A model-based assay design to reproduce in vivo patterns of acute drug-induced toxicity

Kuepfer, Lars; Clayton, Olivia; Thiel, Christoph; Cordes, Henrik; Nudischer, Ramona; Blank, Lars M.; Baier, Vanessa; Heymans, Stéphane; Caiment, Florian; Roth, Adrian; Fluri, David; Kelm, Jens M.; Castell, José V.; Selevsek, Nathalie; Schlapbach, Ralph; Keun, Hector C.; Hynes, James T.; Sarkans, Ugis; Gmuender, Hans; Herwig, Ralf; Niederer, Steven A.; Schuchhardt, Johannes; Segall, Matthew D.; Kleinjans, Jos

doi:10.1007/s00204-017-2041-7

Cited by 25 publications

(36 citation statements)

References 10 publications

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“…This could also include the effect of change in lifestyle on the composition of the intestinal microbiome and subsequent changes in BA composition (Wahlström et al, 2016). Furthermore, specific preclinical in vitro data can be integrated and used for in vitro-in vivo translation of omics data (Kuepfer et al, 2017). This will ideally involve time series of omics data which could be contextualised in the model to describe the adaption of bile acid metabolism toward repeated drug administration or to track specific pathogeneses.…”

Section: Discussionmentioning

confidence: 99%

A Physiology-Based Model of Human Bile Acid Metabolism for Predicting Bile Acid Tissue Levels After Drug Administration in Healthy Subjects and BRIC Type 2 Patients

et al. 2019

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Drug-induced liver injury (DILI) is a matter of concern in the course of drug development and patient safety, often leading to discontinuation of drug-development programs or early withdrawal of drugs from market. Hepatocellular toxicity or impairment of bile acid (BA) metabolism, known as cholestasis, are the two clinical forms of DILI. Whole-body physiology-based modelling allows a mechanistic investigation of the physiological processes leading to cholestasis in man. Objectives of the present study were: (1) the development of a physiology-based model of the human BA metabolism, (2) population-based model validation and characterisation, and (3) the prediction and quantification of altered BA levels in special genotype subgroups and after drug administration. The developed physiology-based bile acid (PBBA) model describes the systemic BA circulation in humans and includes mechanistically relevant active and passive processes such as the hepatic synthesis, gallbladder emptying, transition through the gastrointestinal tract, reabsorption into the liver, distribution within the whole body, and excretion via urine and faeces. The kinetics of active processes were determined for the exemplary BA glycochenodeoxycholic acid (GCDCA) based on blood plasma concentration-time profiles. The robustness of our PBBA model was verified with population simulations of healthy individuals. In addition to plasma levels, the possibility to estimate BA concentrations in relevant tissues like the intracellular space of the liver enhance the mechanistic understanding of cholestasis. We analysed BA levels in various tissues of Benign Recurrent Intrahepatic Cholestasis type 2 (BRIC2) patients and our simulations suggest a higher susceptibility of BRIC2 patients toward cholestatic DILI due to BA accumulation in the liver. The effect of drugs on systemic BA levels were simulated for cyclosporine A (CsA). Our results confirmed the higher risk of DILI after CsA administration in healthy and BRIC2 patients. The presented PBBA model enhances our mechanistic understanding underlying cholestasis and drug-induced alterations of BA levels in blood and organs. The developed PBBA model might be applied in the future to anticipate potential risk of cholestasis in patients.

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Section: Discussionmentioning

confidence: 99%

A Physiology-Based Model of Human Bile Acid Metabolism for Predicting Bile Acid Tissue Levels After Drug Administration in Healthy Subjects and BRIC Type 2 Patients

et al. 2019

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“…For each of the four anthracyclines physiologically based pharmacokinetic (PBPK) models were developed. The models were built with the open source PBPK modeling software PK-Sim and validated according to best practice guidelines for PBPK model qualification 18,68 .…”

Section: Methodsmentioning

confidence: 99%

“…Consequently, in a yet unmet endeavor, we obtained proof-of-principle for such an integrated approach with respect to cardiovascular drug toxicity. We generated dose-over-time cross-omics data from an advanced iPSC-derived human cardiac 3D microtissue model exposed to physiologically relevant doses of anthracyclines (ACs) over a time period of 14 days 18 . ACs are widely used chemotherapies despite the fact that they induce cardiotoxicities in up to 23% of the patients.…”

Section: Introductionmentioning

confidence: 99%

Network integration and modelling of dynamic drug responses at multi-omics levels

et al. 2020

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Uncovering cellular responses from heterogeneous genomic data is crucial for molecular medicine in particular for drug safety. This can be realized by integrating the molecular activities in networks of interacting proteins. As proof-of-concept we challenge network modeling with time-resolved proteome, transcriptome and methylome measurements in iPSC-derived human 3D cardiac microtissues to elucidate adverse mechanisms of anthracycline cardiotoxicity measured with four different drugs (doxorubicin, epirubicin, idarubicin and daunorubicin). Dynamic molecular analysis at in vivo drug exposure levels reveal a network of 175 disease-associated proteins and identify common modules of anthracycline cardiotoxicity in vitro, related to mitochondrial and sarcomere function as well as remodeling of extracellular matrix. These in vitro-identified modules are transferable and are evaluated with biopsies of cardiomyopathy patients. This to our knowledge most comprehensive study on anthracycline cardiotoxicity demonstrates a reproducible workflow for molecular medicine and serves as a template for detecting adverse drug responses from complex omics data.

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“…Doubtlessly, they have been very successful in many respects [67–69]. The results of the PBPK/PD model approach can help to improve the in vitro assay design through reverse dosimetry such that the IFN- α dose of actual physiological relevance are used in the experiments [70]. As described above, the intracellular signalling is four fold reduced in physiological conditions and displays different dynamics due to in vivo drug elimination [71–73].…”

Section: Discussionmentioning

confidence: 99%

Quantitative systems pharmacology of interferon alpha administration: A multi-scale approach

et al. 2019

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The therapeutic effect of a drug is governed by its pharmacokinetics which determine the downstream pharmacodynamic response within the cellular network. A complete understanding of the drug-effect relationship therefore requires multi-scale models which integrate the properties of the different physiological scales. Computational modelling of these individual scales has been successfully established in the past. However, coupling of the scales remains challenging, although it will provide a unique possibility of mechanistic and holistic analyses of therapeutic outcomes for varied treatment scenarios. We present a methodology to combine whole-body physiologically-based pharmacokinetic (PBPK) models with mechanistic intracellular models of signal transduction in the liver for therapeutic proteins. To this end, we developed a whole-body distribution model of IFN- α in human and a detailed intracellular model of the JAK/STAT signalling cascade in hepatocytes and coupled them at the liver of the whole-body human model. This integrated model infers the time-resolved concentration of IFN- α arriving at the liver after intravenous injection while simultaneously estimates the effect of this dose on the intracellular signalling behaviour in the liver. In our multi-scale physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) model, receptor saturation is seen at low doses, thus giving mechanistic insights into the pharmacodynamic (PD) response. This model suggests a fourfold lower intracellular response after administration of a typical IFN- α dose to an individual as compared to the experimentally observed responses in in vitro setups. In conclusion, this work highlights clear differences between the observed in vitro and in vivo drug effects and provides important suggestions for future model-based study design.

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A model-based assay design to reproduce in vivo patterns of acute drug-induced toxicity

Cited by 25 publications

References 10 publications

A Physiology-Based Model of Human Bile Acid Metabolism for Predicting Bile Acid Tissue Levels After Drug Administration in Healthy Subjects and BRIC Type 2 Patients

A Physiology-Based Model of Human Bile Acid Metabolism for Predicting Bile Acid Tissue Levels After Drug Administration in Healthy Subjects and BRIC Type 2 Patients

Network integration and modelling of dynamic drug responses at multi-omics levels

Quantitative systems pharmacology of interferon alpha administration: A multi-scale approach

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