PBPK Modeling

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A PBPK analysis uses models and simulations that combine physiology, population and drug characteristics to mechanistically describe the pharmacokinetic (PK) behavior of a drug. Throughout a drug’s life cycle, PBPK model predictions can be used to support decisions on whether, when and how to conduct certain clinical pharmacology studies and to support dosing recommendations in product labeling.

Use PBPK Modeling for . . . 

  • Early phase development work (bioanalysis, formulation optimization, PK prediction)
  • Dose regimen design and optimization
  • Interspecies scaling/Phase I FIH exposure predictions
  • Population factors (age, ethnicity, gene expression, etc.)
  • Formulation bridging/bioequivalence
  • Prediction of drug-drug interaction 
  • Antibody PBPK to understand target coverage

An Iterative Modeling Process   

As an iterative process, PBPK modeling can be started with very limited information and also be conducted at any point along the drug development continuum. Sometimes the model is used and refined multiple times throughout development. 

For example, a very simple PBPK model for a small molecule can be initiated with only molecule structure information and predicted physical chemical properties. This model can then be used to inform future study design where additional data can be fed back to the model to create a more accurate prediction. The process can be repeated throughout the development process to further refine the model as it moves towards the clinic. 

Once in the clinic, actual human PK data can be used to validate/inform the model so clinical study design can be refined and streamlined.

Regulatory Guidance

While PBPK is not specifically required for a regulatory filing, the FDA has issued the 2018 FDA Guidance on PBPK Modeling Submissions and has strongly suggested including modeling in your data package. In addition, the 2017 EMA guideline for first-in-human (FIH) dosing recommends that estimation of FIH should be based on state-of-the-art modelling (e.g. PK/PD and PBPK) and/or using allometric factors.

PBPK can be used to support drug-drug interaction assessments and, in some cases, has been accepted in lieu of running clinical DDI studies.

Preparation Checklist


  • Fully formatted report and data, ready for regulatory submission 
  • In vitro characterization of small molecule
  • In vitro antibody assays to assess binding potency, occupancy, etc.
  • In vivo PK
  • Clinical PK 

PBPK modeling to support clinical DDI studies

PBPK modeling for optimization of sustained-release orthodontic retainer of Clonidineto

Understanding FDA regulations & applying in vitro & PBPK modeling techniques

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