Physiologically-based Kinetic Modelling (PBK Modelling): Meeting the 3Rs Agenda

d’Yvoire, Michel Bouvier; Prieto, Pilar; Blaauboer, Bas J.; Bois, Frédéric; Boobis, Alan R.; Brochot, Céline; Coecke, Sandra; Freidig, Andreas P.; Gundert‐Remy, Ursula; Hartung, Thomas; Jacobs, Miriam N.; Lavé, Thierry; Leahy, David E.; Lennernäs, Hans; Loizou, George; Meek, Bette; Pease, Camilla; Rowland, Malcolm; Spendiff, Martin; Yang, Jiansong; Zeilmaker, Marco J.

doi:10.1177/026119290703500606

Cited by 57 publications

(7 citation statements)

References 28 publications

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“…For assessing still pending questions with toxicokinetics of Alternaria toxins, which could ultimately allow for an accurate estimation of ADME in humans, researchers are encouraged to carry out further animal studies or preferably to apply computational methods such as physiologically-based pharmacokinetic (PBPK) modelling and in vitro to in vivo extrapolation (IVIVE). These are part of international efforts (e.g., NIH's "Tox21" initiative, the EU's 3R's agenda) to reduce the dependency on animal experiments by providing rapid, high-throughput toxicity testing tools (Bouvier d'Yvoire et al, 2008;Krewski et al, 2010). However, as a necessary first step toward that goal, the quantitative elucidation of metabolic processes in state-of-the-art in vitro test systems is urgently required.…”

Section: Toxicokineticsmentioning

confidence: 99%

Alternaria toxins—Still emerging?

Aichinger

Favero

Warth

et al. 2021

Comp Rev Food Sci Food Safe

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Alternaria molds are known to cause the contamination of food with their secondary metabolites, a chemically very heterogeneous group of compounds. Yet, after decades of research on the occurrence and the toxicity of Alternaria toxins in academia, no regulation has been implemented yet, thus leaving these potential food contaminants in the status of so-called "emerging mycotoxins". However, research on this topic has been far from static, leading to the European Food Safety Authority repeatedly calling for more data on the occurrence and toxicity of genotoxic metabolites such as alternariol (AOH) and its monomethyl ether (AME). To give an overview on recent developments in the field, this comprehensive review summarizes published data and addresses current challenges arising from the chemical complexity of Alternaria's metabolome, mixture effects and the emergence of novel biological targets like cell membranes or the interaction with different receptors. Besides toxicodynamics, we review recent research on toxicokinetics, including the first in vivo studies which incorporated the rarely investigated-but highly genotoxic-perylene quinones. Furthermore, a particular focus lies on the advances of liquid chromatography/tandem mass spectrometry (LC-MS/MS)-based analytical tools for determining a broader spectrum of Alternaria toxins including modified/masked forms and assessing exposure via human biomonitoring (HBM).

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Section: Toxicokineticsmentioning

confidence: 99%

Alternaria toxins—Still emerging?

Aichinger

Favero

Warth

et al. 2021

Comp Rev Food Sci Food Safe

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“…Given that in vitro systems are far removed from the complex dynamics of in vivo systems, to extrapolate these findings to relevance to human health would require the use of a fully characterized physiologically based pharmacokinetic model, which accounts for the absorption, distribution, metabolism and excretion of a compound (D'Yvoire et al, ). Such an undertaking relies heavily on empirically derived chemical‐specific data involving multiple physiochemical, permeability and clearance parameters, data that have not been collected to date for TCEP and TCIPP.…”

Section: Discussionmentioning

confidence: 99%

A toxicogenomics approach to screen chlorinated flame retardants tris(2‐chloroethyl) phosphate and tris(2‐chloroisopropyl) phosphate for potential health effects

Krivoshiev

Beemster

Sprangers

et al. 2017

J of Applied Toxicology

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Tris(2-chloroethyl) phosphate (TCEP) is a pervasive flame retardant that has been identified as a chemical of concern given its health effects and therefore its use has since been tightly regulated. Tris(2-chloroisopropyl) phosphate (TCIPP), an analogue of TCEP, is believed to be its replacement. However, compared to TCEP, little is known of the toxicological impacts of TCIPP. We used RNA sequencing as unbiased and sensitive tool to identify and compare effects on a transcriptome level of TCEP and TCIPP in the human hepatocellular carcinoma cell line, HepG2. We identified that compared to other flame retardants, TCEP and TCIPP had little cytotoxicity. Treatment with sub-cytotoxic concentrations of the two compounds revealed that both chemicals elicited similar effects; both compounds were found to affect genes involved in immune responses and steroid hormone biosynthesis, while also affecting xenobiotic metabolism pathways in a similar manner. Specifically for effects on immune responses, both compounds were shown to alter the expression of the receptor of the potent and pleiotropic complement component, C5a. Additionally, expression of genes encoding for effector proteins involved in the complement cascade along with other potent inflammatory regulators were found altered in response to TCEP and TCIPP, further emphasizing their potential effects on immune function. Taken together, given that TCIPP elicited similar effects compared to TCEP, and at lower concentrations, the potential health effects of TCIPP need to be further studied for a complete risk assessment of the compound.

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“…PBPK modeling is a mechanistic approach that accounts for tissue size, perfusion rates, and partitioning of unbound anticancer drug into physiologically relevant compartments. We anticipate that this modeling method will enable us to readily account for alterations in physiology (e.g., renal, hepatic), and extrapolate dosages across cohorts and across species (d Yvoire, Prieto et al 2007). Adding PBPK modeling to our process will provide us with the ability to examine a wide range of anticancer drugs efficiently and effectively to predict which ones will have the most likelihood of success in future preclinical and clinical trials.…”

Section: 0 Future Plans/summarymentioning

confidence: 99%

Deriving therapies for children with primary CNS tumors using pharmacokinetic modeling and simulation of cerebral microdialysis data

Jacus

Throm

Turner

et al. 2014

European Journal of Pharmaceutical Sciences

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The treatment of children with primary central nervous system (CNS) tumors continues to be a challenge despite recent advances in technology and diagnostics. In this overview, we describe our approach for identifying and evaluating active anticancer drugs through a process that enables rational translation from the lab to the clinic. The preclinical approach we discuss uses tumor subgroup-specific models of pediatric CNS tumors, cerebral microdialysis sampling of tumor extracellular fluid (tECF), and pharmacokinetic modeling and simulation to overcome challenges that currently hinder researchers in this field. This approach involves performing extensive systemic (plasma) and target site (CNS tumor) pharmacokinetic studies. Pharmacokinetic modeling and simulation of the data derived from these studies are then used to inform future decisions regarding drug administration, including dosage and schedule. Here, we also present how our approach was used to examine two FDA approved drugs, simvastatin and pemetrexed, as candidates for new therapies for pediatric CNS tumors. We determined that due to unfavorable pharmacokinetic characteristics and insufficient concentrations in tumor tissue in a mouse model of ependymoma, simvastatin would not be efficacious in further preclinical trials. In contrast to simvastatin, pemetrexed was advanced to preclinical efficacy studies after our studies determined that plasma exposures were similar to those in humans treated at similar tolerable dosages and adequate unbound concentrations were found in tumor tissue of medulloblastoma-bearing mice. Generally speaking, the high clinical failure rates for CNS drug candidates can be partially explained by the fact that therapies are often moved into clinical trials without extensive and rational preclinical studies to optimize the transition. Our approach addresses this limitation by using pharmacokinetic and pharmacodynamic modeling of data generated from appropriate in vivo models to support the rational testing and usage of innovative therapies in children with CNS tumors.

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Physiologically-based Kinetic Modelling (PBK Modelling): Meeting the 3Rs Agenda

Cited by 57 publications

References 28 publications

Alternaria toxins—Still emerging?

Alternaria toxins—Still emerging?

A toxicogenomics approach to screen chlorinated flame retardants tris(2‐chloroethyl) phosphate and tris(2‐chloroisopropyl) phosphate for potential health effects

Deriving therapies for children with primary CNS tumors using pharmacokinetic modeling and simulation of cerebral microdialysis data

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