly be attributed to a background lesion in the animal was the hemorrhage. Because a main focus of the workshop was the increased use of emerging technologies, the ability of in vitro approaches to identify the adverse effects was discussed. For anti-ADAMTS-5, the currently available in vitro tools were considered unable to predict the observed effects, as there are no in vitro models for hemodynamics or potential secondary pharmacologic effects, such as those on the extracellular matrix, that were relevant to this case study. Evaluating the totality of the in vivo findings for this case study highlighted that the most useful information was obtained from the dedicated safety pharmacology evaluation in cynomolgus monkeys.
Limitations of cardiovascular measurements conducted as part of the repeat-dose GLP toxicology study were also discussed and considered insufficient to detect the ECG findings observed in the safety pharmacology study. Delta-like ligand 4 DLL4 is a ligand in the Notch family of endothelial cell receptors that functions to control the balance of tip and stalk cells during normal vascular development. Heterozygous DLL4 knockout mice show embryonic lethality due to vascular abnormalities, and more recent experiments show that conditional knockout of Notch 1 can also lead to the development of vascular tumors in mice.
However, the severity and incidence of these findings differed between species, such that the liver findings were more severe in the rat relative to the cynomolgus monkey, and the decrease in red blood cells was more severe in the cynomolgus monkey. Together, these findings suggest that inhibiting the DLL4 pathway under different conditions e. The breakout group considered that clinically relevant findings in general repeat dose toxicity studies were related to the mechanism of action of the mAb and the majority of the participants agreed with this.
However, it was agreed that only some of the findings, for example those that were characteristic of bevacizumab, were predictable a priori. There were significant, clinically relevant toxicities e. Importantly, the dose-related toxicities seen in rats and monkeys resulted in a decision to terminate both anti-DLL4 molecules before FIH studies. Important gaps identified in currently available in vitro approaches included difficulty in modeling paracrine effects between at least 2 inter-regulated cell types, as well as in modeling potential hemodynamic effects that could lead to pathway-related changes only apparent in an in vivo setting.
For example, data from human cardiomyocytes or hepatocytes would be limited as anti-DLL4 may be acting at the endothelium and the sinusoids, respectively. A primary limitation of current in vitro systems is therefore associated with the ability to integrate multiple cell types e. The potential for Notch signaling studies to provide information on cross-species potency and add value to the overall program was also discussed.
Although signaling studies were considered to be of limited value in predicting in vivo toxicity in this case, the group were interested in evaluating the potential for 3-dimensional 3D tissue models, including novel microfluidic and dynamic flow systems currently in development e. Given the liver phenotype observed following administration of anti-DLL4 in vivo , these more complex organ models were thought to hold potentially greater promise for accurate prediction of toxicities that may only be reproduced in the context of relevant sinusoidal architecture or hemodynamic changes on vascular endothelial cells.
The breakout group agreed that if development of an anti-DLL4 molecule had continued further, a chronic toxicity study in the rat alone rather than the cynomolgus monkey or in both species may be useful to further identify potential effects with long-term treatment, as the rat and monkey exhibited similar toxicity profiles, and it would therefore be appropriate to conduct additional nonclinical studies in the lower-order species to limit NHP use.
The target antigen is primarily present in Alzheimer's Disease state, and is essentially undetectable in normal animals.
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No side effects were observed in a 4-week non-clinical APP mouse study. A tissue cross-reactivity panel in monkeys and humans showed no noticeable binding, and there was no binding to human peripheral blood cells.
Sign up now. Description Intravenous infusion is a necessary mode of delivery for many pharmaceuticals currently on the market or undergoing clinical trials. There is also a movement toward using peripherals and midlines because hospitals want to get patients through to the end of their therapy with as few complications and infections as possible. So, this constant represents the sum of these two processes:. Eur J Clin Pharmacol ; CPT codes covered if selection criteria are met :. Combined intrathecal baclofen and morphine infusion for the treatment of spasticity related pain and central deafferentiation pain.
No side effects were observed following a single low-dose administration in a cynomolgus monkey pharmacokinetics study, but severe toxicological effects were observed in a week repeat-dose cynomolgus monkey study. Thus, the off-target binding was consistent with the thrombocytopenia, vascular changes and infusion reactions that were observed in the cynomolgus monkey toxicity study.
The off-target binding could not have been identified via any other means of in vitro testing available at the time e. A wider range of in vitro approaches may have aided the prediction of the effects observed, for example to screen for plasma or serum component binding before in vivo studies. Since the off-target cross-reactivity was only present in human and cynomolgus plasma, not in mouse, rat or dog plasma, this case demonstrates the importance of testing the safety of therapeutic antibodies in a species relevant for both on-target and off-target binding.
A voting system was used throughout the workshop to gauge participant opinion, and the results are presented and discussed below. Many companies also reported increased requests for juvenile toxicity studies to support pediatric clinical development. One approach to refine in vivo nonclinical development programmes in the future may be to conduct a single toxicology study to enable clinical trials. The current ICH guidelines and regulatory environment should be amenable to this, as the guidelines are meant to act as a guide , and do not currently dictate study duration, aside from that they should be based on the intended duration of clinical exposure and disease indication.
Furthermore, regulators will allow deviation from the guidelines, taking scientific rationale into account on a case-by-case basis. There would also be value in making this information available to other industry stakeholders to reduce redundancy in animal studies and potentially enable broader innovation across the industry. Furthermore, there are often difficulties in publishing this sort of data if the project has been terminated before establishing the exact cause of the toxicity.
In developing a future vision for mAb development, one important aspect for consideration is a continued evolution of regulatory practice and policy.
For example, the amount of knowledge and data that is generated as a by-product of the regulatory submissions process is critical to ensure future strategy is directed and informed by science through a broad evidence-base. Although information collected in surveys is useful for certain purposes, such as in developing recommendations on good practices, in this case the importance of detailed specific case study information was acknowledged.
The scientific and regulatory community clearly share a vision for continued evaluation and integration of emerging technologies to reduce and refine animal use for biotherapeutic mAb development. However, there are still several barriers that must be recognized and overcome to make this a reality. Some of the observed in vivo effects, such as changes in blood pressure or paracrine effects, would not have been predicted using currently available technologies; therefore, the challenge for the future will be to advance and apply novel technologies that have the capability to more closely represent the in vivo situation.
Summary of case-study data and the ability of existing in vitro and in silico technologies to detect or predict toxicities observed in the in vivo studies. The majority of clinically relevant findings for mAbs are based on their mechanism of action. However, the toxicities presented in the case studies were, in general, not predictable before in vivo studies despite their relationship to the pharmacological action of the mAb. It is also important to note that many associated clinical toxicities such as some cancers, progressive multifocal leukoencephalopathy and infection, are so rare that they are not realistically detected in any in vitro or in vivo study.
Currently, the field remains insufficiently confident in the ability of in vitro models to capture unpredictable toxicological findings as highlighted in the case studies, although there is much enthusiasm, commitment, and perceived potential for the industry to work towards this aim. Significant activity will be required to progress this field to be able to confidently predict unexpected toxicities from in vitro models. The development of more sophisticated and relevant in vitro technologies for safety assessment of mAbs may need to be more case-dependent, to take in to account their innate complexity, diversity and size, as well as their specific mechanism of action.
A major recommendation of the participants at the workshop was for the establishment of a framework that could improve pre-competitive data-sharing between companies developing biologic products. Increased communication and data-sharing would enhance progress, increase understanding between industry and regulators, and support advancement toward common goals.
The challenge faced in developing such a framework is in providing incentives for companies to share data on terminated compounds, which could take the form of individual company publications, cross-company initiatives, consideration of coordination with the EMA safe harbour effort, as well as development of an online journal, database or repository that would provide an easily accessible platform to share additional case studies. The NC3Rs could potentially serve as an honest broker to take this type of initiative forward; Biosafe a committee within the Biotechnology Innovation Organization, a trade association for biotechnology-related organizations globally is also working to collect several similar case studies that can be published and presented to the FDA.
As well as consideration of the potential for emerging technologies, the value of the existing in vivo studies was also discussed at the workshop. The regulatory requests were not always deemed to be scientifically driven and many participants disagreed that juvenile toxicity studies were necessary to inform pediatric safety in many cases, as there is potential to better utilize and integrate information from general toxicology studies and clinical data from adult patients.
Since the discussions at the workshop, the guidance published in the ICH S11 concept paper may alleviate some of these concerns. A future vision for mAb development is one in which fewer animals are used, but where the data obtained are more predictive of human safety.
Therefore the typical approach to safety assessment of mAbs was considered. Typically two studies, one to support FIH clinical studies IND-enabling and one to support registration, are performed during mAb development. In some cases for oncology indications, a single study may suffice. Following in the footsteps of the highly praised Handbook of Pre-Clinical Continuous Intravenous Infusion, this new volume covers both up-to-date procedures and equipment. It is organized by species, including all those commonly used in pre-clinical studies: rat, mouse, dog, minipig, large primate, and marmoset.
There are also chapters on juvenile studies and reproductive toxicity studies. Each section addresses the selection of the best model, surgical and non-surgical best practices, practical techniques, equipment selection, and commonly encountered background pathologies.
Using a fresh approach, the authors identify best practices to be shared across the industry, and provide guidance on choices for the most acceptable methodologies from an animal welfare perspective. This volume, along with Volume I: The Science, provides a foundation of knowledge on infusion technology and its importance for safe clinical use of substances via this route of delivery. Features: Emphasizes best practices in accordance with the 3Rs-reduction, refinement, and replacement of animal usage in laboratories Presents step-by-step procedures and practical tips covering a wide range of common animal models, augmented by the liberal use of illustrations Covers modern practices and procedures in accordance with up-to-date equipment development.
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