Opportunities and Challenges in Using the Kinetically Derived Maximum Dose Concept to Refine Risk Assessment
September 30, 2020
Two publications developed following this symposium are now available in Regulatory Toxicology and Pharmacology:
- Lowe et al. 2021. Incorporating human exposure information in a weight of evidence approach to inform design of repeated dose animal studies. https://doi.org/10.1016/j.yrtph.2021.105073.
- Tan et al. 2021. Opportunities and challenges related to saturation of toxicokinetic processes: Implications for risk assessment. https://doi.org/10.1016/j.yrtph.2021.105070.
Questions and Answers for specific participants are linked below with the speakers' slides
Welcome and Introductions
Nicole Kleinstreuer, Ph.D., NICEATM
Use and Evaluation of KMD Data at USEPA's Office of Pesticide Programs
Anna Lowit, Ph.D., EPA
Problem Formulation: Background, Motivation, and Expected Outcomes
Michelle Embry, Ph.D., Health and Environmental Sciences Institute
Maximum Tolerated Dose: Concepts and Background
Chad Blystone, Ph.D., DABT, NTP
Concepts of Non-linear Pharmacokinetics and KMD
Alan Boobis, Ph.D., Imperial College London
Implications of Non-linear PK in Toxicity Testing and Interpretation of Dose-response Data
Salil Pendse, Nuventra, Inc.
Determining an Inflection Point from External-internal Dose Data
Philip Villanueva, EPA
Dose Setting and Considerations for the 3Rs
Fiona Sewell, Ph.D., National Centre for the Replacement Refinement & Reduction of Animals in Research
Integration of TK into Toxicity Studies and Dose Level Setting
Jean Domoradzki, Ph.D., DABT, Corteva Agriscience
Integrating KMD/TK Data with MoA and Other Information in a Weight of Evidence Approach
Harvey Clewell, Ph.D., Ramboll
Cecelia Tan, Ph.D., EPA
Q&A and Additional Discussion
Moderator: Michelle Embry, Ph.D., Health and Environmental Sciences Institute
The kinetically derived maximum dose (KMD) refers to the dose at which a departure from dose proportionality or linear pharmacokinetics (PK) is observed. Non-linear PK can be caused by saturation or limitation of various factors related to absorption, distribution, metabolism, and excretion (ADME). In preclinical studies on new drugs conducted in animals, the KMD is routinely considered to provide perspective on the relevance of these studies to human safety assessment. Specifically, toxicity findings at doses above a KMD may not be relevant to human health risks when potential exposure levels are orders of magnitude lower.
In contrast to its routine use in pharmaceutical development, consideration of the KMD in the design or interpretation of animal toxicity studies for environmental chemicals is rare. Interest is growing in use of the KMD to interpret animal dose-response data or set top dose in chronic toxicity studies of these chemicals, but many technical and scientific issues hinder its proper use. The purpose of this symposium was to highlight these commonly raised issues and provide the background information needed to develop more consistent, transparent approaches to support broader KMD application in risk assessment.
The presentations in this symposium reviewed the application of the KMD in toxicity testing. They summarized commonly raised technical and scientific issues related to the use of KMD as an approach to select doses in toxicology testing studies or to interpret dose-response study results. Examples of these issues include:
- Appropriate use of PK data to determine dose non-linearity.
- The possibility of human exposure levels close to KMD.
- Determination of KMD from sparse blood or tissue concentration data.
- Use of in silico models to predict systemic dose and key ADME parameters.
- Use of KMD to set the top dose in toxicity studies.
The symposium was organized by NICEATM, the U.S. Environmental Protection Agency Office of Pesticide Programs, and the Health and Environmental Sciences Institute.