Dosimetry Translating to equivalent human dose

Physiologically Based Pharmacokinetic (PBPK) Modeling is a predictive tool to estimate how compounds are absorbed, distributed, metabolized, and excreted in a body. PBPK models provide a mechanistic approach to study and predict the disposition of chemicals or drugs based on physiologic and anatomic characteristics, as well as the physical and chemical properties of a given chemical or drug. These models are used in the field of toxicology for the prediction of human and animal exposures to environmental toxin and in the drug industry to help in drug development.   

With PBPK Modeling, we help our clients: 

  • Predict exposure from one species to another: E.g., you have a dose of exposure giving a certain concentration in blood in rats and you would like to estimate the dose of exposure giving the same blood concentration in human.
  • Capture human variability by including in the PBPK model monte Carlo analysis.
  • Estimate a response from varying exposure conditions and across life-stages or vulnerable populations, such as children, the elderly, or those working in specific occupations. In one of our work that was submitted for regulatory purposes, we addressed the concern for age-related sensitivity to pyrethroids with life-stage physiologically based pharmacokinetic (PBPK) modeling supported by in vitro to in vivo extrapolation (IVIVE) to predict age dependent changes in target tissue exposure to pyrethroids.
  • Predict concentration in blood or tissue from dermal exposure using oral exposure data. This is called route-to-route extrapolation.
  • Conduct high-dose to low-dose extrapolation to predict concentration in blood and tissue for exposure at different doses. Most of the time, animal experiments are conducted at high dose to be able to measure effects. PBPK model can extrapolate what will be the concentration in blood or at target organs at lower doses.
  • Estimate population daily exposure intakes that are consistent with blood or urine measures found in biomonitoring surveys (reverse dosimetry).
  • Coupled with pharmacodynamics (PD) models, these PBPK models can predict both dose-response and time-course for the development of adverse effects.
  • Depending on the goal of the project, PBPK modeling can be started with very limited information to prioritize compounds and also be refined with additional data to create a more accurate prediction for a specific compound.

    Why Clients come to ScitoVation to address dosimetry

    • We are pioneers in the field, and we have developed our own PBPK tool, PLETHEM (Population Life-course exposure to health effects model). Because PLETHEM was developed under a memorandum of understanding with the US EPA, and it is open source, submissions to regulatory bodies using it are more likely to be better received if the computations are performed using it.
    • We are a multidisciplinary team working on the development of model that best fit the client needs. With the reduction of animal testing, most of the PBPK model parameters are derived from in vitro testing or in silico tools (metabolism, binding in plasma, partition coefficient). The ability to work with our own laboratory to generate the data needed as input for our models lead to efficiency in delivery to our clients.
    • We developed dozens of PBPK models, some of which are used in regulatory decisions (EPA, ECHA): Clients benefit from our experience in developing these models and interacting with regulators. This experience enables us to give regulators the information they need in a format that they are used to which increases likelihood of approval and decreases time for a decision.
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    Case Study: Investigating Metabolism Impact Of Internal Butylparaben Concentration

    Case Study: The Application Of Benchmark Dose To Toxicogenomic Data,Use Of Computational Approaches To Support Risk Assessment For Pyrethroids For Early Life-Stages