Physiologically Based 
Pharmacokinetic 
Analyses  Format and 
Content  
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
August 2018 
Clinical Pharmacology 
 
Physiologically Based Pharmacokinetic Analyses  Format and Content 
09/03/18   
Physiologically Based 
Pharmacokinetic 
Analyses  Format and 
Content  
Guidance for Industry 
 
 
Additional copies are available from: 
Office of Communications, Division of Drug Information  
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
Silver Spring, MD 20993-0002  
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 
Email: druginfo@fda.hhs.gov  
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
August 2018 
Clinical Pharmacology 
 
Physiologically Based Pharmacokinetic Analyses  Format and Content 
09/03/18  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION ...................................................................................................... 1 
II.  BACKGROUND ........................................................................................................ 1 
III.  FORMAT AND CONTENT....................................................................................... 2 
A.  Executive Summary ...................................................................................................... 2 
B.  Introduction ................................................................................................................. 2 
C.  Materials and Methods.................................................................................................. 2 
1. Overview of Modeling Strategy ......................................................................................... 2 
2. Modeling Parameters ...................................................................................................... 3 
3. Simulation Design .......................................................................................................... 3 
4. Electronic Files and Other Documentation ......................................................................... 3 
5. Software........................................................................................................................ 4 
D.    Results ......................................................................................................................... 5 
1. Model Verification and Modification ................................................................................. 5 
2. Model Application .......................................................................................................... 5 
E.    Discussion .................................................................................................................... 5 
F.    Appendices ................................................................................................................... 6 
1. List of Tables ................................................................................................................. 6 
2. List of Figures................................................................................................................ 6 
3. Table of Acronyms and Abbreviations................................................................................ 6 
4. References ..................................................................................................................... 6 
Physiologically Based Pharmacokinetic Analyses  Format and Content 
09/03/18  Contains Nonbinding Recommendations 
 
Physiologically  Based Pharmacokinetic  Analyses   
Format and Content 
Guidance for Industry1 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You 
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the 
title page.   
 
 
 
 
I.  INTRODUCTION  
 
This guidance outlines  the recommended format and content for a sponsor or applicant to submit 
physiologically  based pharmacokinetic  (PBPK) analyses to the FDA to support applications 
 
including,  but not limited  to, investigational  new drug applications  (INDs), new drug 
applications  (NDAs), biologics  license applications  (BLAs), or abbreviated new drug 
applications  (ANDAs).  To enable efficient and consistent review, the FDA recommends 
including  the following  six sections in a PBPK study report: (A) Executive Summary; (B) 
Introduction;  (C) Materials and Methods; (D) Results; (E) Discussion; and (F) Appendices.  The 
content of each section is described in detail below.  This guidance does not address 
methodological  considerations and best practices for the conduct of PBPK modeling and 
simulation  or the appropriateness of PBPK analyses for a particular drug or a drug product.  The 
decision to accept results from PBPK analyses in lieu of clinical  pharmacokinetic (PK) data is 
made on a case-by-case basis, considering  the intended uses, as well as the quality,  relevance, 
and reliability  of the results from the PBPK analyses.    
 
In general, FDAs guidance documents do not establish legally  enforceable responsibilities.   
Instead, guidances describe the Agencys current thinking  on a topic and should be viewed only 
as recommendations,  unless specific regulatory or statutory requirements are cited.  The use of 
the word should in Agency guidances means that something  is suggested or recommended, but 
not required.  
 
 
II.  BACKGROUND 
 
A PBPK analysis uses models and simulations  that combine physiology,  population,  and drug 
characteristics to mechanistically  describe the PK and/or pharmacodynamic (PD) behaviors of a 
drug.  Throughout a drugs life cycle, PBPK model predictions  can be used to support decisions 
                                              
1 This guidance has been prepared by the Office of Clinical Pharmacology, Office of Translational Sciences, in the 
Center for Drug Evaluation and Research at the Food and Drug Administration. 
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on whether, when, and how to conduct certain clinical  pharmacology studies, and to support 
dosing recommendations in product labeling.   Because of the lack of regulatory guidance, the 
format and content of PBPK analysis reports that are submitted to the FDA vary significantly.   
The goal of this guidance is to standardize the content and format of these reports to facilitate the 
FDAs efficient assessment, consistent application,  and timely decision making during regulatory 
review.    
 
 
III.  FORMAT AND CONTENT 
 
The FDA suggests including  the following  sections in the PBPK study report for all PBPK 
analyses. 
 
A.  Executive Summary 
 
The executive summary should include the objectives and rationale for conducting the PBPK 
analyses, provide a succinct overview of model development and simulation  scenarios, and 
summarize the key conclusions  of the report.  This section should clearly convey how the 
analyses address a specific scientific question in a clinical  setting in support of a regulatory 
decision. 
 
B.  Introduction 
 
This section should provide the following  components, if available:   (1) a high-level  synopsis of 
the drugs physicochemical,  PK, and PD properties; (2) the exposure-response relationships  for 
the efficacy and safety of the drug to the extent that they are known; (3) a brief PBPK-related 
regulatory history (i.e., prior interactions with the FDA and other regulatory agencies) to provide 
context for the PBPK analyses; (4) cross-referencing to PBPK study reports previously  submitted 
to the FDA for different intended uses at different stages of the development of the same drug 
substance or the same drug product. 
 
C.  Materials and Methods 
 
This section should include sufficient information  to allow FDA reviewers to duplicate and 
evaluate the submitted modeling  and simulation  results and to conduct supplemental analyses 
when necessary. Suggested components of the materials and methods section include the 
following: 
 
1.  Overview of Modeling Strategy 
 
This section should detail the modeling  procedures, including  model development,  model 
verification/modification,  and model application.   The procedures should be outlined  in a step-
wise manner using a workflow, decision-tree, table, or other representation.  The sponsor should 
appropriately  reference the data and studies used in each step of the modeling  process.    
 
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2.  Modeling Parameters 
 
All system-specific and drug-specific components, as well as the sources of parameter values, 
should be clearly specified and justified (e.g., appropriate references).  If there are several 
sources of one parameter, the selection should be described.  If a parameter value has been 
estimated, the data source and estimation method should be described or appropriately 
referenced.  The use of clinical PK data to optimize  model parameters should be described and 
justified.  Key model assumptions that may impact the model application,  including  biological 
and/or pharmacological  rationales, patient/disease-related assumptions,  or mathematical 
representations of the biological  system, should be clearly stated.  The sponsor should present the 
modeling  parameters using a table or other visual representation.  For example, drug-dependent 
parameters for the investigational  drug of interest, including  names, values, units, and sources of 
the parameters, prediction  algorithms,  and assumptions should be summarized in table format.  
Procedures for assessing uncertainty (e.g., using sensitivity  analysis) of the PBPK model 
parameters should be provided.    
 
When library drug and system models (e.g., a virtual population)  within a specific software 
platform are used, the sponsor should justify the use of these models and clearly identify  and 
justify modifications  made to the library models. 
 
3.  Simulation Design 
 
The description of simulation  conditions  should include the following  information  for the model 
development,  verification,  and application: 
 
  Route, dose, formulation  of the drug product (either substrate or modulator),  time of 
administration,  and fasting or fed conditions 
 
  Dosing regimen of the drug product 
 
  Duration of the simulated trials  
 
  Demographics of the virtual population and distribution  of demographic information 
 
  Number of simulation  studies for a specific scenario (simulated trials)  
 
  Number of virtual subjects in each simulated trial 
 
  Settings for differential  equation integrators, when applicable 
 
4.  Electronic Files and Other Documentation 
 
Submitting  electronic files streamlines the review process and allows for effective 
communication  between the FDA and the sponsor.  Examples of permissible file types can be 
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found in the Specifications for File Format Types Using eCTD Specifications document.2  This 
includes permissible  file types/extensions and the modules in which they are permissible.  In 
addition,  the Technical Rejection Criteria for Study Data document denotes what modules study 
data validation rules will not be applicable.3 
 
Electronic files related to modeling  software and simulations  should be submitted along with the 
PBPK study report.  Supporting  information  such as clinical  PK or PK/PD data used in PBPK 
analyses, a scientific publication,  or an orientation document for submitted simulation  data and 
model files can also be included.  Cross-references to other parts of the report and other parts of 
the application  should be provided with hyperlinks  or locations of the modules of an IND, NDA, 
BLA, or ANDA submission,  if applicable.  If necessary, consult the FDA regarding the 
feasibility  of submitting  certain types of electronic files.  
 
5.  Software 
 
The FDA does not recommend the use of any particular software for PBPK modeling.  As PBPK 
models are highly  complex in nature, sponsors anticipating  the application  of PBPK modeling in 
their drug development  program should communicate early with the FDA.  Additional  technical 
and instructional  information  beyond the minimum  data listed below may be needed to ensure 
that the FDA has sufficient working knowledge of the specific PBPK model and software to 
facilitate a timely review.      
 
The following  information  should be included  in the submission  to facilitate a timely review:  
 
  Name and version of the software4 
 
  Schematic view of the model structure and mathematical equations (or relevant 
references) based on established theoretical or biological  knowledge 
 
  Parameterization of system information  and sources of parameter values, such as 
databases used to describe the population  variability  and correlation between parameters 
 
  Users manual (i.e., instructions on how to run the code) 
 
                                              
2 The Specifications for File Format Types Using eCTD Specifications can be found at: 
https://www.fda.gov/downloads/drugs/developmentapprovalprocess/formssubmissionrequirements/electronicsubmis
sions/ucm347471.pdf 
 
3 The Technical Rejection Criteria for Study Data can be found at: 
https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSu
bmissions/UCM523539.pdf 
 
4 The sponsor should provide sufficient documentation regarding any changes made by the software vendor to the 
version of the software over the period of PBPK model development and describe how these changes may impact 
the performance of the submitted model. 
 
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D.    Results  
 
The sponsor should both demonstrate that the PBPK model is appropriate for the intended uses 
and describe the results of model application.   Descriptive statistics or other appropriate analysis 
on the results of model-generated simulations  should be presented, and when applicable, 
compared to observed data.  In addition,  a summary of supplementary materials should be 
included.  Often, supplementary tables and figures are needed to facilitate the assessment of a 
PBPK analysis.  Details on suggested components of model verification  and model application 
are provided below. 
 
1.  Model Verification and Modification  
 
This section of the report should provide sufficient information  to clearly demonstrate that the 
proposed PBPK model is appropriate for the modeling  purpose or question asked for the 
particular drug product and study population  and is robust enough to respond to perturbations in 
uncertain parameters. To allow the FDA to evaluate the robustness of the models, the sponsor 
should clearly present results from the methods used to verify the model, confirm model results, 
and conduct sensitivity  analyses.  The sponsor should include and discuss the procedures used 
for model verification  (both the drug and system models).  Results of sensitivity  analyses for 
uncertain parameters should be discussed in the context of the simulation  conditions  and 
potential clinical  relevance.    
 
In some instances, model parameters may be refined during model verification.  Such 
modifications  are important aspects of model refinement and should be described and justified.   
If the assumptions of the model parameters cannot be confirmed during modification,  further 
verification  to predict clinical  scenarios that were not previously  evaluated should also be 
submitted.   
 
2.  Model Application 
 
The sponsor should present the results of using the verified PBPK model to address the study 
question using tables, graphs, and text where appropriate. 
 
E.    Discussion 
 
In this section, the sponsor should discuss how the PBPK modeling and simulation  analyses 
adequately address the proposed scientific,  regulatory, or clinical  questions. The basis for any 
requests to waive the conduct of clinical  studies should be discussed and well substantiated.  If 
simulations  are used to support specific dosing recommendations to be tested in future clinical 
trials or to be incorporated in prescription  drug labeling,  the proposed dosing recommendations 
should be discussed and justified  within the totality  of evidence, including  the context of known 
exposure-response relationships  and the level of confidence in the PBPK model for its intended 
uses.  See the FDAs guidance for industry entitled Clinical Pharmacology Section of Labeling 
for Human Prescription Drug and Biological Products  Format and Content for more details 
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on specific language to include in the labeling.5  The sponsor should also note the limitations  of 
its modeling  approach in this section of the report and assess the potential impact of these 
limitations  on the PBPK study results and interpretation. 
 
F.    Appendices 
 
The following  information  should be included  in the appendices. 
 
1.  List of Tables 
 
Provide a list of all tables used throughout the document. 
 
2.  List of Figures 
 
Provide a list of all figures used throughout the document. 
 
3.  Table of Acronyms and Abbreviations 
 
Spell out all acronyms and abbreviations used in the document. 
 
4.  References 
 
Include a list of all references. 
 
  
                                              
5 We update guidances periodically.  For the most recent version of a guidance, check the FDA guidance web page 
at https://www.fda.gov/RegulatoryInformation/Guidances/default.htm. 
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