Papers by Wolfgang Muster
ChemInform, Jun 24, 2010
ChemInform Abstract Gemäss Formelbild wird das Acetat (I) in die gesuchten Verbindungen (III)über... more ChemInform Abstract Gemäss Formelbild wird das Acetat (I) in die gesuchten Verbindungen (III)übergeführt, die Wirkung gegen Leukämiezellen der Maus besitzen. Am wirksamsten ist die Verbindung (IIIa). (UV-spektroskopische Daten).
Elsevier eBooks, 2017
The present article describes what type of in silico models are applied in the pharmaceutical ind... more The present article describes what type of in silico models are applied in the pharmaceutical industry throughout the drug discovery process to support risk assessment and select the most promising compound for entry into human. The most relevant computational methods are described along with the evaluation of their performance in the context of genotoxic impurities according to the ICH M7 guideline recommendations.
Nature Reviews Drug Discovery
PDA Journal of Pharmaceutical Science and Technology
The threshold of toxicological concern (TTC), i.e., the dose of a compound lacking sufficient exp... more The threshold of toxicological concern (TTC), i.e., the dose of a compound lacking sufficient experimental toxicity data that is unlikely to result in an adverse health effect in humans, is important for evaluating extractables and leachables (E&Ls) as it guides analytical testing and minimizes the use of animal studies. The ELSIE consortium, which consists of member companies that span biotechnology, pharmaceutical, and medical device industries, brought together subject matter expert toxicologists to derive TTC values for organic, non-mutagenic E&L substances when administered parenterally. A total of 488 E&L compounds from the ELSIE database were analyzed and parenteral point of departure (PPOD) estimates were derived for 252 compounds. The PPODs estimates were adjusted to extrapolate to subacute, subchronic, and chronic durations of nonclinical exposure and the lower 5th percentiles were calculated. An additional 100-fold adjustment factor to account for nonclinical species and human variability was subsequently applied to derive the parenteral TTC values for E&Ls. The resulting parenteral TTC values are 35, 110, and 180 μg/day for human exposures of >10 years to lifetime, >1-10 years, and ≤1 year, respectively. These parenteral TTCs are expected to be conservative for E&Ls that are considered non-mutagenic per ICH M7(R1) guidelines.
Journal of Cheminformatics
Unpredicted drug safety issues constitute the majority of failures in the pharmaceutical industry... more Unpredicted drug safety issues constitute the majority of failures in the pharmaceutical industry according to several studies. Some of these preclinical safety issues could be attributed to the non-selective binding of compounds to targets other than their intended therapeutic target, causing undesired adverse events. Consequently, pharmaceutical companies routinely run in-vitro safety screens to detect off-target activities prior to preclinical and clinical studies. Hereby we present an open source machine learning framework aiming at the prediction of our in-house 50 off-target panel activities for ~ 4000 compounds, directly from their structure. This framework is intended to guide chemists in the drug design process prior to synthesis and to accelerate drug discovery. We also present a set of ML approaches that require minimum programming experience for deployment. The workflow incorporates different ML approaches such as deep learning and automated machine learning. It also acc...
Methods in Molecular Biology, 2022
The present contribution describes how in silico models and methods are applied at different stag... more The present contribution describes how in silico models and methods are applied at different stages of the drug discovery process in the pharmaceutical industry. A description of the most relevant computational methods and tools is given along with an evaluation of their performance in the assessment of potential genotoxic impurities and the prediction of off-target in vitro pharmacology. The challenges of predicting the outcome of highly complex in vivo studies are discussed followed by considerations on how novel ways to manage, store, exchange, and analyze data may advance knowledge and facilitate modeling efforts. In this context, the current status of broad data sharing initiatives, namely, eTOX and eTransafe, will be described along with related projects that could significantly reduce the use of animals in drug discovery in the future.
Unpredicted drug safety issues constitute the majority of failures in the pharmaceutical industry... more Unpredicted drug safety issues constitute the majority of failures in the pharmaceutical industry according to several studies[1-3]. Some of these preclinical safety issues could be attributed to the non-selective binding of compounds to targets other than their intended therapeutic target, causing undesired adverse events. Consequently, pharmaceutical companies including Roche, routinely run in-vitro safety screens to detect off-target activities prior to preclinical and clinical studies.Hereby we present a machine learning framework aiming at the prediction of our in-house 50 off-target panel[4] activities for ~ 4000 compounds, directly from their structure. This framework is intended to guide chemists in the drug design process prior to synthesis and accelerate drug discovery. It incorporates different ML approaches such as deep learning and automated machine learning. Outcomes from different methods are compared in terms of efficiency and efficacy. The most important challenges ...
Regulatory Toxicology and Pharmacology, 2012
This is the report from the ''ECVAM-EFPIA workshop on 3T3 NRU Phototoxicity Test: Practical Exper... more This is the report from the ''ECVAM-EFPIA workshop on 3T3 NRU Phototoxicity Test: Practical Experience and Implications for Phototoxicity Testing'', jointly organized by ECVAM and EFPIA and held on the 25-27 October 2010 in Somma Lombardo, Italy. The European Centre for the Validation of Alternative Methods (ECVAM) was established in 1991 within the European Commission Joint Research, based on a Communication from the European Commission (1991). The main objective of ECVAM is to promote the scientific and regulatory acceptance of alternative methods which are of importance to the biosciences and which reduce, refine and replace the use of laboratory animals.
Mutation Research/Genetic Toxicology and Environmental Mutagenesis, 2011
The Mouse Lymphoma Expert Workgroup of the International Workshop for Genotoxicity Tests (IWGT) m... more The Mouse Lymphoma Expert Workgroup of the International Workshop for Genotoxicity Tests (IWGT) met in Basel, Switzerland in August of 2009. The Workgroup (WG) was tasked with discussing the appropriate top concentration for non-pharmaceuticals that would be required for the conduct of the mouse lymphoma assay (MLA) when sufficient cytotoxicity [to between 10 and 20% relative total growth (RTG)] has not been attained. The WG approached this task by (1) enumerating the various regulatory decisions/use for MLA data, (2) discussing the appropriate assays to which MLA data and assay performance should be compared and (3) discussing all the proposals put forth concerning the top concentration for non-pharmaceuticals. In addition, one of the members presented a summary of a re-evaluation of the National Toxicology Program MLA data using the IWGT harmonized guidance that was underway as a separate (non IWGT) activity, being conducted by two members of the Expert WG. The WG was asked to vote on each of the various proposals for top concentration for when cytotoxicity is not concentration limiting. While there was general agreement that the top concentration for non-pharmaceuticals should be re-evaluated and likely lowered from the current recommended levels, there was no agreement on a specific new recommendation.
Mutagenesis, 1998
A positive result in the Ames test is generally taken as a strong indication for a genotoxic (i.e... more A positive result in the Ames test is generally taken as a strong indication for a genotoxic (i.e. DNA damaging) property of the test compound, often sufficient to cause termination of its development as a new therapeutic agent A number of serotonin receptor ligands have been tested for their mutagenic potential in the Ames assay at an early stage of development For several compounds increases in the number of revertant colonies were observed in strain TA1537. Consequently, structure-activity relationship investigations were undertaken to search for compounds without mutagenic liability. All compounds are three ringed heterocyclic structures consisting of a benzene ring, a central (generally non-aromatic) 5-or 6-membered ring and a pyrrole or pyrazole ring. Using a gel shift assay we provide evidence that the observed genotoxic effects are strongly influenced by the intercalating properties of the compounds. The highest mutagenic response was seen with a compound possessing a central aromatic ring. The mutagenic activity of the naphthaleno derivatives appears to be stronger when compared with the indeno compounds, probably because of the less curved structure. Dimethyl substitution of the indeno substructure reduces the intercalating ability of the compounds and leads to loss of mutagenic activity. Pyrazole analogues of both indeno and naphthaleno structures appear to produce stronger mutagenic responses than the pyrrole derivatives.
Chemical Research in Toxicology, 2011
The predictive power of four commonly used in silico tools for mutagenicity prediction (DEREK, To... more The predictive power of four commonly used in silico tools for mutagenicity prediction (DEREK, Toxtree, MC4PC, and Leadscope MA) was evaluated in a comparative manner using a large, high-quality data set, comprising both public and proprietary data (F. Hoffmann-La Roche) from 9,681 compounds tested in the Ames assay. Satisfactory performance statistics were observed on public data (accuracy, 66.4-75.4%; sensitivity, 65.2-85.2%; specificity, 53.1-82.9%), whereas a significant deterioration of sensitivity was observed in the Roche data (accuracy, 73.1-85.5%; sensitivity, 17.4-43.4%; specificity, 77.5-93.9%). As a general tendency, expert systems showed higher sensitivity and lower specificity when compared to QSAR-based tools, which displayed the opposite behavior. Possible reasons for the performance differences between the public and Roche data, relating to the experimentally inactive to active compound ratio and the different coverage of chemical space, are thoroughly discussed. Examples of peculiar chemical classes enriched in false negative or false positive predictions are given, and the results of the combined use of the prediction systems are described.
Regulatory toxicology and pharmacology : RTP, 2013
Genotoxicity hazard identification is part of the impurity qualification process for drug substan... more Genotoxicity hazard identification is part of the impurity qualification process for drug substances and products, the first step of which being the prediction of their potential DNA reactivity using in silico (quantitative) structure-activity relationship (Q)SAR models/systems. This white paper provides information relevant to the development of the draft harmonized tripartite guideline ICH M7 on potentially DNA-reactive/mutagenic impurities in pharmaceuticals and their application in practice. It explains relevant (Q)SAR methodologies as well as the added value of expert knowledge. Moreover, the predictive value of the different methodologies analyzed in two surveys conveyed in the US and European pharmaceutical industry is compared: most pharmaceutical companies used a rule-based expert system as their primary methodology, yielding negative predictivity values of ⩾78% in all participating companies. A further increase (>90%) was often achieved by an additional expert review an...
Chemical research in toxicology, 2019
While dedicated guidelines for industry exist regarding the assessment of the genotoxic potential... more While dedicated guidelines for industry exist regarding the assessment of the genotoxic potential of new pharmaceuticals and impurities, and the general safety assessment of major drug metabolites, only limited guidance exists on the assessment of potential genotoxic minor drug metabolites. In this perspective paper, we discuss challenges associated with assessing the genotoxic potential of human metabolites and share five case studies within the context of an 'aware-avoid-assess' paradigm. A special focus is on a class of potentially genotoxic carcinogens: aromatic amines (arylamines, anilines). This compound class is frequently used as building blocks and may show up as impurities, metabolites or degradants in pharmaceuticals. We propose several recommendations that should help project teams at different stages of pharmaceutical development. In most cases, proactive interactions with the relevant health authority should be considered in order to endorse the proposed genoto...
Regulatory Toxicology and Pharmacology
Regulatory Toxicology and Pharmacology
Regulatory Guidance documents ICH Q3A (R2) and ICH Q3B (R2) state that "impurities that are ... more Regulatory Guidance documents ICH Q3A (R2) and ICH Q3B (R2) state that "impurities that are also significant metabolites present in animal and/or human studies are generally considered qualified". However, no guidance is provided regarding data requirements for qualification, nor is a definition of the term "significant metabolite" provided. An opportunity is provided to define those categories and potentially avoid separate toxicity studies to qualify impurities. This can reduce cost, animal use and time, and avoid delays in drug development progression. If the concentration or amount of a metabolite, in animals or human, is similar to that of the known, structurally identical impurity (arising from the administered test material), the qualification of the impurity on the grounds of it also being a metabolite is justified. We propose two complementary approaches to support conclusions to this effect: 1) demonstrate that the impurity is formed by metabolism in animals and/or man, based preferably on plasma exposures or, alternatively, amounts excreted in urine, and, where appropriate, 2) show that animal exposure to (or amount of) the impurity/metabolite is equal or greater in animals than in humans. An important factor of both assessments is the maximum theoretical concentration (or amount) (MTC1 or MTA) of the impurity/metabolite achievable from the administered dose and recommendations on the estimation of the MTC and MTA are presented.
Regulatory Toxicology and Pharmacology
Methods in Molecular Biology
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Papers by Wolfgang Muster