Neue Analysenmethoden für Metabolismusstudien am Beispiel des Calciumantagonisten Verapamil

[no abstract

A Unique Automation Platform for Measuring Low Level Radioactivity in Metabolite Identification Studies

Generation and interpretation of biotransformation data on drugs, i.e. identification of physiologically relevant metabolites, defining metabolic pathways and elucidation of metabolite structures, have become increasingly important to the drug development process. Profiling using 14C or 3H radiolabel is defined as the chromatographic separation and quantification of drug-related material in a given biological sample derived from an in vitro, preclinical in vivo or clinical study. Metabolite profiling is a very time intensive activity, particularly for preclinical in vivo or clinical studies which have defined limitations on radiation burden and exposure levels. A clear gap exists for certain studies which do not require specialized high volume automation technologies, yet these studies would still clearly benefit from automation. Use of radiolabeled compounds in preclinical and clinical ADME studies, specifically for metabolite profiling and identification are a very good example. The current lack of automation for measuring low level radioactivity in metabolite profiling requires substantial capacity, personal attention and resources from laboratory scientists. To help address these challenges and improve efficiency, we have innovated, developed and implemented a novel and flexible automation platform that integrates a robotic plate handling platform, HPLC or UPLC system, mass spectrometer and an automated fraction collector

The application of organ-on-chip models for the prediction of human pharmacokinetic profiles during drug development

Organ-on-chip (OoC) technology has led to in vitro models with many new possibilities compared to conventional in vitro and in vivo models. In this review, the potential of OoC models to improve the prediction of human oral bioavailability and intrinsic clearance is discussed, with a focus on the functionality of the models and the application in current drug development practice. Multi-OoC models demonstrating the application for pharmacokinetic (PK) studies are summarized and existing challenges are identified. Physiological parameters for a minimal viable platform of a multi-OoC model to study PK are provided, together with PK specific read-outs and recommendations for relevant reference compounds to validate the model. Finally, the translation to in vivo PK profiles is discussed, which will be required to routinely apply OoC models during drug development

Minireview Current Approaches for Absorption, Distribution, Metabolism, and Excretion Characterization of Antibody-Drug Conjugates: An Industry White Paper

ABSTRACT An antibody-drug conjugate (ADC) is a unique therapeutic modality composed of a highly potent drug molecule conjugated to a monoclonal antibody. As the number of ADCs in various stages of nonclinical and clinical development has been increasing, pharmaceutical companies have been exploring diverse approaches to understanding the disposition of ADCs. To identify the key absorption, distribution, metabolism, and excretion (ADME) issues worth examining when developing an ADC and to find optimal scientifically based approaches to evaluate ADC ADME, the International Consortium for Innovation and Quality in Pharmaceutical Development launched an ADC ADME working group in early 2014. This white paper contains observations from the working group and provides an initial framework on issues and approaches to consider when evaluating the ADME of ADCs

Meeting report of the 4th European Biotransformation Workshop

Challenges, strategies and new technologies in the field of biotransformation were presented and discussed at the fourth European Biotransformation Workshop which was held in collaboration with the joint ISSX/DMDG meeting on June 15, 2023 at the University of Hertfordshire in Hatfield, UK. In this meeting report we summarise the presentations and discussions from this workshop. The topics covered are listed below: • Unusual biotransformation reactions • Biotransformation Workflows in Discovery utilizing various softwares for structure elucidation • Biotransformation software for the identification of peptide metabolites • Accelerator Mass Spectrometry (AMS) for endogenous and xenobiotic metabolite profiling • Metabolite profiling using quantitative Nuclear magnetic resonance (NMR) and liquid chromatography coupled to inductively coupled plasma-mass spectrometry (LC-ICP-MS) Keywords: unusual biotransformation reactions, Mass Metasite, biotransformation softwares, AMS, F-NMR for metabolite profiling, LC-ICP-MS for metabolite profiling

A Cross Company Perspective on the Assessment of Therapeutic Protein Biotransformation

Unlike small molecules (SMs), biotransformation of therapeutic proteins (TPs), except for antibody-drug conjugates (ADCs), has not been broadly investigated and included in regulatory filings. Nevertheless, there is an expanding pool of evidence suggesting that the ever increasingly diverse modalities and complexity of the TPs than the conventional monoclonal antibodies (mAbs) can significantly benefit from the insights of biotransformation into this area of therapeutics. For instance, such biotransformation analysis of the TP affords important information on its molecular stability, which may shed light into any potential impact on binding affinity, potency, pharmacokinetics, efficacy, safety and bioanalytical strategy. This white paper is intended to summarize the current practices in studying biotransformation of TPs and related findings in the biopharmaceutical industry. A key objective is to raise the awareness of this topic which remains relatively underexplored in the development of TPs. It is hopeful that continued efforts and the cumulative data could pave the way for establishing a consensus on the biotransformation assessment of TPs in the future between the industry and regulatory authorities

Meeting report of the second European Biotransformation Workshop

Challenges and opportunities in the field of biotransformation were presented and discussed at the 2nd European Biotransformation workshop which was conducted virtually in collaboration with the DMDG November 24/25, 2021. Here we summarise the presentations and discussions from this workshop. The following topics were covered: 1) Regulatory requirements and biotransformation studies for ADCs and ASOs 2) Solutions for mass spectral data processing of peptides and oligonucleotides 3) Future outsourcing needs in biotransformation for new modalities 4) Established quantitative and qualitative workflows for metabolite identification 5) In vitro and microphysiological systems to study new chemical entities (NCEs) with low metabolic turnover 6) New strategies to frontload the human ADME study and to investigate the impact of human microbiome on drug development Keywords: Biotransformation of new modalities, ADCs, ASOs, metabolite quantitation and qualification, microphysiological systems, human ADME, microbiom

Meeting report of the first European Biotransformation Workshop

Challenges and opportunities in the field of biotransformation were presented and discussed at the 1st European Biotransformation workshop which was conducted virtually in collaboration with the DMDG January 27, 2021. Here we summarise the presentations and discussions from this workshop. The following topics were covered: • Needs for radiolabel for IND filing versus quantitation without standards • Applications of cyclic ion mobility in the field of biotransformation • Computational predictions of xenobiotic metabolism • Future (outsourcing) needs in biotransformation • Genotoxicity risk assessment of metabolites and qualification of impurities using metabolite data • Regulatory aspects of MIST Keywords: Biotransformation, metabolite qualification, cyclic ion mobility, MIST, genotoxicity risk assessment, qualification of impuritie

Absorption, Distribution, Metabolism, and Excretion (ADME) of Therapeutic Proteins: A White Paper on Current Industry Practices and Future Perspectives

Therapeutics proteins (TPs) comprise a variety of modalities including antibody-based drugs, coagulation factors, recombinant cytokines, enzymes, growth factors, and hormones to name a few. TPs usually cannot traverse cellular barriers and exert their pharmacological activity by interacting with targets on the exterior membrane of cells or with soluble ligands in the tissue interstitial fluid/blood. Due to large size, lack of cellular permeability, variation in metabolic fate, and distinct physicochemical characteristics, TPs are subjected to different absorption, distribution, metabolism, and excretion (ADME) processes as compared to small molecules. Limited regulatory guidance makes it challenging to determine the most relevant ADME data required for regulatory submissions. The TP ADME working group (WG) was sponsored by the Translational and ADME Sciences Leadership Group (TALG) within the Innovation and Quality (IQ) consortium with objectives to: i) better understand the current practices of ADME data generated for TPs across IQ member companies, ii) learn about their regulatory strategy and interaction experiences, and iii) provide recommendations on best practices for conducting ADME studies. To understand current ADME practices and regulatory strategies, an industry-wide survey was conducted within IQ member companies. In addition, ADME data submitted to FDA was also collated by reviewing regulatory submission packages of TPs approved between 2011-2020. This article summarizes the key learnings from the survey and an overview ADME data presented in BLAs along with future perspectives and recommendations for conducting ADME studies for internal decision making as well as regulatory submissions for TPs

New guidelines for the pharmacokinetic and Drug drug interaction assessments of ADCS-input to templates for IQ consortium

Novartis is member of IQ consortium on ADCs. Dominic Hainzl and myself represnet Novartis at Consortium to define new guidelines for Pharmacokinetic monitoring and DDI assessment of ADCs. The final goal of consortium is to draft a white paper with cross comany recommendation. To accomplish this goal we need to populate the templates with preclinical and clinal information of ADcs. Although we have currently only 1 ADC program in clinical deveopment (PCA062) , we have not mentioned the Novartis code, nor the target. However, preclinical information about the payload (DM1) was shared at this information is already available. For other information provided information in these templates we have referred to public available information (journal articles) as listed below. We seek your approval to submit the prefilled templates to the IQ consortium. papers from which we extracted information: New Insights in Tissue Distribution, Metabolism, and Excretion of [3H]-Labeled Antibody Maytansinoid Conjugates in Female Tumor-Bearing Nude Rats. Walles M, Rudolph B, Wolf T, Bourgailh J, Suetterlin M, Moenius T, Peraus G, Heudi O, Elbast W, Lanshoeft C, Bilic S. Drug Metab Dispos. 2016 Jul;44(7):897-910. doi: 10.1124/dmd.115.069021. Epub 2016 Apr 27. ADME and Safety Aspects of Non-cleavable Linkers in Drug Discovery and Development. Walles M, Connor A, Hainzl D. Curr Top Med Chem. 2017;17(32):3463-3475. doi: 10.2174/1568026618666180118153502. Review