Table 4.

Suggested sections of a PBPK modeling report intended for regulatory submission

Title	Purpose	Audience	Important elements of content
Executive summary (synopsis)	Summary of modeling process Key results and conclusions	All readers	• Objective(s) of the modeling process • High‐level methodology • Key results • Main conclusions • Suggestion: limit to 1‐2 pages
Introduction (background)	Background information to clarify the purpose and the context of the analysis	All readers	• Background information to place the modeling work in the context of the development program • Background information on the modeled drug (e.g, ADME properties)
Objective(s)	Statement of the analysis objective	All readers	Precise objectives that answer important development question(s)
Materials and methods	A detailed documentation of methods used in the modeling process	Technical	See detailed description of the subsections below.
Overview of modeling strategy	An overview to describe the adopted strategy from model building to model application	All readers	• For example, a graphical workflow illustrating the sequence of the modeling steps.
Model assumptions	Description and discussion/justification of the main assumptions in the drug model	Technical	A summary of the main assumptions, such as: • ADME related assumptions, for example, Perfusion limited or permeability limited distribution is needed or assumed; any assumptions on transporters involved; assumptions on the involved metabolizing enzymes and/or percent of enzyme contributions/fraction metabolized, etc. • Population related assumptions, for example, assumed changes in any system‐specific parameters, assumed enzyme ontogeny profiles when scaling to children (especially if the ontogeny profile is not included in the built‐in database)
Modeling parameters	A summary of the main model parameters	Technical	• System‐Specific Parameters • Drug‐Specific Parameters
System‐specific parameters	Description of the system‐specific parameters incorporated in the model	Technical	• Highlight any system‐specific data that were modified/added by the modeler to the software built‐in database • If specialized PBPK modeling software tools are used, list or provide references to the most relevant system‐parameters
Drug specific parameters	Summary of the drug‐specific parameters utilized in the model	Technical	• Table summarizing all drug specific parameters that were utilized in the model such as the drug physicochemical properties, fraction unbound, blood to plasma ratio, intrinsic clearance and metabolic pathways information, permeability, solubility, etc. • If any parameters were optimized/fitted, a description/discussion should be provided
Parameter estimation	An optional subsection devoted to explain and discuss parameter estimation procedures, if applicable	Technical
Drug model structure	Short description of the individual components of the final PBPK model	Technical	• A summary of the sub‐models that constitute the final PBPK model, for example: • Absorption: First order vs. ACAT vs. ADAM • Distribution: minimal vs. full PBPK; method used to calculate tissue partition coefficients • Elimination: method used to represent drug clearance (in vivo measure vs. organ clearance vs. enzyme kinetics)
Pharmacokinetic/clinical data	Description of the clinical data used in model development or evaluation	All readers	If pharmacokinetic/clinical data were used, a summary of the main information regarding the number of clinical studies and brief description of their design, dose route.
Simulation design (conditions)	Description of simulation conditions for the model development, verification) evaluation), and application	All readers	A description of simulation conditions, which usually includes information such as: • Characteristics of the virtual population (defining demographics, diseased or healthy status, adult vs. pediatric vs. geriatric, number of virtual subjects/trials, etc.) • Dosing information (dose, route of administration, formulation, fed/fasting condition) • Simulation duration
Model evaluation and qualification Criteria	A detailed description of how model results will be evaluated with the acceptance criteria.	All readers	A detailed description of how model results will be evaluated with the acceptance criteria and the strategy of model qualification depending on the available observed data. This usually includes one or more elements such as: • Visual predictive checks (VPC) • Comparison of key PK parameters • Numerical metrics
Sensitivity analysis	A component devoted to investigate how changes in the model key input parameters can influence the simulation outputs	Technical
Software tools	List software tools used in the model development and evaluation process with the corresponding version.	All readers	Summary of all software tools used in the model development and evaluation process with the corresponding version(s): • PBPK modeling software • Tools for data evaluation or visualization • Tools for data digitizing, if applicable
Results	Description of the obtained results	Technical/All readers	• Description of the evaluation/qualification results • Description of model application results
Model evaluation/qualification	One or more sub‐sections on the model evaluation/qualification results	All readers	• Graphical and tabular displays • if possible provide Forest plots showing the AUC and Cmax ratios
Model application	One or more subsections on the model application results	All readers	• Graphical and tabular displays
Discussion and conclusion	• Explanation of the relevance of the results • Present main findings • Discuss model limitations	All readers	• Place results in technical and clinical context • Discuss clinical relevance of the analysis • Highlight any model limitations • Present conclusions as a bullet point list
Appendices			• Modeling Analysis Plan, if applicable • Quality Control documentation, if applicable • List of Model Data Files, if applicable