PBPK Modeling

PBPK Modeling: Predicting and Assessing Drug Efficacy, Safety, and Toxicity

We are exposed to a wide range of chemicals from multiple sources including food, textiles, household cleaning products, cosmetics, fragrances, and medicines. Whether animal or cell-based studies are conducted to determine the dosage at which toxicity starts to occur, PBPK models can then be used to predict the equivalent doses for humans that would cause similar effect. The traditional and most common use for PBPK models in risk assessment is to understand how the compound is absorbed, distributed, metabolized and excreted (ADME). Beyond the traditional ADME, using PBPK models, we assist clients in:

  • Intra-species extrapolation: Predicting exposure for vulnerable populations such as children, the elderly or occupational exposure.
  • Route-to-route extrapolation: Predicting concentration in blood or tissue from dermal exposure using oral exposure data.
  • High-to-low dose extrapolation: Using high dosage exposure to predict concentration in blood and tissue for exposure at a lower dose.
  • Population variability assessment: using PBPK modeling and statistical analysis such as Monte Carlo simulations to estimate variability in internal target doses across a population.
  • Human biomonitoring data and epidemiological data: Estimating population daily exposure intakes that are consistent with blood or urine measures found in biomonitoring surveys.

Making PBPK Modeling Accessible for Everyone with PLETHEM

Traditionally, exercising a PBPK model to answer specific questions required technical expertise to run the software supporting the modeling. To address this challenge, ScitoVation developed PLETHEM: PLETHEM (Population Life-course exposure to health effects model)

This interactive modeling platform makes PBPK modeling more accessible to risk assessors and chemical safety practitioners. Advantages to using PLETHEM include its open-source access, the development took place under a memorandum of understanding with US EPA, and submissions are more likely to be accepted. https://scitovation.wpengine.com/plethem/

Pendse, S., Efremenko, A., Hack, C.E., Moreau, M., Mallick, P., Dzierlanga, M., Nicolas, C.I., Yoon, M., Clewell, H.J., and McMullen, P.D. 2020. Population Life-course exposure to health effects model (PLETHEM): An R package for PBPK modeling.

Drug development and research: Proposing an initial dose recommendation for clinical trials.

Regulatory agencies like the FDA provide guidelines on how to predict DDI with in vitro testing and PBPK modeling. ScitoVation provides a validated platform for predictive simulation of enzyme-based or transporter drug-drug interaction (DDI). DDIs happens when two or more drugs interact with each other. These interactions result in different pharmacological responses that can differ from the response of each compound separately. This means that DDIs can have effects on absorption, elimination, and excretion of the compound by decreasing, delaying or enhancing absorption or metabolism of either compound. Our goal is to use DDI to help pharmaceutical companies propose an initial dose recommendation for their clinical trials.

Pyrethroids Case Study

Butlyarabens Case Study