PBPK and IVIVE

ToxStrategies professionals can assist clients with the development, application, and evaluation of high-throughput physiologically-based pharmacokinetic/toxicokinetic (PBPK) models and in vitroin vivo extrapolation (IVIVE) models. PBPK and IVIVE models represent computational methods that can be employed in an efficient manner to better understand and quantify the relationships between external/internal exposures and toxicological responses. Results from these models can be used to facilitate drug discovery, product development, and chemical risk assessment.

High-throughput PBPK models predict the relationship between the internal doses of a substances (e.g. a pharmaceuticals or environmental chemicals) and the external exposure to that substance by accounting for the physiological processes of absorption, distribution, metabolism, and excretion (ADME) using one or two-compartment generalizations. IVIVE models allow in vitro data to be extrapolated to estimate corresponding in vivo effects. Because in vitro methods are often lower-cost and higher-throughput than in vivo methods, IVIVE provides efficient characterization of potential chemical risk.

Applications of high-throughput PBPK and IVIVE modeling constitute a fast-evolving field that is receiving growing interest. These methods also carry some challenges, particularly related to the knowledge needed to organize and interpret large amounts of data and identify and/or develop fit-for-purpose models. ToxStrategies is uniquely suited to assist clients in this area, with extensive experience in the development, application, and evaluation of high-throughput PBPK and IVIVE models. ToxStrategies remains at the forefront of this field through primary research, participation in workshops, professional society conferences, and application of these methods to assist client goals.

Areas of expertise in this field include the following:

 

High-throughput PBPK model development and novel applications

  • Generalized model development, application, and evaluation for multiple chemical parameterization
    • Example: Open-source R package httk containing a framework for high-throughput PK/TK modeling suitable for parameterizing multiple chemicals and species
  • Incorporation of in silico modeling approaches (e.g. QSARs)
  • Incorporation of inter-individual variability
  • Quantification of uncertainty/error/confidence and sensitivity analysis of models
  • Results enable efficient risk characterization by enabling comparisons between external exposure estimates and toxicity/hazard estimates

 

IVIVE model development and novel applications

  • Identification of fit-for-purpose models for specific applications
  • Incorporation of inter-individual variability
  • Quantification of uncertainty/error/confidence and sensitivity analysis of models
  • High-throughput IVIVE of in vitro high-throughput screening (HTS) toxicity data to estimate in vivo equivalent doses
  • IVIVE of in vitro ADME data (e.g. metabolism measured in hepatocytes or liver microsomes; plasma protein binding measured in plasma)

 

Integration of high-throughput PBPK and IVIVE models

  • IVIVE can inform PBPK models: for example, IVIVE of in vitro ADME data can be used to parameterize PBPK models
  • PBPK models can inform IVIVE: for example, reverse PK used in IVIVE of in vitro high-throughput screening (HTS) toxicity data to estimate in vivo equivalent doses
  • PBPK and IVIVE modeling can both incorporate inter-individual physiological variability, which can be used to:
    • Estimate differences in risk for potentially sensitive sub-populations and life stages
    • Estimate range of risk across population(s)
  • Results of PBPK/IVIVE model integration efforts can be used to inform potential adverse drug reactions, metabolism, drug-drug interactions, chemical mechanism of action, dose considerations, response variability, and overall risk.
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