We are on a next-generation chemical risk assessment (NGRA) adventure, where we are gradually breaking free from old-school toxicity testing and moving into the exciting world of new approach methodologies (NAMs)! Animal use is being swapped as much as possible for high-tech NAMs, including in-vitro screening to assess chemical risks faster than ever before. In vitro–in vivo extrapolation (IVIVE) is a technique we are using to close the gap between laboratory research and real-world scenarios. By utilizing high-throughput toxicokinetic (HTTK) techniques, we are accelerating our toxicokinetic data processing beyond our past capabilities. HTTK is helping us to (1) turn external dose metrics (such as mg/kg/day) to internal/tissue dose metrics and (2) relate in vitro points of departure (PODs) to human-relevant doses.
And guess what? As we prioritize public health and include more efficient cutting-edge techniques in chemical risk assessment, stakeholders such as the US Environmental Protection Agency (US EPA), Health Canada, and the European Food Safety Authority (EFSA) are watching where the science is going and considering these methods. It’s time to transform the way chemical risk assessment is done and take a fascinating journey toward everyone’s safer and healthier future!
The objectives of the 2024 SOT Continuing Education (CE) course “High-Throughput In Vitro–In Vivo Extrapolation for Predictive Toxicology” were threefold:
- To equip researchers with the skills to utilize high-throughput IVIVE effectively for estimating toxicological PODs
- To enhance the understanding of decision-makers regarding the potential and limitations of high-throughput IVIVE
- To familiarize attendees with the necessary data, models, and tools for creating bioactivity:exposure ratio (BER) risk-based prioritizations.
The focus of the course was not on individual chemical IVIVE but on employing IVIVE to inform toxicity models applicable to a wide array of chemicals. This course was led and instructed by esteemed experts in the field, who boast extensive experience in developing and employing tools such as SimCyp, httk, and WebICE. John Wambaugh was the Chair of the session while Barbara Wetmore was the Co-Chair.
Dr. Wetmore presented a historical overview of the evolution of HTTKs. Despite the abundance of chemicals, there remains a scarcity of information. This scarcity prompted the development of alternative methods, such as in vitro screening and bioinformatics, to address the challenges of toxicity testing. The necessary models for high-throughput IVIVE are now being developed by utilizing decades of knowledge about clearance and steady-state pharmacokinetics. The period from 1980 to 2023 witnessed a rise in the utilization of physiology-based pharmacokinetic and toxicokinetic (PBPK/TK) models. Notably, initiatives like the US EPA ToxCast program, launched in 2007, have contributed to this progression, alongside growing regulatory interest and tool development. However, despite all the progress, more has to be done. For instance, models must incorporate additional ADME (Absorption, Distribution, Metabolism, and Excretion) inputs, exposure routes, and considerations for sensitive populations to enhance prediction accuracy.
Hiba Khalidi introduced PBPK modeling and the Simcyp simulator, an advanced PBPK platform used to optimize clinical study design, determine first-in-human dose, assess novel drug formulations, establish dosage in untested populations, conduct virtual bioequivalence analyses, and forecast drug-drug interactions (DDIs). Developed by Certara, Simcyp is used for small molecules, biologics, antibody–drug conjugates (ADCs), generics, and novel modality medications. PBPK modeling offers two key advantages over conventional drug development methods: it is more cost-effective and less time-consuming. Furthermore, PBPK models can undergo validation, improvement, and testing. These models describe concentration-time (C-T) profiles based on physiological insights into flows, partition coefficients, volumes, and other factors. In addition to allowing simulations in preclinical species and offering many routes of administration, Simcyp has a variety of built-in human populations and predicts the concentration-time profiles of the drug in the various tissue compartments (human and animal) of the PBPK model. Preclinical data, such as gathered from in vitro and in silico methods, as well as compound-specific data, like ADME, are gathered for this modeling to forecast clinical results. To be more precise, the PBPK parameters that Simcyp uses are the compound’s physicochemical characteristics, such as its molecular weight, pKa, and polar surface area; metabolic and excretory data, such as the intrinsic clearance of the kidney and liver; and blood and plasma binding parameters, such as the blood to plasma ratio. In cases where experimental values for PBPK parameters are unavailable, Simcyp can predict them. Parameters like effective permeability, steady-state volume of distribution, and renal clearance can all be forecasted through Simcyp. The Simcyp-R package is used to add automation, and SimRFlow is utilized for high-throughput simulations.
Caroline Ring discussed the ideas of clearance, the incorporation of physiologic population variability, and generic model construction considerations. She also presented the US EPA R Package httk for High-Throughput IVIVE (HT-IVIVE). Dr. Ring used a case study scenario to highlight the httk IVIVE workflow while demonstrating the data and algorithms accessible for this tool. Much like Simcyp, the httk models require certain parameters, the sources of which are integrated within the tool. It’s worth noting that the httk models, along with their associated data and algorithms, are freely accessible through the open-source R package httk.
Using IVIVE case studies, Xiaoqing Chang illustrated possible uses of the Integrated Chemical Environment (ICE) platform, an open-source tool for doing PBPK/IVIVE. Users can use the same PBPK models to convert in vitro activity concentration to in vivo equivalent administered dose and calculate internal chemical concentrations using PBPK models from the US EPA httk R Package. They can also search for structurally similar chemicals and expand information within the ICE workflow. These are but a few of the features that this model offers.
During her presentation, Katie Paul Friedman showcased practical applications illustrating the utilization of HTTK in toxicology. She emphasized the integration of in vitro data for IVIVE evaluations and discussed potential enhancements to the HT-IVIVE approach. The presentation covered various aspects, including sourcing bioactivity data for IVIVE from platforms like ToxCast, computing the BER, accessing animal toxicity data from databases such as ToxRefDB or ToxValDB for IVIVE benchmarking, and refining IVIVE using the HTTK library.
Altogether, these tools follow a similar workflow and rely on simplified assumptions.
This blog reports on the Continuing Education course titled “High-Throughput In Vitro–In Vivo Extrapolation for Predictive Toxicology” that was held during the 2024 SOT Annual Meeting and ToxExpo. All 2024 Continuing Education courses were recorded and are available for virtual viewing through the SOT CEd-Tox online library. SOT Postdocs and Students and individuals from select countries receive free access to all CE courses.
This blog was prepared by an SOT Reporter and represents the views of the author. SOT Reporters are SOT members who volunteer to write about sessions and events in which they participate during the SOT Annual Meeting and ToxExpo. SOT does not propose or endorse any position by posting this article. If you are interested in participating in the SOT Reporter program in the future, please email SOT Headquarters.
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