Establishing a systematic framework to characterise in vitro methods for human hepatic metabolic clearance

complete replacement of animal tests is not yet possible. Especially in case of the more complex systemic endpoints (e.g., carcinogenicity and reproductive toxicity), adequate animal-free methods are not yet available. Similarly, sufficiently predictive animal-free models to obtain information on toxicokinetics (absorption, metabolism and excretion), which is indispensable to calculate safe exposure limits for humans from in vitro assays, are still lacking. In short, from a regulatory point of view, the transition to a more predictive safety assessment of chemical and pharmaceutical substances requires the development of novel models and methods that reflect complex human physiology and biology in vitro.In this respect, one of the fastest-growing, most promising innovative technologies is the organ-on-chip (OC) technology (Marx et al., 2016). However, its value for regulatory safety assessment of chemical substances and pharmaceuticals is still unclear. Its role is in part dependent on the future development of regulatory safety assessment, which is widely recognized to be in need of a transition to accommodate the increased level of toxicological knowledge and animal welfare considerations (Piersma et al., 2018b).

Section: Liver Clearance Ratementioning

confidence: 98%

The value of organs-on-chip for regulatory safety assessment

Heringa

2019

“…Particularly, the generation of standardized approaches and a TG for hepatic metabolic clearance with primary hepatocytes or hepatic microsomes/S9 is considered a high priority. Gouliarmou et al (2018) already made a start by establishing a systematic framework to characterize in vitro methods for human hepatic metabolic clearance to provide a basis for harmonization within the OECD. A TG for hepatic clearance can potentially be developed further into TGs for metabolite identification and extrahepatic (i.e., intestine, kidney, lung, skin) clearance.…”

Section: Methods That Are Considered Ready For the Development Of Tgsmentioning

confidence: 99%

“…Rather than directly focusing on covering all sources of species differences in kinetics, it will be important first to enhance the use of individual (human-based) NAMs for kinetics and to make sure that these are sufficiently understood and provide robust results for application in a regulatory context. In case of hepatic clearance studies, for example, the European Union Reference Laboratory for alternatives to animal testing (EURL ECVAM) recently established a systematic framework to characterize in vitro methods for human hepatic metabolic clearance in terms of their design, applicability and performance (Gouliarmou et al, 2018). In addition, guidelines are needed on the integration of in vitro kinetic data into in silico kinetic models (Paini et al, 2019).…”

Section: Opportunities For New Scientific Developmentsmentioning

confidence: 99%

New approach methodologies (NAMs) for human-relevant biokinetics predictions

Punt

Bouwmeester

Blaauboer

et al. 2020

Whereas much work has been devoted to the development of in vitro screening methods to capture biological effects (toxicodynamics) of chemicals, insight into the absorption, distribution, metabolism and excretion (i.e., ADME/biokinetics) of chemi- IntroductionThere are clear societal and scientific needs for the development and validation of predictive animal-free methods for safety evaluations to prevent adverse effects in humans caused by exposure

“…To gain confidence in the outcomes obtained with PBK models that rely on in vitro input data, it is important to have insight into the robustness of the in vitro ALTEX, accepted manuscript published July 25, 2022 doi:10.14573/altex.2202131 2 input data that are used and the combined impact of experimental variation in each of the individual parameters on the model predictions. In addition, each in vitro kinetic assay has its own inherent boundaries with respect to the conditions under which the in vitro experiments should be performed, including, for example, boundaries with respect to the applied substrate concentration, enzyme concentration, or incubation time (Hubatsch et al, 2007;Gouliarmou et al, 2018;Seibert and Tracy, 2014). There are furthermore restrictions with respect to the applicability domain of different in vitro kinetic studies.…”

Section: Introductionmentioning

confidence: 99%

Impact of in vitro experimental variation in kinetic parameters on physiologically based kinetic (PBK) model simulations_suppl1

Punt

2022

In vitro toxicokinetic data are critical in meeting an increased regulatory need to improve chemical safety evaluations towards a better understanding of internal human chemical exposure and toxicity. In vitro intrinsic hepatic clearance (CLint), the fraction unbound in plasma (Fup), and the intestinal apparent permeability (Papp) are important parameters as input in a physiologically based kinetic (PBK) model to make first estimates of internal exposure after oral dosing. In the present study we explored the experimental variation in the values for these parameters as reported in the literature. Furthermore, the impact that this experimental variation has on PBK model predictions of maximum plasma concentration (Cmax) and the area under the concentration time curve (AUC0-24h) was determined. As a result of the experimental variation in CLint, Papp, and Fup, the predicted variation in Cmax for individual compounds ranged between 1.4-to 28-fold and the predicted variation in AUC0-24h ranged between 1.4-and 23-fold. These results indicate that there are still some important steps to take to achieve robust data that can be used in regulatory applications. To gain regulatory acceptance of in vitro kinetic data and PBK models based on in vitro input data, the boundaries in experimental conditions as well as the applicability domain and the use of different in vitro kinetic models need to be described in guidance documents.