The Importance of using Kinetically Derived Maximum Dose (KMD)

A graph showing value of KMD

KMD allows for design of in-life experiments that are not confounded by non-linear effects, including saturation of absorption processes. This results in a data package that is more easily interpreted because of its increased relevance to human exposures. 

by Jeff Fisher

For those who design repeated dose, subchronic and chronic animal toxicity studies, this concept may be an additional responsibility for you.  Gone are the ‘good old days’ when study design will consist of discussions about dose spacing, and lower and upper dose selections.  Now a more comprehensive understanding of absorption, distribution, metabolism, and excretion (ADME) is required to speculate about saturation of biological processes that handle a chemical.  If there is sufficient information, speculation should include deviations in dose-proportionality for pharmacodynamics.  The integration of ADME considerations into in-life study design can lead to the selection of a kinetically derived maximum dose (KMD).  As a PBPK modeler who developed and used animal PBPK models to interpret orally administered doses of 1 gram/kg body weight or above, KMD is a long overdue and a welcomed consideration.  The more information is gathered and used to translate administered dose to internal dose, the more robust an animal study becomes.  This can be accomplished without additional animal studies, using a combination of in vitro and in silico tools and microsampling of animals early in the study design, if necessary (not total radioactivity type studies).     

Of course, what is at stake is a dose selection step, the maximum tolerated dose (MTD), which is usually based on expected toxicity.  With KMD the study design phase may be more complicated and requires expertise beyond in vivo toxicity testing.  One compelling reason for the KMD approach is that human exposures to chemicals are generally thought to be lower than the exposures used in in-life testing, requiring both species extrapolations and dose extrapolations.  If a KMD is identified for an animal study and doses are selected that saturate biological processes, then the interpretation of the animal toxicity studies, relative to human health, is further impaired beyond the normal species extrapolation challenges.  

A 2020 workshop organized by The NTP Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM), the U.S. Environmental Protection Agency Office of Pesticide Programs, and the Health and Environmental Sciences Institute (HESI) resulted in a large stakeholder turnout to discuss KMD.   

At this workshop ScitoVation presented pharmacokinetic simulations to highlight the consequences of saturating conditions in animal studies using the software PLETHEM.  Today ScitoVation scientists are involved in case study investigations as part of the PBPK Working Group, a Memorandum of Understanding between Health Education Systems Incorporated (HESI) and Office of Chemical Safety and Pollution Prevention (EPA OPP).  The best practices emerging from this collaboration are being implemented in PLETHEM, providing a freely accessible resource for implementing KMD techniques.  As the National Toxicology Program shifts its emphasis to advance alternatives to animal models and the cutting edge for new technologies, chronic whole animal toxicity testing will be the responsibility of industry to improve study design with the involvement of regulators.