Opportunities and Challenges in Using the Kinetically Derived Maximum Dose Concept to Refine Risk Assessment
September 30, 2020 – 8:00 a.m.-1:30 p.m. EDT
View agenda (updated September 16)
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 is 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 will review the application of the KMD in toxicity testing. They will summarize 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 is organized by NICEATM, the U.S. Environmental Protection Agency Office of Pesticide Programs, and the Health and Environmental Sciences Institute.
Individuals with disabilities who need accommodation to participate in this event should contact Dr. Elizabeth Maull at phone: (984) 287–3157 or email: firstname.lastname@example.org. TTY users should contact the Federal TTY Relay Service at (800) 877–8339. Requests should be made at least five business days in advance of the event.