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Physiologically Based Pharmacokinetic Analyses — Format and Content

Physiologically Based

Pharmacokinetic

Analyses — Format and

Content Guidance for Industry

DRAFT GUIDANCE

This guidance document is being distributed for comment purposes only.

Comments and suggestions regarding this draft document should be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit electronic comments to http://www.regulations.gov. Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1601, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register.

For questions regarding this draft document contact (CDER) Office of Clinical Pharmacology, at 301-796-5008 or This e-mail address is being protected from spambots. You need JavaScript enabled to view it .

U.S. Department of Health and Human Services Food and Drug Administration
Center for Drug Evaluation and Research (CDER)

December 2016 Clinical Pharmacology

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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 th 10001 New Hampshire Ave., Hillandale Bldg., 4

Floor

Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353
Email: This e-mail address is being protected from spambots. You need JavaScript enabled to view it
http://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)

December 2016 Clinical Pharmacology

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I. II. III.

A. B. C.

D.

E. F.

IV.

1. 2. 3. 4. 5.

1. 2.

1. 2. 3. 4.

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TABLE OF CONTENTS

INTRODUCTION............................................................................................................. 1 BACKGROUND ............................................................................................................... 1 FORMAT AND CONTENT ............................................................................................ 2 Executive Summary ....................................................................................................................... 2 Introduction.................................................................................................................................... 2 Materials and Methods.................................................................................................................. 2

Overview of Modeling Strategy ....................................................................................................... 2 Modeling Parameters....................................................................................................................... 3 Simulation Design............................................................................................................................3 Electronic Files and Other Documentation ..................................................................................... 3 Software...........................................................................................................................................4 Results ............................................................................................................................................. 4

Model Verification and Modification............................................................................................... 4 Model Application............................................................................................................................ 5 Discussion ....................................................................................................................................... 5

Appendices...................................................................................................................................... 5

List of Tables.................................................................................................................................... 6 List of Figures..................................................................................................................................6 Table of Acronyms and Abbreviations.............................................................................................6 References........................................................................................................................................6 REFERENCES.................................................................................................................. 6

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  1. 1 Physiologically Based Pharmacokinetic Analyses —

  2. 2 Format and Content 1

34 Guidance for Industry

5 6 7 8 9

10 11

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I. INTRODUCTION 16

  1. 17  This guidance outlines the recommended format and content for a sponsor to submit

  2. 18  physiologically based pharmacokinetic (PBPK) analyses to the FDA to support applications

  3. 19  including investigational new drug (INDs) applications, new drug applications (NDAs),

  4. 20  biologics license applications (BLAs), or abbreviated new drug applications (ANDAs). To

  5. 21  enable efficient and consistent review, the FDA recommends including the following five

  6. 22  sections in a PBPK study report: (1) Executive Summary; (2) Materials and Methods; (3)

  7. 23  Results; (4) Discussion; and (5) Appendices. The content of each section is described in detail

  8. 24  below. This guidance does not address methodological considerations and best practices for the

  9. 25  conduct of PBPK modeling and simulation, or the appropriateness of PBPK analyses for a

  10. 26  particular drug or a drug product (i.e., both small molecules and biologics). The decision to

  11. 27  accept results from PBPK analyses in lieu of clinical pharmacokinetic (PK) data is made on a

  12. 28  case-by-case basis, taking into account the intended use for the analyses, as well as the quality,

  13. 29  relevance, and reliability of the study results.

30

  1. 31  In general, FDA’s guidance documents do not establish legally enforceable responsibilities.

  2. 32  Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only

  3. 33  as recommendations, unless specific regulatory or statutory requirements are cited. The use of

  4. 34  the word should in Agency guidances means that something is suggested or recommended, but

  5. 35  not required.

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II. BACKGROUND 39

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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This draft guidance, when finalized, will represent 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 staff responsible for this guidance as listed on the title page.

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  1. 40  A PBPK analysis uses models and simulations that combine physiology, population, and drug

  2. 41  characteristics to mechanistically describe the PK and/or pharmacodynamic (PD) behaviors of a

  3. 42  drug (Rowland, Peck, et al. 2011; Rostami-Hodjegan 2012). Throughout a drug’s life cycle,

  4. 43  PBPK model predictions can be used to support decisions on whether, when, and how to conduct

  5. 44  certain clinical pharmacology studies, and to support dosing recommendations in product

  6. 45  labeling (Zhao, Zhang, et al. 2011; Jones, Chen, et al. 2015; Shepard, Scott, et al. 2015; Wagner,

  7. 46  Zhao, et al. 2015). Because of the lack of regulatory guidance, the format and content of PBPK

  8. 47  analyses that are submitted to the FDA vary significantly across drug developers. Therefore,

  9. 48  standardizing the content and format of PBPK study reports that are submitted to the FDA can

  10. 49  facilitate FDA’s efficient assessment, consistent application, and timely decision making during

  11. 50  regulatory review and is the goal of this guidance.

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III. FORMAT AND CONTENT 54

  1. 55  PBPK analyses may be appropriate at multiple points in the drug development process, for

  2. 56  example in IND applications, NDAs, BLAs, ANDAs, or in the postmarketing stage. The depth

  3. 57  and breadth of PBPK analyses at each stage may vary significantly because of the availability or

  4. 58  quality of clinical data. The FDA, however, suggests including the following sections in the

  5. 59  PBPK study report for all PBPK analyses.

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61
A. Executive Summary 62

  1. 63  The executive summary should include the rationale for conducting the PBPK analyses, provide

  2. 64  a succinct overview of model development and simulation scenarios, and summarize the key

  3. 65  conclusions of the report. This section should clearly convey how the analyses address a specific

  4. 66  scientific question in a clinical setting in support of a regulatory decision.

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B. Introduction 69

  1. 70  The section should provide (1) a high-level synopsis of the drug’s PK and PD properties; (2) the

  2. 71  exposure-response relationships for the efficacy and safety of the drug; and (3) a brief regulatory

  3. 72  history to provide context for the PBPK analyses.

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C. Materials and Methods 75

  1. 76  This section should include sufficient information to allow the FDA reviewers to evaluate the

  2. 77  submitted modeling and simulation results and to conduct supplemental analyses when

  3. 78  necessary. Sharing this information streamlines the review process, and enables further analyses

  4. 79  (Zhao, Rowland, et al. 2012). Suggested components of the materials and methods section

  5. 80  include the following:

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1. Overview of Modeling Strategy 83

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  1. 84  This section should detail the modeling procedures, including the model development, model

  2. 85  verification/modification, and model application. The procedures should be outlined in a step-

  3. 86  wise manner using a workflow, decision-tree, table, or other representation. The sponsor should

  4. 87  appropriately reference the data and studies used in each step of the modeling process.

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2. Modeling Parameters 90

  1. 91  All system and drug-specific components, as well as the sources of parameter values, should be

  2. 92  clearly specified. If a parameter value has been estimated, the data source and estimation

  3. 93  method should be described. When clinical PK data are used to optimize model parameters,

  4. 94  justification for selecting a particular optimization technique should be documented. All model

  5. 95  assumptions, including the biological and/or pharmacological rationale for the assumptions,

  6. 96  should be clearly stated (Zhao, Rowland, et al. 2012).2 The sponsor should present the modeling

  7. 97  parameters using a table or other visual representation.

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3. Simulation Design

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  1. 101  The description of simulation conditions should include the following information for the model

  2. 102  development, verification, and application:

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116

  1. 117  Submitting electronic files streamlines the review process and allows for effective

  2. 118  communication between the FDA and the sponsor or the applicant. Electronic files related to

  3. 119  modeling software and simulations should be submitted along with the study report. Supporting

  4. 120  information such as clinical pharmacokinetic or pharmacokintetic/pharmacodynamic data used in

  5. 121  PBPK analyses or a scientific publication or an orientation document for submitted simulation

  6. 122  data and model files can also be included. Cross-references to other parts of the report and other

  7. 123  parts of the application should be provided with hyperlinks. If necessary, consult the FDA

  8. 124  regarding the feasibility of submitting certain types of electronic files.

    2 International Programme on Chemical Safety,“Characterization and Application of Physiologically Based Pharmacokinetic Models in Risk Assessment” available at http://www.who.int/ipcs/methods/harmonization/areas/pbpk_models.pdf.

Route, dose, formulation of the drug product, time of administration, and fasting or fed conditions

Simulation duration
Demographics of the virtual population
Number of simulation studies for a specific scenario (simulation trials) Number of virtual subjects in each simulation trial
4. Electronic Files and Other Documentation

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5. Software 127

  1. 128  The FDA does not require the use of a particular PBPK modeling software. Because of

  2. 129  substantive differences in software models and versions, sponsors should include information on

  3. 130  the PBPK modeling software. Table 1 below highlights the information that should be included

  4. 131  regarding commercial PBPK modeling software (commercial PBPK platform) versus custom

  5. 132  modeling software (e.g., commercial software that has been modified with custom codes or

  6. 133  otherwise revised for the purpose of PBPK modeling).

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Table 1. Software Information for PBPK Modeling

Suggested Software Information

PBPK Models

Custom Modeling Software

Commercial PBPK Platform

Name and version of the software

Yes

Yes

Schematic view of model structure and differential equations based on established theoretical or biological basis

Yes

Optional

Parameterization of system information and sources of parameter values

Yes

Optional

Table of drug-dependent parameters for the investigational drug of interest, including names, values, units, and sources of the parameters, prediction algorithms, and assumptions being made

Yes

Yes

Literature references and the sponsor’s prior experience/knowledge in using the software for PBPK modeling (to help the reviewer understand how PBPK models are coded using the modeling software that was tested)

Yes

Yes

Manuals on model implementation of the software (to be provided as supporting documents)

Yes

Optional

Library system models (e.g., virtual population), including justifications for any modifications made to the model’s physiological parameters by the sponsor

Not applicable

Yes

Library drug models, including justifications for any modifications to the model made by the sponsor and information on model verification

Not applicable

Yes

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D. Results 138

  1. 139  The sponsor should both demonstrate that the PBPK model is relevant and appropriate for

  2. 140  subsequent analyses and describe the results of model application. Details on suggested

  3. 141  components of model verification and model application are provided below.

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1. Model Verification and Modification 144

  1. 145  The sponsor should clearly present the methodological approach used to verify the model,

  2. 146  confirm model results, and conduct sensitivity analyses to allow the FDA to evaluate the

  3. 147  robustness of the model. The methods best suited for model verification are dependent upon the

  4. 148  availability of clinical data to independently either confirm or reject the proposed model.

  5. 149  Clinical PK data (e.g., steady-state plasma PK data or certain drug-drug interaction data) are

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  1. 150  generally expected to establish confidence in the appropriateness of the PBPK model in

  2. 151  addressing the study question (Vieira, Kim, et al. 2014, Wagner, Pan, et al. 2015, Wagner, Pan,

  3. 152  et al. 2016).

153

  1. 154  Sensitivity analyses are important components of model verification, especially for uncertain

  2. 155  parameters with a high potential to influence the outcome of the simulation. For example, if a

  3. 156  PBPK model is used to predict the inhibition effect of an investigational drug on the exposure of

  4. 157  a cytochrome P450 substrate, sensitivity analyses—such as simulations that test a plausible range

  5. 158  of inhibition potency (e.g., a reversible inhibition constant Ki)—would be informative. Results

  6. 159  of sensitivity analyses for uncertain parameters should be discussed in the context of the

  7. 160  simulation conditions and potential clinical consequences.

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  1. 162  In some instances, model parameters can be refined during model verification. Such

  2. 163  modifications are important aspects of model refinement and should be described. If the

  3. 164  assumption of the model parameters cannot be confirmed during modification, further

  4. 165  verification may be needed before the model can be applied to predict untested clinical

  5. 166  situations. The ultimate goal of PBPK analyses is to obtain the most accurate model that can

  6. 167  predict unknown situations with confidence. The sponsor should clearly demonstrate that the

  7. 168  proposed PBPK model is relevant to the study population and to the modeling purpose/question

  8. 169  asked, appropriate for the drug under investigation, and robust enough to handle perturbations in

  9. 170  uncertain study parameters.

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2. Model Application 173

  1. 174  The sponsor should present the results of using the verified PBPK model to address the study

  2. 175  question using tables, graphs, and text where appropriate. The best data representation is

  3. 176  dependent upon the study question, PBPK model, and other relevant parameters.

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E. Discussion 179

  1. 180  In this section, the sponsor should discuss how the PBPK modeling and simulation analyses

  2. 181  adequately address the proposed scientific, regulatory, or clinical questions. The basis for any

  3. 182  requests to waive the conduct of clinical studies should be discussed and well substantiated. If

  4. 183  simulations are used to support specific dosing recommendations to be tested in future clinical

  5. 184  trials or to be included in prescription product labeling, the proposed dosing recommendations

  6. 185  should be discussed within the context of known exposure-response relationships and the level of

  7. 186  confidence in the PBPK model for the intended application (Wagner, Zhao, et al. 2015). The

  8. 187  sponsor should also note the limitations of its modeling approach and assess the potential impact

  9. 188  of these limitations on the study results and interpretation.

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F. Appendices
191
192 The following information should be included in the appendices. 193

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194 1. List of Tables
195
196 Provide a list of all tables used throughout the document.
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2. List of Figures
199
200 Provide a list of all figures used throughout the document.
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3. Table of Acronyms and Abbreviations
203
204 Spell out all acronyms and abbreviations used in the document. 205
206
4. References
207
208 Include a list of all references.
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IV . REFERENCES
212

  1. 213  Jones, HM, Y Chen, C Gibson, T Heimbach, N Parrott, SA Peters, J Snoeys, VV Upreti, M

  2. 214  Zheng, and SD Hall, 2015, Physiologically Based Pharmacokinetic Modeling in Drug Discovery

  3. 215  and Development: A Pharmaceutical Industry Perspective, Clin Pharmacol Ther, 97(3):247-262.

216

  1. 217  Rostami-Hodjegan, A, 2012, Physiologically Based Pharmacokinetics Joined With In Vitro-In

  2. 218  Vivo Extrapolation of ADME: A Marriage Under the Arch of Systems Pharmacology, Clin

  3. 219  Pharmacol Ther, 92(1):50-61.

220

  1. 221  Rowland, M, C Peck and G Tucker, 2011, Physiologically Based Pharmacokinetics in Drug

  2. 222  Development and Regulatory Science, Annu Rev Pharmacol Toxicol, 51:45-73.

223

  1. 224  Shepard, T, G Scott, S Cole, A Nordmark, and F Bouzom, 2015, Physiologically Based Models

  2. 225  in Regulatory Submissions: Output From the ABPI/MHRA Forum on Physiologically Based

  3. 226  Modeling and Simulation, CPT Pharmacometrics Syst Pharmacol, 4(4):221-225.

227

  1. 228  Vieira, MD, MJ Kim, S Apparaju, V Sinha, I Zineh, SM Huang, and P Zhao, 2014, PBPK Model

  2. 229  Describes the Effects of Comedication and Genetic Polymorphism on Systemic Exposure of

  3. 230  Drugs That Undergo Multiple Clearance Pathways, Clin Pharmacol Ther, 95(5):550-557.

231

  1. 232  Wagner, C, Y Pan, V Hsu, JA Grillo, L Zhang, KS Reynolds, V Sinha, and P Zhao, 2015,

  2. 233  Predicting the Effect of Cytochrome P450 Inhibitors on Substrate Drugs: Analysis of

  3. 234  Physiologically Based Pharmacokinetic Modeling Submissions to the US Food and Drug

  4. 235  Administration, Clin Pharmacokinet, 54(1):117-127.

236

  1. 237  Wagner, C, Y Pan, V Hsu, V Sinha, and P Zhao, 2016, Predicting the Effect of CYP3A Inducers

  2. 238  on the Pharmacokinetics of Substrate Drugs Using Physiologically Based Pharmacokinetic

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  1. 239  (PBPK) Modeling: An Analysis of PBPK Submissions to the US FDA, Clin Pharmacokinet,

  2. 240  55(4):475-483.

241

  1. 242  Wagner, C, P Zhao, Y Pan, V Hsu, J Grillo, SM Huang, and V Sinha, 2015, Application of

  2. 243  Physiologically Based Pharmacokinetic (PBPK) Modeling to Support Dose Selection: Report of

  3. 244  an FDA Public Workshop on PBPK, CPT Pharmacometrics Syst Pharmacol, 4(4):226-230.

245

  1. 246  Zhao, P, M Rowland, and SM Huang, 2012, Best Practice in the Use of Physiologically Based

  2. 247  Pharmacokinetic Modeling and Simulation to Address Clinical Pharmacology Regulatory

  3. 248  Questions, Clin Pharmacol Ther, 92(1):17-20.

249

  1. 250  Zhao, P, L Zhang, JA Grillo, Q Liu, JM Bullock, YJ Moon, P Song, SS Brar, R Madabushi, TC

  2. 251  Wu, BP Booth, NA Rahman, KS Reynolds, E Gil Berglund, LJ Lesko, and SM Huang, 2011,

  3. 252  Applications of Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulation

  4. 253  During Regulatory Review, Clin Pharmacol Ther, 89(2):259-267.

254

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