“All substances are poisons; there is none which is not a poison. The right dose differentiates a poison.” –Paracelsus (AD 1493–1541)
The first step in designing a successful nonclinical toxicity study is the selection of appropriate dose levels. Risk assessment of a drug or chemical involves the use of toxicokinetic data to characterize the exposure through a better understanding of the dose-response relationship. However, there are significant challenges in interpreting these dose-response relationships, and this was addressed in a Symposium Session during Virtual SOT 60th Annual Meeting and ToxExpo titled “Opportunities and Challenges in Utilization of Toxicokinetic Data in Dose-Level Selection for Repeated-Dose Toxicity Studies.”
Dr. Cecilia Tan, scientist at the US Environmental Protection Agency Office of Pesticide Programs, provided an overview of the challenges in incorporating kinetic data to design human-relevant toxicity studies. Toxicokinetics (TK) determines the internal target tissue dose, which is more closely related to the toxic response than the administered dose. The internal dose can become significantly disproportionate to the administered dose upon saturation, leading to nonlinear toxicokinetics, resulting in difficulty in interpretation of the dose-response relationship.
It is important to know the basic concepts in dose-response studies to understand the role toxicokinetics and toxicodynamics play in such studies. This was highlighted by Dr. Hugh Barton, Adjunct Professor at the University of North Carolina. In repeat dosing in linear and nonlinear conditions, there is a significantly higher difference in fold-change with increasing doses in a nonlinear condition compared with a linear condition. This is important to consider during risk assessment to understand the elicited toxic response. Hence, dose selection becomes important. Further, mode of action also is dose dependent and transitions may occur when either or both kinetics or dynamics become nonlinear. These transitions in mode of action can result in effects that require biologically appropriate extrapolation to lower doses when converting animal to human-relevant dose. Dr. Barton explained the numerous factors that need to be considered for a toxicity study design.
Dr. Jeanne Domoradski from Corteva Agriscence, who also was chairing the session, spoke about integrating toxicokinetics in repeated-dose toxicity studies for agrochemicals and how dose levels are selected. She spoke about the scientific drivers, which are the underlying reasons for integrating toxicokinetics in toxicology studies. Apart from these scientific drivers, there also are regulatory drivers to conduct TK studies. Dr. Domoradski highlighted the regulatory documents from the European Union, US Environmental Protection Agency, and Organisation for Economic Co-operation and Development (OECD), which provide recommendations on how to use dose level selection and avoid nonlinear toxicokinetics to select the highest dose that is not above the dose that results in saturation of absorption and clearance. Basically, this helps in selecting the Kinetically Derived Maximum Dose (KMD), which is more relevant. Modern pesticide toxicology programs are using the KMD approach for a clear understanding of measured or predicted exposures for use in human health risk assessments.
It is important to know how regulatory agencies scrutinize applications for methods and data when clinical doses are proposed based on nonclinical studies. Dr. Jessica Hawes, Deputy Director, Division of Systems Biology at the US Food and Drug Administration, highlighted the role that nonlinear kinetics play during review of drug applications. She explained how the minimal anticipated biological effect level (MABEL) dose can be selected from in vitro pharmacology data and integrated into PK/PD models to predict pharmacological response in humans. Although the toxicological endpoint of no-observed-adverse-effect levels (NOAEL) is the gold standard for selecting the dose in first-in-human (FIH) studies, pharmacology endpoints like MABEL and pharmacologically active dose (PAD) also can be used when there are no relevant nonclinical species or when the NOAEL cannot be identified. It also is critical to provide justifications when safety factors are used when converting data from animals to humans. Dr. Hawes also explained how starting dose is selected for FIH oncology trials. The final section of her presentation covered how dose exposure response curves can inform dosing regimen considerations in early-phase clinical trials.
The previous speakers explained how to avoid nonlinear kinetics in dose selection, and in contrast, Dr. James Bus, scientist at Exponent Inc., provided case studies considering the use of nonlinear kinetics in dose selection and its value in interpretation of animal toxicity studies. Case studies pertaining to 2,4-Dichlorophenoxyacetic acid (2,4-D) and ethylbenzene were presented. Animal toxicokinetic data were compared with human biomonitoring data of 2,4-D. Toxicities in experimental animals observed at doses exceeding a KMD are not quantitatively relevant to human exposures. Dr. Bus demonstrated how the KMD dose from in vivo studies was successfully used to derive the top dose in an in vitro endocrine disruption screening program.
Dr. Catherine Adcock, Section Head, Toxicology, at Health Canada, provided the Canadian regulatory perspectives on consideration of toxicokinetic data in dose selection for toxicity studies. The audience learned about the three different regulatory branches of Health Canada, which deal with therapeutic products, consumer products, and pesticides. All three branches conduct health hazard assessments and require studies conducted per international guidelines like ICH and OECD. Dr. Adcock explained the types of data requirements for pre- and post-market reviews. Health Canada considers studies that are conducted based on the maximum tolerated dose (MTD) and/or KMD. Dose selection should not rely solely on toxicokinetic data, but also on mode of action, and the intended use of a product also should be considered. Dr. Adcock provided couple of case studies wherein toxicokinetic data for pesticides were submitted by two applicants—one applicant did not use the KMD approach in dose selection and the other applied the KMD approach—and how Health Canada reviewed the applications.
To summarize this session, toxicokinetics should be considered in selecting doses for a toxicity study while accounting for nonlinearity and appropriate use of the KMD approach, which can provide a more meaningful dose-response relationship and relevant extrapolation to humans.
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 Giuliana Macaluso.
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