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PHYSIOLOGICALLY BASED
PHARMACOKINETIC
(PBPK) MODELING AND
SIMULATIONS
PHYSIOLOGICALLY
BASED
PHARMACOKINETIC
(PBPK) MODELING
AND SIMULATIONS
Principles, Methods,
and Applications in the
Pharmaceutical Industry
Second Edition
Sheila Annie Peters

Merck Healthcare
Translational Quantitative Pharmacology
Darmstadt
Germany
This edition first published 2022
© 2022 by John Wiley & Sons, Inc.
Edition History
Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulations: Principles, Methods, and Applications in the
Pharmaceutical Industry, 1st Edition, © 2012 by John Wiley & Sons, Inc.
All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form
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The right of Sheila Annie Peters to be identified as the author of this work has been asserted in accordance with law.
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Library of Congress Cataloging-in-Publication Data

Names: Peters, Sheila Annie, author.
Title: Physiologically based pharmacokinetic (PBPK) modeling and
simulations : principles, methods, and applications in the
pharmaceutical industry / Sheila Annie Peters.
Description: Second edition. | Hoboken, NJ : Wiley, 2021. | Includes
bibliographical references and index.
Identifiers: LCCN 2021038143 (print) | LCCN 2021038144 (ebook) | ISBN
9781119497684 (hardback) | ISBN 9781119497769 (adobe pdf) | ISBN
9781119497790 (epub)
Subjects: MESH: Pharmacokinetics | Drug Design | Models, Biological
Classification: LCC RM301.5 (print) | LCC RM301.5 (ebook) | NLM QV 38 |
DDC 615.7–dc23
LC record available at https://lccn.loc.gov/2021038143
LC ebook record available at https://lccn.loc.gov/2021038144
Cover Design: Wiley

Cover Image: Courtesy of Sheila Annie Peters
Set in 9.5/11.5pt Times by Straive, Pondicherry, India
10 9 8 7 6 5 4 3 2 1
To my readers whose tremendous support for the first edition inspired
me to give my best to this edition.
CONTENTS
Preface to the Second Edition xix

Preface to the First Edition xxi
Acknowledgments xxiii
About the Companion Website xxv
SECTION I. PRINCIPLES, METHODS, AND

BACKGROUND INFORMATION 1
1 A REVIEW OF PHARMACOKINETIC AND PHARMACODYNAMIC

PRINCIPLES 3
1.1 Introduction 4
1.2 Pharmacokinetic Principles 4
1.2.1 Routes of Drug Administration 4
1.2.2 Intravenous Bolus 4
1.2.3 Plasma Protein Binding and Blood–Plasma Ratio 9
1.2.4 Hepatic, Renal, and Biliary Clearances 12
1.2.5 Extravascular (Subcutaneous, Intramuscular, and Per Oral)
Absorption 16
1.2.6 Absorption from Solid Dosage Forms 20
1.2.7 Role of Transporters in ADME 22
1.2.8 Linear and Non-Linear Pharmacokinetics 24
1.2.9 Intravenous Infusion, Repeated Dosing, Steady State Kinetics,
and Accumulation 25
1.2.10 Active Metabolite and Prodrug Kinetics 28
1.3 Pharmacokinetic Variability 32
1.4 Pharmacokinetics Optimization in Drug Discovery 34
1.5 Pharmacodynamic Principles 34
1.5.1 Pharmacological Targets and Drug Action 35
1.5.2 Functional Adaptation Processes 39
1.5.3 Biomarkers, Surrogate Endpoints, and Clinical Endpoints 41
Keywords 47
References 48
vii
viii CONTENTS
2 A REVIEW OF DRUG–DRUG INTERACTIONS 51

2.1 Introduction 51
2.2 Drug Interactions Mediated by Enzymes and Transporters at Various
Sites 54
2.3 Factors Affecting DDI 54
2.4 In Vitro Methods to Evaluate Drug–Drug Interactions 56
2.4.1 Candidate Drug as a Potential Perpetrator 57
2.4.2 Candidate Drug as a Potential Victim of Inhibition 58
2.5 Sources of Uncertainty 59
2.6 Therapeutic Protein–Drug Interaction 59
Keywords 60
References 61
3 MODELING PHARMACOKINETICS, PHARMACODYNAMICS, AND

DRUG INTERACTIONS 65
3.1 Introduction 66
3.2 Modeling Pharmacokinetics 66
3.2.1 Compartmental Modeling of Linear and Nonlinear
Pharmacokinetics (Enzyme and/or Transporter Capacity
Limitation as Well as Target-Mediated Drug Disposition) 67
3.2.2 Population Pharmacokinetics 76
3.3 Pharmacokinetics/Pharmacodynamics and PK/Efficacy (Exposure/
Response) Modeling 80
3.3.1 PK/PD Models for Direct Effect: Sigmoid Emax Model 84
3.3.2 PK/PD Models for Direct Effect: Classical Receptor Theory 86
3.3.3 PK/PD Models Accommodating Delayed Pharmacological
Response 89
3.3.4 PK/PD Models Accommodating Functional Adaptation
Leading to Nonlinearity in Pharmacological Response with
Respect to Time 96
3.3.5 PK/Efficacy Modeling 97
3.3.6 Translation of PK/PD and PK/Efficacy Modeling to Human 100
3.3.7 Average, Minimum, and Maximum Steady-State
Concentrations 104
3.3.8 Estimation of Biologically Effective Dose in Human 107
3.3.9 Therapeutic Window 109
3.3.10 Static Models for Drug Interactions 109
3.4 Physiologically Based Pharmacokinetic (PBPK) Modeling and Its
Integration with Pharmacodynamics and Efficacy Models 112
3.4.1 PK Modeling Compartmental vs PBPK 112
3.4.2 PK Variability: Population PK (popPK) Modeling vs PBPK 114
3.4.3 Integration of PBPK with PD, Quantitative Systems
Pharmacology (QSP) Models or Quantitative Systems
Toxicology and Safety (QSTS) 114
3.4.4 PBPK Models to Evaluate Drug–Drug Interactions 115
CONTENTS ix
3.4.5 DDI Risk Assessment with PBPK vs Static Models 118

Keywords 123
References 125
4 PHYSIOLOGICAL MODEL FOR ABSORPTION 129

4.1 Introduction 130
4.2 Drug Absorption and Gut Bioavailability 130
4.2.1 Solubility and Dissolution Rate 130
4.2.2 Permeability: Transcellular, Paracellular, and Carrier-Mediated
Pathways 136
4.2.3 Barriers to Membrane Transport – Luminal Degradation, Efflux,
and Gut Metabolism 138
4.3 Factors Affecting Drug Absorption and Gut Bioavailability 140
4.3.1 Physiological Factors Affecting Oral Drug Absorption and
Species Differences in Physiology 140
4.3.2 Compound-Dependent Factors 144
4.3.3 Formulation-Dependent Factors 144
4.4 In Silico Predictions of Passive Permeability and Solubility 147
4.4.1 In Silico Models for Permeability 147
4.4.2 In Silico Models for Solubility 147
4.5 Measurement of Permeability, Solubility, Luminal Stability, Efflux,
Intestinal Metabolism 148
4.5.1 In Vitro, In Situ, and In Vivo Models for Effective Permeability 148
4.5.2 Measurement of Thermodynamic or Equilibrium Solubility 153
4.5.3 Luminal Stability 154
4.5.4 Efflux 154
4.5.5 In Vitro Models for Gut Metabolism and Estimation of Fraction
Escaping Gut Metabolism 155
4.6 Absorption Modeling 156
Keywords 162
References 163
5 PHYSIOLOGICAL MODEL FOR DISTRIBUTION 169

5.2 Factors Affecting Tissue Distribution of Xenobiotics 170
5.2.1 Physiological Factors and Species Differences in Physiology 171
5.2.2 Compound-Dependent Factors 176
5.3 In Silico Models of Tissue Partition Coefficients 176
5.4 Measurement of Parameters Representing the Rate and Extent of Tissue
Distribution 181
5.4.1 Assessment of Rate and Extent of Brain Penetration 181
5.5 Physiological Model for Drug Distribution 186
5.6 Drug Concentrations at the Site of Action 187
Keywords 189
References 190
x CONTENTS
6 PHYSIOLOGICAL MODELS FOR DRUG METABOLISM AND

EXCRETION 193
6.2 Factors Affecting Drug Metabolism and Excretion of Xenobiotics 194
6.3 Models for Hepatobiliary and Renal Excretion 197
6.3.1 In Silico Models 197
6.3.2 In Vitro Models for Hepatic Metabolism 197
6.3.3 In Vitro Models for Transporters 200
6.4 Physiological Models 203
6.4.1 Hepato-Biliary Elimination of Parent Drug and Metabolites 205
6.4.2 Renal Excretion 208
References 211
7 GENERIC WHOLE-BODY PHYSIOLOGICALLY BASED

PHARMACOKINETIC MODELING 217
7.2 Structure of a Generic Physiologically-Based Pharmacokinetic (PBPK)
Model 218
7.3 Somatic Compartments 220
7.3.1 Lungs (LU) 220
7.3.2 Arterial Blood (ART) 220
7.3.3 Venous Blood (VEN) 220
7.3.4 Stomach (ST) 220
7.3.5 Gut (GU) 220
7.4 Model Assumptions 221
7.5 PBPK Software 221
References 223
8 PBPK MODELING OF BIOTHERAPEUTICS 225

8.2 Therapeutic Proteins 226
8.2.1 Peptides and Proteins 226
8.2.2 Antibodies and Antibody-Based Therapies 227
8.3 Pharmacokinetics of Therapeutic Proteins 234
8.3.1 Absorption 234
8.3.2 Renal Elimination 235
8.3.3 Immunogenicity 235
8.3.4 PEGylation 239
8.3.5 Transport by Convective and Transcytotic Extravasation 239
8.3.6 Catabolic Elimination (Proteolysis) 239
8.3.7 FcRn-Mediated Protection of IgGs Against Catabolism in
FcRn-Rich Cells 241
8.3.8 Distribution and lymphatic elimination 242
CONTENTS xi
8.3.9 Target-Mediated Drug Disposition and Receptor-Mediated

Endocytosis 243
8.4 PBPK Modeling of Monoclonal Antibodies 244
8.4.1 Full PBPK Model for Monoclonal Antibodies 244
8.4.2 Minimal PBPK Model for Monoclonal Antibodies 253
8.5 Applications of PBPK Modeling of Monoclonal Antibodies 253
8.5.1 Pharmacokinetic Scaling 253
8.5.2 PBPK Integration with Pharmacodynamics of Monoclonal
Antibodies 255
Keywords 256
References 258
9 UNCERTAINTY AND POPULATION VARIABILITY 263

9.2 Distinguishing Uncertainty and Variability 264
9.3 Sources of Uncertainty in Drug-related Parameters 264
9.4 Sources of Variability in System Parameters 266
9.5 Handling Population Variability 269
9.5.1 A POSTERIORI and A PRIORI Approaches to Handling
Population Variability 269
9.5.2 Correlations Between Parameters 271
9.6 Uncertainty and Sensitivity Analysis 272
9.6.1 Local Sensitivity Analysis (One-at-a-time (OAT) and
Derivative-based Methods) 272
9.6.2 Parameter Interactions and Global Sensitivity Analysis (GSA) 275
9.6.3 Global Sensitivity Analysis for Correlated Parameters (cGSA) 278
9.6.4 Applications of Sensitivity Analysis for PBPK Models 280
9.6.5 Limitations of Global Sensitivity Analysis 281
9.7 Uncertainty and Population Variability in Clinical Efficacy and Safety 282
Keywords 285
References 285
10 NONCLINICAL, CLINICAL, AND MODEL-INFORMED

DRUG DEVELOPMENT 293
10.1 Introduction: An Overview of Different Phases of Drug Development 294
10.2 Nonclinical Development 295
10.2.1 Preclinical Pharmacology, PK/PD Modeling, and Human Dose
Prediction 297
10.2.2 Safety and Toxicology Studies 297
10.2.3 Studies with Radiolabeled Compound 298
10.3 Clinical Pharmacology Studies 302
10.3.1 First-in-Human, Single, and Multiple Ascending Dose Studies 302
10.3.2 Biopharmaceutics – Absolute Oral Bioavailability and
Bioequivalence Study 304
10.3.3 Food Effect Study 304
10.3.4 Organ (Hepatic and Renal) Impairment Study 305
xii CONTENTS
10.3.5 Pediatric Assessment 306

10.3.6 Mass Balance Study 307
10.3.7 Drug Interaction Study 307
10.3.8 Pharmacogenomics Study 308
10.3.9 Thorough QT (TQT) and Concentration QT (C-QT) Study 308
10.3.10 Immunogenicity Assays and Comparability Study for
Biologics 309
10.3.11 Drug Labelling 309
10.4 Clinical Development in Oncology 310
10.5 Fast Track Routes to Address Unmet Medical Need in the Treatment
of Serious Conditions 311
10.6 Model-Informed Drug Development 312
10.7 Physiologically Based Pharmacokinetic Models Complementing
Clinical Pharmacology Studies 314
10.8 PBPK in Oncology 315
Regulatory Guidelines 316
References 319
SECTION II. APPLICATIONS IN THE PHARMACEUTICAL

INDUSTRY 323
11 OVERVIEW OF PBPK APPLICATIONS 325

11.2 PBPK Applications for Internal Decisions 326
11.3 PBPK Applications for Regulatory Filing 328
11.4 PBPK Modeling and Simulations Along the Value Chain 332
References 335
12 APPLICATIONS OF HYPOTHESIS GENERATION AND TESTING

WITH PBPK MODELS 337
12.2 Hypothesis Generation and Testing with PBPK Models 338
12.2.1 Parameter Estimation from Intravenous Pharmacokinetic
Profiles 338
12.2.2 Simulation of Oral PK Profile 341
12.2.3 Sensitivity Analysis 342
12.2.4 Verification of Hypotheses 346
12.2.5 Auto-inhibition of Drug-Metabolizing Enzymes, Uptake and
Efflux Transporters 347
12.3 Hypothesis Generation and Testing Along the Value Chain 348
12.4 Conclusions 351
References 351
CONTENTS xiii
13 APPLICATIONS OF PHYSIOLOGICALLY BASED PHARMACOKINETIC

MODELS INTEGRATED WITH DRUG EFFECT MODELS (PBPK/PD) 353
13.1 Introduction: Integration of PBPK with Drug Effect Models 354
13.2 Dosing in Specific Populations 355
13.3 PBPK/PD for Bottom-Up Prediction of Inter-Patient Variability in
Drug Response 357
13.4 PBPK/PD for Predicting the Inter-Patient Variability in Response to
Prodrugs and Active Metabolites 358
13.5 PBPK/PD When Systemic Concentrations are not the Driver for Drug
Response 359
13.5.1 Pre-Systemic Drug Target 359
13.5.2 Effect-Site Drug Concentration Different from Systemic
Concentration 360
13.6 PBPK/PD for Monoclonal Antibodies 362
13.7 PBPK Models Linked to Quantitative Systems Pharmacology and
Toxicology Models 363
13.7.1 PBPK–QST Models to Predict Drug-Induced Liver Injury 363
13.7.2 PBPK–QST Models to Predict Drug-Induced Cardiotoxicity 367
References 371
14 PBPK MODELING AND SIMULATIONS TO EVALUATE CLINICAL

DRUG-DRUG INTERACTIONS 375
14.2 Clinical DDI Studies and Modeling Approaches to Address Key
Questions Related to Drug–Drug Interactions 376
14.2.1 Dedicated Clinical DDI Studies 378
14.2.2 Investigation of Phenotypic Effects for NMEs Predominantly
Cleared by Polymorphic Enzyme or Transporter 379
14.2.3 Prospective Nested DDI Study 380
14.2.4 Cocktail DDI Study 381
14.2.5 PBPK Modeling and Simulations 381
14.2.6 Claims Relating to Results of DDI Studies 381
14.2.7 Impact on Label 382
14.3 PBPK Modeling of Different Types of Drug Interactions 382
14.3.1 PBPK Modeling Strategy: New Molecular Entity as Victim
of CYP-Based Drug Interactions 382
14.3.2 PBPK Modeling Strategy: New Molecular Entity as
Perpetrator of CYP-Based Drug Interactions 383
14.3.3 Non-CYP Based Drug Interactions 384
14.3.4 Transporter-Mediated Drug Interactions 385
14.4 DDI Predictions with PBPK Modeling and Simulations in Clinical
Drug Development and Regulatory Submissions 387
14.4.1 DDI Predictions Along the Value Chain (Figure 14.5) 387
xiv CONTENTS
14.4.2 Possible Regulatory Outcomes, Based on the Predictions from

a Verified and Validated PBPK Model 389
14.4.3 Regulatory Acceptance of PBPK Analyses Included in
Regulatory Submissions 390
14.4.4 Predictive Performance of PBPK Models 391
14.5 Comparison of DDI Prediction Using Static and Dynamic Models 392
References 394
15 DOSE EXTRAPOLATION ACROSS POPULATIONS (HEALTHY ADULT

CAUCASIAN TO PEDIATRIC, PREGNANT WOMEN, DIFFERENT
ETHNICITIES, GERIATRIC, SMOKERS AND OBESE POPULATIONS) 397
15.2 PBPK Modeling Strategy for Dose Extrapolation
to Specific Populations 398
15.3 Potential Benefits of PBPK Modeling for Dose Extrapolations to
Specific Populations 399
15.4 Dose Extrapolations to Specific populations 404
15.4.1 Pediatric Starting Dose Selection 404
15.4.2 Pregnancy 406
15.4.3 Ethnicity – Japanese Population 407
15.4.4 Geriatric Population 408
15.4.5 Obese 409
15.4.6 Smokers 410
References 411
16 DOSE EXTRAPOLATION ACROSS POPULATIONS: HEALTHY

ADULT TO HEPATIC AND RENAL IMPAIRMENT POPULATIONS 417
16.2 Pathophysiological Changes in Organ Impairment 419
16.2.1 Hepatic Impairment 419
16.2.2 Renal Impairment 420
16.3 PBPK Modeling Strategy: Model Development,
Verification, Validation, and Application 420
16.4 Benefits of Applying Validated PBPK Models to Organ-Impaired
Populations 421
16.4.1 Enhancing Regulatory Confidence in the Application
of PBPK Modeling for the Prediction of Exposure in the
Organ-Impaired Population 421
16.4.2 Contribution of PBPK to the Totality of Evidence
in Evaluating the Effect of Renal Impairment on Drug
Exposure to Inform Labelling 424
CONTENTS xv

References 426
17 ABSORPTION-RELATED APPLICATIONS OF PBPK MODELING 429

17.2 In Vitro – In Vivo Disconnect, Parameter Non-Identifiability and the
Importance of Identifying Factors Limiting Absorption Through a
Deconvolution of the Mechanisms Contributing to Gut Bioavailability 431
17.3 Non-Regulatory Internal Applications of PBPK Modeling and
Simulations 433
17.3.1 Prediction of Fraction Absorbed 433
17.3.2 Oral Formulation Development 433
17.4 Regulatory Applications of PBPK Modeling and Simulations 438
17.4.1 Food–Drug Interactions 438
17.4.2 Interactions of a Poorly Soluble Weak Base with Acid
Reducing Agents (ARAs) 444
17.4.3 In Vitro – In Vivo Correlations (IVIVCs) to Serve
as Surrogate for Bioequivalence Testing (Case Study 12) 445
17.4.4 Biowaivers Based on Virtual Bioequivalence 449
17.4.5 Virtual Bioequivalence of Locally Acting Products (LAPs) 450
References 452
18 REGULATORY GUIDELINES ON THE REPORTING OF

PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK)
MODELING ANALYSIS 457
18.2 Food and Drug Administration (FDA) Guidelines 458
18.3 European Medicines Agency (EMA) Guidelines 459
18.4 Comparison of FDA and EMA Guidelines 461
18.5 Risk-Informed Evidentiary Framework to Assess PBPK
Model Credibility 463
18.6 Drug Model Verification of Locally Acting Products (LAPs) 464
References 466
19 RESOLVING THE CHALLENGES TO ESTABLISHING CONFIDENCE

IN PBPK MODELS 469
19.2 Requirements for Developing Mechanistically Credible PBPK Models
for the Three Broad Categories of Applications 470
19.3 Challenges to Developing Mechanistically Credible PBPK Models
and Consequences 473
19.3.1 Model Building 473
xvi CONTENTS
19.3.2 Model Verification of Predicted Exposure and Validation of

Predictive Performance 476
19.4 Resolving the Challenges to Developing Mechanistically Credible
PBPK Models 476
19.5 Totality of Evidence 478
References 481
20 EPILOGUE 483
20.1 PBPK Modeling Successes 483
20.2 Challenges 484
20.2.1 Drug Model Parameterization 484
20.2.2 Knowledge Gaps in Physiological Parameters 485
20.2.3 Prospective Validation of Prediction Performance 485
20.3 Meeting the Challenges 485
20.4 Future Directions for PBPK Modeling 486
References 488
SECTION III. CASE STUDIES OF PBPK APPLICATIONS IN

THE PHARMACEUTICAL INDUSTRY 491
CASE STUDY 1 HYPOTHESIS TESTING (SOLUBILITY) 493
CASE STUDY 2 HYPOTHESIS TESTING (GASTRIC EMPTYING) 499
CASE STUDY 3 HYPOTHESIS TESTING (INTESTINAL LOSS) 505
CASE STUDY 4 PBPK/PD 509
CASE STUDY 5 DRUG–DRUG INTERACTION (INHIBITION) 515
CASE STUDY 6 DRUG–DRUG INTERACTION (INDUCTION) 521
CASE STUDY 7 GENETIC POLYMORPHISM 527
CASE STUDY 8 PEDIATRIC EXTRAPOLATION 535
CASE STUDY 9 PREGNANCY 541

CONTENTS xvii
CASE STUDY 10 HEPATIC IMPAIRMENT 547
CASE STUDY 11 RENAL IMPAIRMENT 555
CASE STUDY 12 ABSORPTION – IVIVC 561
APPENDICES 567
Index 579
PREFACE TO THE SECOND
EDITION
I am excited to bring out this much improved second edition, encouraged by the success of
the first edition of “Physiologically-Based Pharmacokinetic (PBPK) Modeling and Simula-
tions: Principles, Methods, and Applications in the Pharmaceutical Industry”. The applica-
tions of PBPK modeling and simulations have exponentially grown since the publication of
the first edition of the book in 2012. Since that time, a surge in PBPK regulatory submissions
has prompted the regulatory agencies to release guidelines for the reporting of PBPK mod-
eling results that accompany submissions.
The adverse impact of the COVID-19 pandemic on global economies is still being
evaluated. Pharma companies have had their fair share of losses too. Clinical studies
for various indications have been affected by stretched healthcare infrastructure, recruit-
ment challenges, lockdown, logistics issues, and confounding disease influence on out-
comes. Along with World Health Organization’s SOLIDARITY trial and Institut
national de la santé et de la recherche médicale (INSERM)’s Discovery trial, nearly thou-
sand clinical studies related to COVID-19 have been registered worldwide in the first half
of 2020. In a race against time to bring innovative medicines to the market, a heightened
need for Model-Informed Drug Development (MIDD) and the totality of evidence it advo-
cates has become apparent. The applications of PBPK modeling, an important component
of MIDD, supporting dose optimization and assessment of benefit-risk ratios have been
further catalyzed by the pandemic.
The book is intended to serve the interests of a broad and diverse audience from aca-
demia, industry, and regulatory agencies. Similar to the first edition of the book, this sec-
ond edition has a section that covers the principles underlying pharmacokinetics, drug
interactions, and physiological modeling of pharmacokinetic processes as well as interin-
dividual variability for small molecule drugs and biologics. The second part exposes the
reader to the powerful applications of PBPK modeling along the value chain in drug dis-
covery and development. To facilitate potential use of the book in courses or workshops, a
new third section providing case studies in the different areas of application of PBPK mod-
eling has been introduced in this edition at the request of readers and reviewers. Most of
these case studies are built using PK-Sim®, a comprehensive software tool within the
Open Systems Pharmacology Suite for the physiologically based pharmacokinetic mod-
eling of small and large molecules.
xix
xx PREFACE TO THE SECOND EDITION
In addition to introducing a third section to the book, this second edition simplifies
complex topics and provides a balanced view of the vast potential of PBPK modeling
alongside current challenges. Section-I provides substantially revised and reordered con-
tent with updated literature in all chapters. A new chapter has been added on Nonclinical,
Clinical and Model Informed Drug Development. Chapters in Section-II are entirely new
and focus on the vast array of applications in the field. Two-thirds of the figures in the
second edition are either revised or new.
I hope that the inclusion of recent advances in PBPK modeling and the revisions made
in the current edition will serve to benefit and engage the readers.
PREFACE TO THE FIRST EDITION
Physiologically-based pharmacokinetic (PBPK) modelling has made rapid strides in the

pharmaceutical industry in the last decade or so, thanks to an increasing awareness of the
potential applications of this powerful tool. As pharmaceutical companies are working to
integrate PBPK modelling into their lead selection cycle and clinical development, the avail-
ability of commercial software has played a key role in enabling even those without mod-
elling expertise to come on board. However, this entails the risk of misuse, misinterpretation
or over-interpretation of modelling results, if the principles and underlying assumptions of
PBPK modelling are not clearly understood by the users. Today, the challenge facing phar-
maceutical companies is educating and training their staff to achieve an effective application
of PBPK/PD in projects across the value chain. In the future, providers of education should
take on the responsibility of making available, modellers with appropriate skills. Given the
complexity of PBPK modelling, it is certainly not an easy task for a beginner with little or no
background to understand the model structure and to be aware of its limitations. The lack of
a text book on PBPK has been a further deterrent. It is hoped that the book will serve as a
primary source of information on the principles, methods and applications of PBPK mod-
elling, exposing the power of a largely hidden and unexplored tool. Applications in the
pharma sector will be the main focus, as applications in environmental toxicology and
human health risk assessment, have already been the subject of a previous publication.
Target audiences for the book include students and researchers in the academia, apart
from scientists and modellers in the pharmaceutical industry. The book can also be a
resource for R&D managers in the pharmaceutical industry, seeking a quick overview
of the benefits of applying PBPK modelling along the drug discovery and development
value chain. An understanding of the principles of PBPK modelling by R&D management
would enhance their acceptance and appreciation, which in turn can translate to effective
managerial support for PBPK modelling. The book is intended to serve the interests of
both the general reader, who may only want an overview of the applications of PBPK mod-
elling without wanting an in-depth understanding of the underlying methods, and the spe-
cialist reader who may be interested to build new models. For the general reader, keywords
highlighted in capitals are explained at the end of the chapters. No particular expertise is
assumed in order to keep the book accessible to a diverse audience. An extensive list of
bibliographic references will help the specialist reader to build on the concepts developed
in the book. A generous use of figures to illustrate concepts will help the reader to gain
valuable insights into this fascinating subject.
The book comprises two parts. The first part provides a detailed and systematic treat-
ment of the principles behind physiological modelling of pharmacokinetic processes,
inter-individual variability and drug interactions for small molecule drugs and biologics.
The second part exposes the reader to the powerful applications of PBPK modelling along
the value chain in drug discovery and development.
xxi
ACKNOWLEDGMENTS
My sincere thanks are due to Prof. Amin Rostami-Hodjegan who reviewed chapters of the
book relating to applications of PBPK modeling, despite other demands on his time. Being
at the forefront of research in the field of PBPK modeling, his suggestions were very
valuable in structuring the content and updating the chapters with the latest developments
in the area. I am grateful to Adam Darwich, Nicola Melillo, Dan Liu, and Alexander
Cooper whose help with reviewing my chapters is greatly appreciated. I would like to
thank my colleagues at Merck Healthcare KGaA, Joao NS Pereira, Ulrike Graadhand,
Andreas D Becker, and Akash Khandelwal who also helped review some of the chapters,
and Rainer Strotmann for letting me use some figures he created. My deep appreciation
goes to Christina Peters for finding time in the midst of her busy career to create some
excellent figures for this edition. I would like to acknowledge the enthusiastic support I
received from Vignesh Murugesan for gathering some data for the book. I am extremely
grateful to Jan Schlender, Annika Schneider, and Michael Krug, who over the last two
years, devoted their time to creating the case studies in PK-Sim as well as HELP manuals.
This work would not have been possible without the consistent support extended by my
friends and family.
xxiii
ABOUT THE
COMPANION WEBSITE
This book is accompanied by a companion website
www.wiley.com/go/peters/PBPK_modeling_simulations
The website includes case studies.
xxv
SECTION I
PRINCIPLES, METHODS
AND BACKGROUND
INFORMATION
1
A REVIEW OF
PHARMACOKINETIC AND
PHARMACODYNAMIC
PRINCIPLES
CONTENTS
1.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
1.2 Pharmacokinetic Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
1.2.1 Routes of Drug Administration . . . . . . . . . . . . . . . . . . . . . . . . 4
1.2.2 Intravenous Bolus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
1.2.3 Plasma Protein Binding and Blood–Plasma Ratio . . . . . . . . . . . . . 9
1.2.4 Hepatic, Renal, and Biliary Clearances . . . . . . . . . . . . . . . . . . . 12
1.2.5 Extravascular (Subcutaneous, Intramuscular, and Per Oral) Absorption 16
1.2.6 Absorption from Solid Dosage Forms . . . . . . . . . . . . . . . . . . . . 20
1.2.7 Role of Transporters in ADME . . . . . . . . . . . . . . . . . . . . . . . . 22
1.2.8 Linear and Non-Linear Pharmacokinetics . . . . . . . . . . . . . . . . . . 24
and Accumulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
1.2.10 Active Metabolite and Prodrug Kinetics . . . . . . . . . . . . . . . . . . . 28
1.3 Pharmacokinetic Variability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
1.4 Pharmacokinetics Optimization in Drug Discovery . . . . . . . . . . . . . . . . . 34
Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulations: Principles,

Methods, and Applications in the Pharmaceutical Industry, Second Edition. Sheila Annie Peters.
© 2022 John Wiley & Sons, Inc. Published 2022 by John Wiley & Sons, Inc.
Companion website: www.wiley.com/go/peters/PBPK_modeling_simulations
3
4 A REVIEW OF PHARMACOKINETIC AND PHARMACODYNAMIC PRINCIPLES
1.5 Pharmacodynamic Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

1.5.1 Pharmacological Targets and Drug Action . . . . . . . . . . . . . . . . . . 35
1.5.2 Functional Adaptation Processes . . . . . . . . . . . . . . . . . . . . . . . . 39
1.5.3 Biomarkers, Surrogate Endpoints, and Clinical Endpoints . . . . . . . . 41
Keywords . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
1.1 INTRODUCTION
The dose and dosing frequency of a drug (dosage regimen), needed to maintain an effi-
cacious concentration at the site of its pharmacological action, for a duration that is long
enough to achieve the therapeutic objective, should be safe and convenient to the patient.
To achieve this optimal exposure at the target site of pharmacological action in humans,
the rate and extent of multiple processes like drug absorption from the site of administra-
tion into systemic circulation, tissue distribution, metabolism, and elimination (ADME)
are optimized during lead optimization in drug discovery. Pharmacokinetics (PK) is the
study of the fate of drug in the body, that determines its exposure/concentration at the tar-
get effect site, driven by ADME processes. The relationship of the exposure/concentration
at the target effect site to the onset, intensity, and duration of drug action is determined by
pharmacodynamics (PD). A well-defined, quantitative relationship between drug concen-
trations in biological fluids and pharmacodynamic effect can support the selection of dose
and dosing regimen for early clinical trials. This chapter is intended to provide a brief over-
view of PK and PD principles. The forthcoming chapters will draw heavily upon the con-
cepts laid out in this chapter.
1.2 PHARMACOKINETIC PRINCIPLES
1.2.1 Routes of Drug Administration
Common routes of drug administration include per oral (PO), intramuscular (IM), subcu-
taneous (SC) intravenous (IV) bolus and infusion, and intrathecal (around the spinal cord).
Other less common routes include buccal, sublingual, rectal, transdermal, inhalational, and
topical. The oral route is the most preferred route, but it is not suitable for drugs that are not
stable in the gut, like for example peptide and protein drugs.
1.2.2 Intravenous Bolus
Intravenous (IV) administration ensures rapid, complete drug availability for drugs that are
not in the form of suspensions or oils, by bypassing absorption barriers. Drugs having poor
oral bioavailability or causing unacceptable pain when administered intramuscularly or
subcutaneously may be administered by this route. However, it is potentially hazardous,
1.2 PHARMACOKINETIC PRINCIPLES 5
as the initial high drug concentration may elicit toxic effects. Therefore, the use of IV route
is restricted to situations demanding a rapid onset of action as in anesthesia, emergency
medicine etc. or, when the patient is persistently vomiting, is unconscious or is too young
to safely swallow solid forms of medication. Controlled drug administration through IV
infusions offers one way to mitigate the risk of toxicity, as the infusion may be halted in the
unexpected event of adverse effects during administration. Apart from causing severe
pain, intra-arterial administration is associated with the risk of dangerous pressure buildup
in the muscles leading to decreased blood flow and consequently to nerve and muscle dam-
age. Intra-arterial injections are therefore reserved to situations in which localizations to
specific tissues are desired.
1.2.2.1 Zero- and First-Order Kinetics. Drug elimination from the body may follow
zero or first-order kinetics (Figure 1.1). In zero-order kinetics, a constant amount of the
drug is eliminated in a certain time (e.g., 20 mg per hour). In first-order processes, a con-
stant proportion of the drug is eliminated in a certain time (e.g., 20% per hour). Though
relatively rare, zero-order kinetics may be encountered in intravenous infusions as well as
in elimination of some drugs (e.g. ethanol) but will not be further elaborated here.
The temporal changes in the drug concentrations following an IV bolus injection of
50 mg of a drug with first-order kinetics are depicted in Figure 1.2. The slope and area
under the curve (AUC) are the two parameters that can be extracted from the concentra-
tion-time profile as shown in the semilogarithmic and linear plots respectively. Other
useful pharmacokinetic parameters may be derived from these two parameters, as will
become evident from the mathematical derivations below.
1.2.2.2 Clearance, Volume of Distribution, Half-life, and AUC. The first-order

rate equation depicting the rate of change of drug concentrations in the blood (C) is
given by
− dC − dA
= = k el × C (1.1)
dt Vdt
(a) (b)
10 Time (h) C (mg/L) 10 Time (h) C (mg/L)
0 10 0 10
Drug Concentration (mg/L)
8 1 8 8 1 5
2 6 2 2.5
3 4 3 1.25
6 6
4 2 4 0.63
5 0 5 0.31
4 4
2 2
0 0
0 2 4 6 0 2 4 6
Time (h) Time (h)
Figure 1.1. Temporal changes in drug concentrations for (a) zero-order and (b) first-order
kinetics.
(a) (b)
10 10
8

Slope = (ln(C2) - ln(C1)/(t2–t1)
= –kel = –0.693/half-life
6
1
4
2 Area under
the curve
0 0.1
0 2 4 6 0 2 4 6 8
Time (h) Time (h)
Dose (mg) 1000

kel (h–1) 0.70
half-life (h) 1
AUC (mg.h/L) 17.5

CL (L/h) = Dose/AUC 57.1
V (L) = CL/kel 81.6
Figure 1.2. Linear (a) and semilogarithmic (b) plots of drug concentrations vs. time. Area
under the curve (AUC) and slope are the two parameters that can be obtained from the
plot. C2 and C1 are drug concentrations at times t2 and t1 respectively. kel, first-order
elimination rate constant; CL, is the total drug clearance; and V, volume of distribution.
− dA
= V × k el × C = CL × C = k el × A (1.2)
dt
where A is the amount of drug in the body at any time, t, kel is the first-order elimination
rate constant, and V is the volume of distribution of the drug. The product of kel and V is
defined as the total clearance, CL, of the drug from blood.
Integrating Equation 1.1 (−dC/dt = kel × C),
C = C 0 × e − kel × t (1.3)
Taking natural logarithms on both sides,
ln C = ln C 0 − kel × t (1.4)
Thus, kel may be obtained by measuring the slope of a semilogarithmic plot of drug
concentration vs time (Figure 1.2).
Similarly, integrating Equation 1.2 (−dA/dt = kel × A) yields
A = A0 × e − kel t (1.5)
where A0 is the initial amount of drug in the body, the dose administered as IV bolus.
Bringing A0 to the left-hand side, Equation 1.5 becomes,
A
= fraction of dose remaining in the body = e − kel t (1.6)
A0
Taking the natural logarithms on both sides of the resulting equation leads to the
following:
A
ln = − kel × t (1.7)
A0
The half-life (t1/2) of a drug, defined as the time taken for half of the administered drug
to get eliminated from the body (time taken for drug amount in body to go from A0, to A0/2,
or time taken for the drug concentration to be halved), is given by:
ln 2 ln 2 × V
t 12 = = (1.8)
kel CL
Using Equation 1.8, the half-life of a drug can be calculated from the elimination rate
constant kel which is obtained from the semilogarithmic plot of concentration vs. time
(Figure 1.2).
Integrating the Equation 1.2 (−dA = CL × C dt) yields
t t t
dA = CL × Cdt = CL × Cdt = CL × AUC (1.9)
t=0 t=0 t=0
where AUC is the area under the drug concentration-time profile (Figure 1.2), which may
be estimated from the plot by applying the trapezoidal rule. Recognizing that the integral
dA over time 0 to t is the dose, Equation 1.9 becomes,
Dose = CL × AUC (1.10)
Knowing the dose administered and the AUC, clearance can be calculated using
Equation 1.10. The volume of distribution, V, of the drug can be determined using
Equation 1.11, knowing that clearance is the product of kel and V.
CL
V= (1.11)
kel
Most small molecule drugs bind reversibly to plasma proteins such as albumin and
alpha-glycoprotein. Drug binding to plasma proteins is of major interest in pharmacoki-
netics as it impacts both clearance and volume of distribution. Thus far, the term clearance
refers to blood clearance. However, measurements of drug concentrations are often done in
plasma, as whole blood contains cellular elements (red and white blood cells, platelets etc.)
and proteins (albumin, glycoproteins, globulin, lipoproteins etc.). The clearance of a drug
determined using the AUC estimated from plasma drug concentration-time profile is
referred to plasma clearance. To convert plasma clearance to blood clearance, the distri-
bution of a drug between blood and plasma should be measured. The ratio of drug con-
centrations in blood to plasma is known as blood–plasma ratio (R).
Mean residence time is a parameter closely related to half-life and is defined as the
average time drug molecules spend in the body before being eliminated. It is expressed as
the sum of the residence times of all drug molecules, divided by the total number of mole-
cules. If dAe is the number of drug molecules exiting the body at time interval t, MRT is
given by:
∞
0 dAe ×t
MRT = (1.12)
A0
Differentiating Equation 1.5 (A = A0 × e − kel × t ),
dA
= A0 × − kel × e − kel × t (1.13)
dt
Recognizing that the rate of decline in A = − rate of amount exiting the body, Ae:
dAe
= A0 × kel × e − kel × t (1.14)
dt
dAe = A0 × kel × e − kel × t × dt (1.15)
Substituting for dAe using Equation 1.15 in Equation 1.12 and dividing both numer-
ator and denominator by kel, we get
∞ ∞ ∞
0 A0 × e − kel × t × t dt 0 C0 × e − kel × t × t dt 0 C × t dt
MRT = = = (1.16)
A0 kel C 0 kel C 0 k el
The numerator of equation is the first moment of the concentration–time integral, or

the area under the curve formed by time and the product of concentration and time, also
called the area under the first moment curve (AUMC). The denominator of equation is the
same as AUC as shown below:
∞
C0 ∞ C0 C0
AUC = C 0 × e − kel × t dt = × e − kel × t = × 0−1 = (1.17)
− k el 0 − k el k el
0
Thus, MRT for an IV bolus is given by the ratio of AUMC and AUC
AUMC
MRT = (1.18)
AUC
1.2.3 Plasma Protein Binding and Blood–Plasma Ratio
Drugs reversibly bind to plasma proteins depending upon their lipophilicity and ionizabil-
ity. In general, the greater the lipophilicity of a compound, the greater its extent of plasma
protein binding. The binding equilibrium can be represented as:
KA
Protein + drug Protein-drug complex
P Cu Cb
[P] is protein concentration; Cu and Cb are the unbound and bound concentrations of the
drug at equilibrium. The equilibrium constant, KA, also called the affinity constant is
given by
Cb
KA = (1.19)
Cu × P × n
n is the number of binding sites per mole of the binding protein. Since the therapeutic con-
centrations of most drugs are low relative to the total protein concentration, [P] can be
assumed to be the total protein concentration [P]Total. The fraction unbound in plasma
(fup) can be obtained from Equation 1.20 in terms of [P]Total or in terms of the concentra-
tions of α1-acidic glycoprotein (AGP), [P]AGP and albumin [P]albumin:
C u + K A C u × P Total × n = C u + C b
C u 1 + K A × P Total × n = C u + C b
Cu 1
f up = = (1.20)
Cu + Cb 1 + K A × P Total × n
1
f up =
1 + K A,AGP × P AGP × nAGP + K A,albu min × P albu min × nalbu min
The fraction unbound in plasma (fup) thus depends on the concentrations of plasma
proteins and the affinity of the drug to the plasma proteins. Albumin is the principal protein
to which many drugs bind, followed by AGP. Other plasma proteins include lipoproteins
and globulins. The concentrations of various plasma proteins are shown in Table 1.1.
Albumin is distributed in intravascular (plasma: 43 g/kg organ) and extravascular organs
T A B L E 1.1. Plasma proteins.

Molecular Concentration
Plasma proteins Binding weight (Da) (μM)
Albumin Binds mainly to anionic compounds 67 000 500–700

α1-acidic glycoprotein Binds mainly to cationic drugs. E.g.: 42 000 9–23
(AGP) tricyclic antidepressants
Lipoproteins 200 000 Variable
α-, β- and γ-globulins 53 000 0.6–1.4
(muscle: 2.3 g/kg, skin: 7.7 g/kg, liver: 1.4 g/kg, gut: 5 g/kg, and other tissues: 3 g/kg).
Albumin exists abundantly in the interstitial fluids.
Albumin has six distinct binding sites, two of which specifically bind to long-chain
fatty acids, another selectively binds to bilirubin and two others bind to acidic and lip-
ophilic drugs. One of these two drug binding sites binds drugs like warfarin, and phen-
ylbutazone, while the other binds drugs such as diazepam and ibuprofen. Drugs binding
to different binding sites do not compete with one another. When more than 20% of the
sites are occupied, concentration dependence of binding begins to get appreciable, ulti-
mately leading to saturation at higher concentrations. Saturation of albumin is rare and
restricted to drugs (especially acids) with high therapeutic concentration. However, the
binding sites of a few drugs such as tolbutamide and some sulfonamides are saturated
even at therapeutic concentrations. AGP concentrations being much lower compared
to albumin, saturation of AGP occurs at lower therapeutic concentrations. The concen-
trations of several plasma proteins can be altered by many factors including stress, sur-
gery, liver dysfunction, and pregnancy. Most commonly, disease states increase AGP
concentration while reducing albumin concentration. Higher levels of AGP have been
reported in obese patients with nephrosis. Stress, cancer, and arthritis have been asso-
ciated with lower AGP levels. Neonates have higher AGP levels. AGP is associated with
a higher inter-individual variability compared to albumin. Reduced levels of albumin
have been reported in myalgia patients. Drugs that are highly bound to plasma proteins
are confined to the vascular space and are not readily available for distribution to other
tissues and organs. Many carboxylic acid drugs are not easily displaced from plasma
proteins and have a low distribution volume. However, this is not true if the affinity
of a drug to tissue proteins is higher than that to plasma proteins. Ultrafiltration and equi-
librium dialysis are the two commonly employed methods for the determination of
plasma protein binding (Wright et al., 1996). Albumin is the principal drug-binding pro-
tein in tissues followed by ligandin. Measurement of tissue binding is not as straight for-
ward as that in plasma, as the tissue must be disrupted, and it is not readily accessible for
sampling. Tissue proteins cannot be easily separated into its constituents and cannot
easily be quantified.
The clearance (CL) of many low hepatic-extraction drugs is limited by protein bind-
ing. Only the unbound drug is available for glomerular filtration and therefore for renal
elimination. An increase in unbound drug concentration due to a reduced plasma protein
binding will enable higher tissue distribution and higher CL. However, since the half-life
of a drug is directly proportional to the distribution volume and inversely proportional to
CL, there is no net effect on the half-life. Thus, changes in plasma protein binding of a
drug are not likely to be clinically relevant (Benet and Hoener, 2002) except in the fol-
lowing cases:
(i) The drug is >98% bound to plasma proteins. In this case, even a small shift in
plasma protein binding can have a substantial effect on the clearance but less
so on the distribution volume, thus temporarily altering the unbound drug
concentrations.
(ii) The drug has high hepatic extraction. The clearance of such drugs will be depend-
ent only on the hepatic blood flow rate and not on the product of fup × CLint. Thus,
an increase in distribution volume is not sufficiently compensated for by an
increase in CL, leading to a temporary increase in unbound drug concentrations.
(iii) There is a rapid equilibrium between drug concentration and pharmacological

response (e.g., lidocaine with a PK-PD equilibration time of two minutes) com-
pared to the time required for the body to regain equilibrium (about 30 minutes).
Many anti-arrhythmic drugs and anesthetics require only a short time for a change
in concentration to cause a change in drug effect. In these cases, the response is
sensitive to small transient changes in unbound drug concentrations.
Differences in unbound drug concentrations discussed in (i) or (ii) will have a greater
impact on a drug with a narrow therapeutic window/safety margin. Scaling of pharmaco-
kinetic (PK) parameters like clearance or volume of distribution or translation of pharma-
codynamic properties (Mager et al., 2009) from preclinical species to man should always
be done with the unbound parameters. Any comparisons/correlations of PK parameters
should also be done with unbound values.
Some drugs also bind to and distribute into erythrocytes, the main drivers being lipo-
philicity, pKa and active uptake into the erythrocytes. Binding sites within erythrocytes are
hemoglobin, proteins like carbonic anhydrase, and plasma membrane. The blood–plasma
concentration ratio (R) of a drug is a measure of its binding and distribution to erythrocytes
relative to plasma. A compound having a similar extent of binding to the constituents of
erythrocytes and plasma has a blood–plasma ratio of 1. Acids tend to have R values of
around 0.5 and rarely exceed 1, and bases tend to have a higher range of values, often
exceeding 1 while neutrals and ampholytes have values of around 1 (Hinderling,
1997). Uchimura et al. (2010) describe several methods to determine R. Commonly, it
is determined by measuring the concentrations of 14C-labelled drug in erythrocytes (Ce)
and plasma (Cp) in freshly collected blood. Then, knowing the hematocrit, H (the volume
fraction of blood occupied by erythrocytes), R is obtained as follows:
Ce × H + Cp × 1 − H
R= (1.21)
Cp
According to Equation 1.21, considering an average H of 0.45, the minimum value of

R can be 0.55 which corresponds to no distribution into erythrocytes. However, there is no
upper limit. For tacrolimus, R is as high as 55 and exhibits concentration dependence
(Jusko et al. 1995). R can also be predicted (Paixão et al., 2009).
Partitioning can be fast for some drugs and distribution equilibrium is reached within
a few seconds to minutes. However, many drugs with primary amine groups show delayed
equilibrium probably due to the formation of Schiff bases with membrane fatty acids and
aldehydes. While the displacement of the plasma–protein–bound drug to the unbound is
rapid (except for protein molecules), displacement of erythrocyte bound drug is relatively
slow. For acids with high plasma protein binding, distribution into erythrocytes can sig-
nificantly affect its distribution volume, as other tissue compartments are not as significant.
If blood–plasma concentration ratios exceed 1, as is the case for lipophilic bases, then
plasma clearance significantly overestimates blood clearance and could even exceed
hepatic blood flow. This is because the concentrations measured in plasma will always
be much smaller compared to that measured in whole blood. This is due to greater distri-
bution into the erythrocytes when R is >1. Thus, blood clearance is related to plasma clear-
ance and blood–plasma ratio by the following equation:
Cb CLp
R= = (1.22a)
Cp CLb
Similarly, plasma and blood volume are related by
Cb V p
= (1.22b)
Cp V b
1.2.4 Hepatic, Renal, and Biliary Clearances
The CL estimated from dose and AUC (Equation 1.10) is the overall clearance of the drug
from blood, also called the total clearance. Several clearance pathways could contribute to
the total clearance of a drug. Hepatic metabolism, renal, and biliary pathways are some of
the clearance routes available for a xenobiotic. The most common route is hepatic metab-
olism. A drug may utilize one or more clearance pathways depending on its physicochem-
ical properties. The total clearance of a drug is the sum of its hepatic (CLH), renal (CLR),
and biliary (CLB) clearances.
CL = CLH + CLR + CLB

(1.23)
Qorgan × C ART − C VEN
CLorgan =
C ART
CLorgan is the clearance from an eliminating organ, Qorgan is the blood flow rate
to that organ, CART and CVEN are the arterial and venous concentrations.
(Qorgan × CART − Qorgan × CVEN) is the rate of elimination from that organ.
1.2.4.1 Hepatic Clearance. The liver is the most important eliminating organ, where
phase I and phase II metabolizing enzymes convert low molecular weight drugs into more
hydrophilic compounds with greater molecular weight which can enter bile or undergo
renal elimination. About 40 human CYP450 genes have been cloned and classified accord-
ing to sequence homology. Of these, only 3 CYP450 families and <12 unique enzymes
play a substantial role in the hepatic metabolism of drugs in humans. The rate of such
an enzyme driven biotransformation reaction, v, depends on the free concentration of
the drug, C, according to the Michaelis–Menten equation:
vmax × C
v = CLint × C = (1.24)
KM + C
CLint is the intrinsic clearance of the drug, vmax is the maximum velocity of the reaction,
and KM is the Michaelis–Menten constant (Figure 1.3). When the therapeutic concentra-
tion range is low relative to KM (true for many drugs), Equation 1.24 becomes:
vmax × C
v= (1.25)
KM
vmax
vmax
2
KM
Substrate concentration
Figure 1.3. Rate of an enzyme-catalyzed reaction as a function of substrate concentration.
Equation 1.25 suggests that the rate of a metabolic reaction varies linearly with the
drug concentration at concentrations not exceeding KM. CLint then equals the ratio of vmax
to KM and is independent of the drug concentration. However, when drug concentrations
are comparable with or exceeds KM, which can be the case at high drug doses, CLint is
dependent on C (see Equation 1.24). The greater the drug concentration, the greater
the extent of enzyme saturation and smaller the value of CLint. A maximal rate of metab-
olism vmax is reached at concentrations much higher relative to KM. Under these condi-
tions, zero-order kinetics is said to prevail, and a constant amount of drug is eliminated
per unit time, independent of the amount of drug in the body. Well-known examples of
drugs exhibiting nonlinear clearance include phenytoin, ethanol, methyl salicylate, and
theophylline (in some individuals). Apart from CLint, the hepatic clearance CLH is
dependent on how fast the drug is delivered to the enzymes in the hepatocytes determined
by the total blood flow rate to the liver, QLI. A basic tenet of pharmacokinetics is that only
the fraction of drug that is not bound to blood, fub, is available for distribution into tissues
and for clearance. The dependencies of CLH on CLint, QLI, and fub are encapsulated in the
well-stirred model, in which drug concentration in the liver is assumed to be uniform
throughout the tissue. According to this model, the hepatic clearance from blood,
CLH, is given by:
QLI × f ub × CLint
CLH = (1.26)
QLI + f ub × CLint
Equation 1.26 shows that when the product fup × CLint is high compared to QLI, then
CLH is simply determined by the blood flow rate to the liver. The drug clearance is limited
by the rate at which it is delivered to the drug metabolizing enzymes. On the other hand,
when the product fup × CLint is low compared to QLI, then the hepatic clearance linearly
varies with the product of fraction unbound in plasma and the intrinsic clearance.
The fraction of drug unbound in blood, fub is related to fup and R as follows:
Cb C ub × f up f up
R= = =
Cp C up × f ub f ub
(1.27)
f up
f ub =
R
1.2.4.2 Hepatic Extraction. The hepatic extraction ratio of a drug is obtained by tak-
ing QLI to the left-hand side in Equation 1.26
CLH f ub × CLint
= (1.28)
QLI QLI + f ub × CLint
For high CLint compounds, the displacement of the drug from plasma proteins is rapid
and equilibrium cannot be established between concentrations of the bound and unbound
drug in blood (Cb, Cu,b) and in liver (Cu,liver). This can be represented as:
Cb C u,b C u,liver
For low CLint compounds, there is equilibrium between the bound drug and unbound
drug in blood and liver and only the Cu,liver is available to the drug metabolizing enzymes.
The equilibrium between the different drug concentrations is shown below:
Cb C u,b Cu,liver
1.2.4.3 Renal Clearance. Hydrophilic drugs can get eliminated in the urine,
unchanged. For example, renal elimination is the predominant route for about 60% of
anti-infection compounds (Varma et al., 2009). The fraction of the dose excreted in the
urine unchanged (fe) is
Ae,unchanged CLR
fe = = (1.29)
Dose CL
where Ae,unchanged is the amount of drug excreted in the urine unchanged. Therefore,
CLR is
Ae,unchanged,IV Ae,unchanged,oral
CLR = = (1.30)
AUC iv AUC oral
Efferent
arteriole
Afferent
arteriole
Glomerulus
Glomerular
filtration Peritubular
capillary
Proximal Tubular
tubule reabsorption
Tubalar
secretion
To venous system
Urinary
elimination
Figure 1.4. Renal elimination of a drug: glomerular filtration, active tubular secretion, and
tubular reabsorption. Lipophilic drugs are readily reabsorbed, making renal elimination an
important route only for hydrophilic drugs.
CLR = fub × GFR, where GFR is the glomerular filtration rate, for a drug lacking tubular
active secretion or tubular reabsorption (Figure 1.4). GFR reflects passive diffusion of a
drug through the glomeruli. Active tubular secretion is evident if CLR > fub × GFR and tubu-
lar reabsorption is apparent when CLR < fub × GFR. Reported values of GFR are measured
with endogenous filtration markers like creatinine, which is freely filtered and secreted
(15%) in the proximal tubule. However, since the synthesis and blood concentration of cre-
atinine are influenced by several factors including age, sex, ethnicity, muscle mass, and
chronic illness, other markers such as serum cystatin C, 51CrEDTA or inulin are employed.
Drugs cleared exclusively in the kidney (such as hydrophilic acids and bases with high PSA
and rotatable bond count), generally tend to have low rates of renal clearance. This is due to
limited glomerular filtration and in some cases, absent active secretion. Apart from low
clearances, these compounds are also unaffected by CYP-related issues such as polymorph-
isms, drug–drug interaction (DDI) and reactive metabolites.
1.2.4.4 Biliary Clearance. Amphiphilic compounds (compounds with both acidic and
basic groups), with molecular weights >350 Da also have the possibility of being actively
transported into the bile and excreted via faces. Biliary clearance can be estimated by deter-
mining the concentration of a drug in the bile (Cbile) collected from a bile-duct cannulated
preclinical species.
Amount of drug secreted in bile per minute

CLB =
C (1.31)
Bile flow × C bile
CLB =
C
The parent drug in bile is emptied into the duodenal section of the small intestinal tract
via the sphincter of Oddi and may be reabsorbed back into the portal vein as it transits
down the intestine. This is called the enterohepatic recirculation (EHR). EHR contributes
to an increased half-life of a drug. Some phase II conjugates are also secreted into bile and
converted back to parent in the distal small intestine and reabsorbed as parent.
A metabolite of the drug can also be emptied into bile and into duodenum Figure 1.5.
Certain phase II metabolites such as glucuronides are emptied into bile and into duode-
num, get reconverted to the parent drug by the gut microflora in the distal intestine and
are reabsorbed and recirculated. Although the pharmacokinetic profile is very similar to
that associated with parent EHR, the measured Cbile for the parent drug in this case would
be low, allowing one to distinguish between parent and metabolite EHR.
1.2.5 Extravascular (Subcutaneous, Intramuscular, and Per Oral) Absorption
Other than IV administration, all other routes require the drug to be absorbed into the capil-
laries that surround the site of administration. The rate of absorption of a drug in solution
administered by IM and SC routes is limited by the perfusion to the tissue. It also depends
on the type of tissue at the site of administration – the density, vascularity, and the fat con-
tent. The IM route for example has higher rate of absorption compared to the SC because of
lesser fat and greater vascularity of the dense muscles. The muscle tissue has a greater
blood supply than the tissue just under the skin and can hold a larger volume of medication
than subcutaneous tissue.
Oral drug absorption refers to the transport of drug molecules across the enterocytes
lining the gastrointestinal (GI) tract into the venous capillaries along the gut wall. The rate
of oral drug absorption depends on several physiology-, drug-, and formulation-dependent
factors such as gastric emptying rate, intestinal motility, porosity of tight junctions, lumi-
nal and mucosal enzymology, carrier and efflux transporters, small-intestinal secretions
(bile and digestive enzymes), regional differences in pH, membrane permeability, solubil-
ity, and dissolution rate. An orally absorbed drug is subjected to first pass metabolism in
the gut and liver before it is available in systemic circulation.
PK profiles from all extravascular routes are characterized by a maximum systemic
concentration (Cmax) and tmax, the time at which the Cmax is achieved (Figure 1.6a). Only a
fraction of the administered dose is available for systemic circulation. This fraction is
called bioavailability (F) of the drug.
Cystic Common
duct hepatic duct
Right hepatic duct
Left hepatic duct
Liver
Bile
capillaries
Gallbladder
Portal Pyloric
vein sphincter
Small intestine
Figure 1.5. Entero-hepatic recirculation of a parent drug or a metabolite.
Considering first-order absorption, the rate of change of the amount of drug in the
body following oral administration is given by the rate of drug absorbed into systemic cir-
culation (F × A0 × e − ka t is the amount available at any time for absorption) minus the rate
of drug elimination from systemic circulation as shown in Equation 1.32a:
dA
= F × k a × A0 × e − ka t − kel × A (1.32a)
dt
Integrating 1.32a, and dividing both sides by volume,
F × k a × A0
C= × e − kel t − e − ka t (1.32b)
V ss × k a − k el
The oral bioavailability of a drug can be estimated from the areas under the PK profiles
of intravenous and oral doses, by assuming that the hepatic clearance does not vary between
the IV and oral routes. When the oral and IV doses are the same (see Figure 1.6b, c),
AUC oral
F= (1.33)
AUC iV
When the oral and IV doses are different,
AUC oral
Doseoral CLIV
F= AUC IV
= (1.34)
DoseIV
CLoral
Therefore,
Doseoral
F × CLoral = F × = CLIV (1.35)
AUC oral
Similar Equations 1.32–1.35 apply for other extravascular routes also. If absorption
from the site of administration is fast, the terminal slope of the semilogarithmic concen-
tration-time profile is defined by drug elimination rate. It is therefore parallel to the termi-
nal slope of IV profile (see Figure 1.6b, c). It is then possible to extract the absorption rate
constant and the elimination rate constant by the curve stripping method illustrated in
Figure 1.6d. Alternatively, tmax may be calculated (tmax = ln(ka/kel)/(ka − kel)), assuming
that contributions from processes other than absorption to tmax are negligible. In SC
and topical administrations, drug absorption is slow, and the absorption rate constant,
ka, is much slower than the kel (elimination constant) (Figure 1.6e). This is also referred
to as flip-flop kinetics. The PK profile in these routes is sometimes characterized by a lag
time tlag. Flip-flop kinetics and lag time can also occur when the oral route of administra-
tion is used, if gastric emptying is delayed for some reason (fed state, elderly, drug-induced
etc.).
The oral bioavailability of a drug is given by
F = f abs × f gut × f hep (1.36)
where fabs is the fraction of dose absorbed, fgut is the fraction escaping gut extraction, and
fhep is the fraction escaping hepatic extraction. If the IV PK profile is available, knowing
the hepatic clearance, hepatic extraction, EH, can be calculated using Equation 1.26. fhep is
related to EH by
f hep = 1 − EH (1.37a)
(a) (b) (c)
10
100 100
IV IV
PO
Concentration (mg/L)
Cmax PO PO
10 10 Slope defined by
elimination rate
= –kel/2.303
tmax
1 1 1
0 20 40 60 0 20 40 60 0 10 20 30 40 50 60
Time (h) Time (h) Time (h)
(d) (e)
10 100
(4, 6.6) PO IV
PO
(4, 5.2) Slope defined by

10 absorption and
elimination
Residual
slope = –ka
slope = –ka
(4, 1.4) tlag
1 1
0 20 40 60 0 10 20 30 40 50 60
Time (h) Time (h)
Figure 1.6. Oral pharmacokinetic profiles. (a) Maximum systemic concentration (Cmax) and time at which Cmax is achieved (tmax) following oral
administration of a drug. (b) AUC for an orally administered drug that is nearly half of the AUC following IV administration of the same dose of that
drug, indicating that the drug has about 50% oral bioavailability. (c) Area under the curve (AUC) for an orally administered drug that is nearly the
same as the AUC following IV administration of the same dose of that drug, indicating that the drug has high oral bioavailability. (d) Curve stripping:
Absorption rate constant ka is obtained from the residual slope of the straight line constructed by plotting the differences between the back-
extrapolated terminal slope and the observed curve in a semilogarithmic plot (illustrated with one of the four points plotted). (e) Flip-flop kinetics
with a lag time, tlag. Using the curve stripping method described in (d), the tlag and the ka can be obtained as shown.
Substituting for EH using Equation 1.28, and assuming systemic clearance (CLIV) is
driven by hepatic metabolism only,
CLH CLIV
f hep = 1 − = 1− (1.37b)
QLI QLI
Knowing the F (Equation 1.34) and fhep, the gut bioavailability (fabs × fgut) of a drug may
be estimated using Equation 1.36. Often, the IV PK may not be available, especially for
poorly soluble drugs requiring separate formulations. These are costly to develop and may
not be stable. Estimation of oral PK parameters in the absence of IV PK is described in
Box 1.1. In the absence of IV PK, fhep may be estimated by assuming complete drug absorp-
tion and neglecting gut metabolism, in which case the value of gut bioavailability becomes 1.
In the absence of flip-flop kinetics, the elimination rate and the half-life may be obtained from
the terminal slope of the oral PK profile. Obtaining clearance from fhep, the volume of dis-
tribution may be calculated. If gut metabolism cannot be neglected, then clearance can be
calculated from the terminal half-life, using a predicted volume of distribution.
1.2.6 Absorption from Solid Dosage Forms
An oral drug may be available in several dosage forms including the more common tablets
and soft/hard gel capsules. A tablet comprises of the active pharmaceutical ingredient
(API) and excipients compacted together and coated. Excipients include binders, flow-
aids, lubricants, preservatives, solubilizing, and flavoring agents. The release from these
dosage forms and the dissolution of the drug may limit the rate of absorption.
The oral route is noninvasive and thus the most convenient route of drug administration.
However, the bioavailability of many oral drugs is limited by drug solubility, dissolution,
membrane permeability, or gut metabolism. Special formulations may therefore be needed
to enhance drug exposure to the target tissue and control the exposure profile of a drug
through the development of enabling and controlled-release formulations respectively.
During drug development, the performance of different formulations, dosage forms,
routes and different conditions of disease, fed/fasted states etc., may be compared even
without IV PK, by determining the relative bioavailability, defined by Equation 1.38:
Doseoral
FA CLIV AUC oral A
Relative bioavailability = = (1.38)
FB CLIV Doseoral
AUC oral B
Assuming that the IV clearance (CLIV) is same in both conditions, Equation 1.38
reduces to
Doseoral
FA AUC oral B CLoral B
Relative bioavailability = = = (1.39)
FB Doseoral CLoral A
AUC oral A
To ensure equivalent performance of different batches of drug formulations, regula-

tory agencies require bioequivalence studies to be performed. To establish bioequivalence,
the 90% confidence interval about the geometric mean test/reference ratios for both AUC
and Cmax must fall within the bioequivalence range, which is 80–125%.
Box 1.1
(a) 1. Gut bioavailability fabs × fgut = 1 2. Assuming validity of predicted plasma volume
6 PO
Plasma concentration (mg/L)
• Estimate oral plasma clearance (CLoral,p) using • Using a predicted plasma volume (Vp) of 1 L/kg,
5
Dose (mg) 500 AUCoral,p (Fig a on the right) calculate Vb. If R = 0.8 and body weight is 70 kg
4 AUCoral,p (mg.h/L) 175.8
= = 2.9 L/h = = 87.5 L
,
3 ,
• Estimate IV blood clearance (CLV;b) using kel

2 • Convert oral plasma clearance, CLoral,p, to oral blood (Fig b)
Extrapolated clearance, CLoral,b using equation 1.22a. If R = 0.8 = × = 3.5 L/h
1 Area under ,
the cuve, area
AUCoral,p = ,
= 3.6 L/h • Using liver blood flow (QLi = 90 L/h), estimate
,
0 fraction escaping hepatic extraction (fhep)
0 50 100 150
Time (h) • According to equations 1.36 and 1.37
fhep = 1 – ,
= 0.96
F= ,
; f hep = 1 – ,
(b) 10 PO
,
• Estimate oral plasma clearance (CLoral,p) using
Plasma concentration (mg/L)
AUCoral,p (Fig a on the right)

kel (h–1) 0.04 • Estimate Cliv,b.: Assuming gut bioavailability (fabs ×
fgut) to be 1, fraction escaping hepatic extraction
half-life (h) 17 (fhep) is eqaul to bioavailability (F) (equation 1.36). , = = 2.9 L/h
,
Equating the right hand sides of the two equations,
Slope = –kel = rearranging and using liver blood flow (QLi = 90 L/h) • Convert oral plasma clearance, CLoral,p, to oral blood
–0.693/half-life
, × clearance, CLoral,b using equation 1.22a. If R = 0.8
, = = 3.5 / ; = 0.96; = 0.97
, +
,
= = 3.6 L/h
• Use CLiv,b and kel (Fig b on the right) to calculate
,
1 Vb.
0 20 40 60 , • Calculate bioavailability (F) using equation 1.34
= = 90 L
Time (h) and gut bioavailability (Fgut), using equation 1.36
F= , = 0.97; = × = =1
,
1.2.7 Role of Transporters in ADME
Transporters (Figure 1.7a) play an important role in enhancing or limiting the disposition
of drugs (Ho and Kim, 2005) in plasma, target issue, as well as in blood–brain barrier
(Shen and Zhang, 2010) as shown in Table 1.2. About 400 genes code for transporters
(a)
Intestine Brain
OATPs 2, 3
PEPT1
BCRP
MCT1
MRP2
OATP
ASBT
MCT1
OAT3
P-gp
ATP ATP ATP

ATP ATP
ATP ATP
OATP1A2
OATP2B1
MRPs 1, 3
MRPs 4, 5
OST α/β
OCT1
BCRP
P-gp
OA
Vascular space
1B1,1B3,2 B1
OC
OATs 1, 2, 3
OATP4C1
OATPs
PEPT1, 2
OST α/β
OCT2
OAT2
OCT1
NTCP
MRP1
OAT7
OC
OC
ATP
DC ATP
ATP
ATP
DC
ATP
ATP ATP ATP MRPs 3, 4, 6

MATE 1, 2-K
ATP
OCTNs 1, 2
MRP s 2, 4
MATE1
PEPT1, 2
ATP
BSEP
MDR3
URAT1
P-gp
RP
OAT4
BCRP
P2
P-gp
BC
MR
PM
H
Bile
OA
H
H
OA
Liver Urine
Proximal
tubule
in kidney
Figure 1.7. (a) Uptake and efflux drug transporters in intestine, liver, kidney, and brain. OAT,
organic anion transporter; OATP, organic anion-transporting polypeptide; NTCP, sodium
taurocholate cotransporting peptide; OCT, organic cation transporter; OCTN, novel-type
OCT; PEPT, oligopeptide transporter; ASBT, apical sodium-dependent bile acid transporter;
MDR, multidrug-resistant (or resistance); MRP, multidrug resistance-associated protein;
BCRP, breast cancer resistance protein; MATE, multidrug and toxin extrusion; MCT,
monocarboxylate transporter; OST, organic solute transport; URAT, urate transporter.
(b) Primary active ATP-Binding Cassette (ABC) efflux transporters derive energy from the
hydrolysis of ATP to ADP and are shown in dark shade. The secondary active transporter
families or solute carrier (SLC) uptake transporters, utilize either ion gradients across
membranes or cotransport with intracellular and/extracellular ions. These are either
symports (unshaded) or antiports (lightly shaded). Multi-drug efflux pump, MATE is a
cation-coupled family of transporters. OST α/β is a heterodimer that together transports
bile acids, conjugated steroids, and structurally related molecules. Clinically relevant
transporters are shown in bold (Source: Ho and Kim 2005).
Co-transporters ion,
(b) usually H + , Na + , HCO3–
C
EC
IC
I ATP
T
DP
ADP
Uniport Symport
ymport Antiport
nti ort ATP binding
SLC passive SLC active SLC active cassette (ABC) efflux,
unidirectional coupled coupled active unidirectional
facilitated transport transport transport. MDRs, BCRP,
diffusion PEPT, ASBT OATPs, MATEs MRPs, BSEP
OCTs, GLUT
Figure 1.7. (Continued)
T A B L E 1.2. Role of transporters in ADME.

ADME Transporter Example Role
Absorption Carriers PEPT Enhances absorption by transporting

hydrophilic compounds with specific
groups like peptide linkages
Absorption Efflux P-gp Limits absorption of large lipophilic
BCRP molecules. P-gp has broad specificity
MRP2
Absorption Uptake OATP Uptake of organic ions
Distribution Uptake, efflux Various Increases or decreases tissue distribution
Metabolism Uptake OATP1B1 Increases or decreases exposure to drug-
OATP1B3 metabolizing enzymes thereby increasing
OATP2B1 or decreasing metabolism
Biliary elimination Efflux P-gp Increases biliary elimination of lipophilic,
BCRP amphiphilic compounds
Renal elimination Uptake OAT 1,2,3 Increases uptake and elimination of
OCT2 hydrophilic compounds
OATP4C1
Renal elimination Efflux P-gp, MATE1, Removal (active secretion) of toxins
MATE2-K
MRP2, 4
in human and animals and these are classified into two large super-families – the solute
carrier or SLC superfamily containing 364 proteins in 48 subfamilies (Fredriksson
et al., 2008) and the ATP-binding cassette or ABC transporters of 49 proteins in 7 sub-
families. The SLC transporters mediate cellular influx of substrates either by facilitated
diffusion or by secondary active transport, driven by co-transport (symport or antiport)
of endogenous organic ions (Zhang et al., 2002; Hediger et al., 2004; Hagenbuch and
Gui, 2008; Duan and You, 2010). ABC transporters mediate the primary active transport
of unidirectional efflux of drugs often against a steep diffusion gradient, deriving energy
from ATP hydrolysis (Van De Water et al., 2005; Szakács et al., 2008; Schinkel and
Jonker, 2012). The transporters that play an important role in human disposition are the
active SLC transporters OATP1B1, 1B3 and 2B1, SLC transporters that mediate facili-
tated diffusion OCTs 1 and 2, SLC antiport transporters MATE1 and MATE2K, and
the ABC efflux transporters P-gp (MDR1), MRP2 (important in the transport of glucur-
onide and glutathione conjugates), BCRP and BSEP. ATP-independent secondary efflux
transporters are probably present an additional mechanism for toxin extrusion even if cells
are energy-deprived. The different types of transporters are shown in (Figure 1.7b).
The role of the efflux transporter P-gp in restricting absorption, transporting amphi-
philic compounds into bile and keeping out lipophilic compounds from the brain has long
been recognized. It is difficult to predict the disposition of compounds that are transported,
as the substrate specificity to most transporters are dependent on the chemical structure of
the drug. However, there are some general principles for identifying transporter substrates
(Wright and Dantzler, 2004; El-Sheikh et al., 2008; Nies et al., 2008; Ahn and Nigam,
2009; Kusuhara and Sugiyama, 2009). For example, P-gp substrates are mostly large
and lipophilic. Substrates of the uptake transporter OATP1B1 are mostly carboxylic acids
and so on. Efflux transporters like MRP2 and BCRP have similar substrate specificity to
uptake transporters, reducing the possibility for toxin accumulation.
Absorption, distribution, renal elimination, and biliary elimination are all dependent
on physicochemical properties of the drug, particularly lipophilicity and acid/base/neutral
characteristics and physiology of the species like blood flow, organ volumes, transit rates
etc. The chemical structure of a drug dictates its rate and extent of biotransformation as
well as affinity to transporters.
Although in vitro assays may identify potential substrates of transporters, their rele-
vance in vivo depends very much on the expression levels of transporters in the tissue and
on the concentration of the drug relative to its KM. If the affinity of the drug to the protein is
high (low KM) and/or the drug concentrations are high, the transporters are easily saturated.
For example, P-gp efflux in the enterocytes is easily saturated by many of its substrates.
The rate of P-gp efflux in the gut also depends on the membrane permeability of the drug
and the rate of gut metabolism. For high permeability drugs with high gut extraction, the
rate of efflux is low. The impact of uptake or efflux transporters in increasing or decreasing
intracellular concentrations of their substrates is much more for low permeability drugs
compared to high permeability drugs. P-gp and CYP3A4 share a common substrate spec-
ificity. In the gut, where drug concentrations can be high, this enzyme–transporter inter-
play (Benet, 2009) increases the probability of contact between the drug and enzyme, by
making it possible for CYP3A4 to remain unsaturated due to the dilution effects of P-gp
efflux. The mean residence time of drug and enzyme also increases, as the drug is pre-
sented to the enzymes repeatedly while it transits down the small intestine. P-gp efflux
however, also offers a competing mechanism to metabolism both in the liver and in the
gut. The roles of renal anionic and cationic transporters in drug disposition have been
reviewed (Dresser et al., 2001; Masereeuw and Russel, 2010).
1.2.8 Linear and Non-Linear Pharmacokinetics
Most drugs are expected to have linear PK at therapeutic concentrations. However, mul-
tiple factors can contribute to nonlinearity even at therapeutic concentrations. For drugs in
infection and cancer therapeutic areas, where therapeutic doses are generally high, the high
drug concentrations can saturate the enzymes and transporters that are involved in their
metabolism and elimination in the gut, liver, and other elimination organs. For example,
nonlinear PK is frequently observed for antiretroviral drugs. Drugs that inhibit or induce
enzymes can cause auto-inhibition or auto-induction, leading to time- or concentration-
dependent changes in exposure. Drugs binding plasma proteins, especially to AGP can
also exhibit nonlinear kinetics due to the saturation of protein binding. Certain drugs (most
monoclonal antibody drugs and some small molecules) bind to their pharmacological tar-
get (such as a receptor) with high affinity. The internalization of the receptor–drug com-
plex triggered by the high-affinity receptor binding can then influence the distribution and
elimination of the drug. This phenomenon is called target-mediated drug disposition
(TMDD). Saturation of enzyme-, transporter- and plasma proteins, autoinhibition, autoin-
duction, and TMDD-driven clearance leads to higher exposures at higher doses, while
autoinduction leads to lower exposures at higher doses. Poorly soluble drugs with high
therapeutic doses are at a risk of incomplete absorption and therefore lower exposures
at higher doses. An important clinical implication of nonlinear pharmacokinetics
(Ludden, 1991) is the altered half-life, which leads to a longer or shorter time to achieve
a given fraction of steady state. Since dose predictions are often done for the steady state,
nonlinearity makes any predictions of disposition highly uncertain.

and Accumulation
For short half-life drugs that require plasma or tissue concentrations to be maintained at the
therapeutic level for a short treatment period, a constant-rate IV infusion administered in
hospital-settings via a drip or pump offers the best solution. With a constant-rate infusion,
the rate of change in the amount of drug in plasma is the difference between the rate of drug
infusion, R0, (what goes in) and its rate of elimination (what goes out). Expressing this
mathematically (see Equations 1.1 and 1.2),
− dA
= R0 − k el × A (1.40)
dt
− VdC
= R0 − CL × C (1.41)
dt
At steady state (SS), the rates of what goes in and what goes out are equal and there is
no net change in the drug amount or concentration in the plasma. In other words, the left-
hand sides of both Equations 1.40 and 1.41 become zero. It follows that at steady state, the
amount and the concentration of a drug in plasma at steady state are given by
R0
ASS = (1.42)
k el
R0
C SS = (1.43)
CL
Recognizing that MRT is the same as the inverse of the elimination rate constant (i.e.,
time spent by a molecule in the body), it follows from Equations 1.42 and 1.2 that
1 V SS ASS
MRT = = = (1.44)
k el CL R0
Thus, knowing MRT and CL, the steady state volume of distribution (VSS) of a drug
can be estimated.
The elimination of an IV bolus dose generally follows an exponential decay starting
from an initial concentration, C0. If the initial concentration is assumed to be the steady
state concentration, Css, the concentration of the drug at any time, t, (Ct), after the cessation
of infusion is given by:
C t = Css e − kel × t (1.45)
When a drug is infused intravenously at a constant rate, the plasma concentration con-
tinues to rise until elimination equals the rate of delivery into the body, at which point a
steady state is said to have been reached. This is illustrated in Figure 1.8a. Mathematically,
the time dependence of the infusion curve is obtained by subtracting the exponential term
from 1 and expressed as follows:
C t inf = C SS × 1 − e − kel × t (1.46)
Ct(inf ) is the concentration of the drug at any time t, following a constant rate infusion of
the drug. Equation 1.46 suggests that this concentration will tend towards the steady state
concentration, as t approaches infinity. Also, regardless of the drug, 50% of the plateau
concentration is attained in 1 half-life of the drug. 75, 87.5, and 93.75% of the plateau
concentration are reached in 2, 3, and 4 half-lives, respectively. For all practical purposes,
the time to reach steady state is about 3–5 half-lives. Thus, the time required to reach
steady state depends only on the drug’s half-life. The shorter the half-life, the more rapidly
the steady state is reached. The size of the dose and the route of administration have little
effect. Figure 1.8b shows the concentration-time profile of a successively administered
oral drug. The profile parallels that observed for the constant rate infusion. However, fluc-
tuations occur within each dosing interval, as a dose is absorbed and eliminated, leading to
a Css,max and a Css,min. Cav is the average of Css,max and Css,min. The Css after an IV infusion
or Css,av following repeated oral doses are simply given by the ratio of dosing rate to clear-
ance and given by:
Dosing rate Dose × F Dose × F

C SS = ; C SS,av = ; C SS,av,u = f up × (1.47)
Clearance τ × CL τ × CL
F is the bioavailability of a non-IV drug, and τ is the dosing interval, which is 24 hours
for a once daily drug. Css,av.u is the unbound steady state drug concentration and fup is
the fraction unbound in plasma. According to Equation 1.47, the steady state concen-
tration of the drug increases as clearance decreases. This is the case for drugs exhibiting
nonlinear clearance at therapeutic doses either due to enzyme saturation or autoinhibi-
tion. In addition, since clearance decreases with increasing doses, the apparent half-life
increases with increasing dose. Consequently, the time to reach steady state increases
with dose.
The magnitude of drug concentrations at steady state compared with that after the first
dose is determined by the relationship between dosing interval and the half-life. The ratio
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quexarme quise, y no fuy
escuchado,
huyr quise de amor, quedé
corrido;
de solo oluido, no podré
quexarme,
porque aun no se acordaron
de oluidarme.
Yo hago a todo mal solo vn
semblante,
jamas estuue oy triste, ayer
contento,
no miro atras, ni temo yr
adelante;
vn rostro hago al mal, o al bien
que siento.
Tan fuera voy de mi, como el
dançante,
que haze a qualquier son
mouimiento,
y ansí me gritan todos como a
loco;
pero segun estoy aun esto es
poco.
La noche a vn amador le es
enojosa,
quando del dia atiende bien
alguno:
y el otro de la noche espera
cosa
qu'el dia le haze largo y
importuno;
con lo que vn hombre cansa,
otro reposa,
tras su desseo camina cada
vno,
mas yo siempre llorando el dia
espero:
y en viendo el dia, por la
noche muero.
Quexarme yo de amor, es
escusado:
pinta en el agua, o da bozes al
viento:
busca remedio en quien jamas
le ha dado
que al fin venga a dexalle sin
descuento.
Llegaos a él a ser aconsejado,
dirá os un disparate y otros
ciento.
Pues quién es este amor? Es
una sciencia
que no la alcança estudio ni
experiencia.
Ama a mi señora a su
Sireno;
dexaua a mí, quiça que lo
acertaua:
yo triste a mi pesar, tenia por
bueno,
lo que enla vida y alma me
tocaua.
A estar mi cielo algun dia
sereno,
quexara yo de amor si le
añublaua,
mas ningun bien diré que me
ha quitado,
ved cómo quitará lo que no ha
dado.
No es cosa amor, que aquel
que no lo tiene
hallará feria a do pueda
comprallo,
ni cosa que en llamandola, se
uiene,
ni que le hallareys, yendo á
buscallo:
Que si de uos no nace, no
conuiene
pensar que ha de nascer de
procurallo:
y pues que jamas puede amor
forçarse,
no tiene el desamado que
quexarse.
No estaua ocioso Sireno, al

tiempo que Syluano estos versos
cantaua, que con sospiros
respondia a los vltimos accentos
de sus palabras, y con lagrimas
solennizaua lo que dellas
entendia. El desamado pastor,
despues que vuo acabado de
cantar, se començo a tomar
cuenta de la poca que consigo
tenia: y como por su señora Diana
auia oluidado todo el hato y
rebaño, y esto era lo menos.
Consideraua que sus seruicios
eran sin esperanza de galardon,
cosa que a quien tuuiera menos
firmeza, pudiera facilmente atajar
el camino de sus amores. Mas
era tanta su constancia que
puesto en medio de todas las
causas que tenia de oluidar a
quien no se acordaua dél, se salia
tan a su saluo dellas, y tan sin
perjuyzio del amor que a su
pastora tenia, que sin miedo
alguno cometia qualquiera
imaginación[1213] que en daño de
su fe le sobreuiniesse. Pues como
viό Sireno junto a la fuente, quedó
espantado de velle tan triste, no
porque ignorasse la causa de su
tristeza, mas porque le paresció,
que si él huuiera rescebido el mas
pequeño fauor que Sireno algun
tiempo rescibio de Diana, aquel
contentamiento bastara para toda
la uida tenelle. Llegó se a él, y
abraçandose los dos, con muchas
lagrimas se boluieron a sentar
encima de la menuda yerba: y
Syluano començo á hablar desta
manera: ¡Ay, Sireno, causa de
toda mi desuentura, o del poco
remedio della, nunca Dios quiera
que yo de la tuya reciba
uengança, que quando muy a mi
saluo pudiesse hacello no
permitiria el amor que a mi señora
Diana tengo, que yo no fuesse
contra aquel en quien ella con
tanta voluntad lo puso. Si tus
trabajos no me duelen, nunca en
los mios haya fin: si luego que
Diana se quiso desposar, no se
me acordo que su desposorio y tu
muerte auian de ser a vn tiempo,
nunca en otro mejor me vea que
este en que aora estoy. Pensar
deues, Sireno, que te queria yo
mal, porque Diana te queria bien
y que los fauores que ella te hazia
eran parte para que yo te
desamasse: Pues no era de tan
baxos quilates mi fe, que no
siguiesse a mi señora, no solo en
quererla, sino en querer todo lo
que ella quisiesse. Pesarme de tu
fatiga, no tienes porque
agradescermelo: porque estoy tan
hecho a pesares que aun de
bienes mios me pesaria, cuanto
más de males agenos.
No causó[1214] poca admiracion a
Sireno las palabras del pastor
Syluano; y ansi estuuo un poco
suspenso, espantado de tan gran
suffrimiento y de la qualidad del
amor que a su pastora tenia. Y
boluiendo en si, le
respondio[1215]. Por ventura,
Syluano, has nascido tú para
exemplo de los que no sabemos
suffrir las aduersidades que la
fortuna delante nos pone? O
acaso te ha dado naturaleza tanto
animo en ellas que no solo baste
para suffrir las tuyas, mas que
aun ayudes a sobrelleuar las
agenas? Veo que estás tan
conforme con tu suerte, que no te
prometiendo esperança de
remedio, no sabes pedille mas de
lo que te da. Yo te digo, Syluano,
que en ti muestra bien el tiempo,
que cada dia va descubriendo
nouedades muy agenas de la
imaginacion de los hombres. O
quánta más embidia te deue tener
este sin ventura pastor, en verte
suffrir tus males, que tú podrias
tenelle a él al tiempo que le veias
gozar sus bienes. ¿Viste los
fauores que me hazia? Viste la
blandura de palabras, con que me
manifestaua sus amores? Viste
como lleuar el ganado al rio,
sacar los corderos al soto, traer
las ouejas por la siesta a la
sombra destos alisos, jamas sin
mi compañia supo hazello? Pues
nunca yo vea el remedio de mi
mal, si de Diana esperé, ni
desseé, cosa que contra su
honrra fuesse, y si por la
ymaginacion me pasaua, era
tanta su hermosura, su valor, su
honestidad, y la limpieza del amor
que me tenia, que me quitauan
del pensamiento qualquiera cosa
que en daño de su bondad
imaginaua[1216]. Esto creo yo por
cierto, dixo Syluano sospirando:
porque lo mesmo podré affirmar
de mi. Y creo que no vuiera nadie
que en Diana pusiera los ojos,
que osara dessear otra cosa, sino
verla y conuersarla. Aunque no sé
si hermosura tan grande, en algun
pensamiento, no tan subiecto
como el nuestro, hiziera algun
excesso, y mas si como yo un dia
la vi, acertara de vella, que estaua
sentada contigo, junto a aquel
arroyo, peinando sus cabellos de
oro: y tú estauas teniendo el
espejo, en que de quando en
quando se miraua. Mas no
sabiades los dos, que os estaua
yo acechando deste aquellas
matas altas, que estan junto a las
dos enzinas: y aun se me acuerda
de los uersos que tú le cantaste,
sobre auerle tenido el espejo en
quanto se peinaua. Cómo los
vuiste a las manos, dixo Sireno?
Syluano le respondió: El otro dia
siguiente hallé aqui vn papel, en
que estauan escritos, y los leí, y
aun los encomende a la memoria.
Y luego vino Diana por aqui
llorando, por auellos perdido, y
me preguntó por ellos; y no fue
pequeño contentamiento para mí,
ver en mi señora lagrimas que
pudiesse[1217] remediar.
Acuerdome, que aquella fue la
primera vez que de su boca oí
palabra sin yra, y mira quan
necessitado estaua de su
fabor[1218], que de decirme ella
que me agradecía darle lo que
buscaba, hize tan grandes
reliquias[1219] que mas de un año
de grandisimos males desconte
por aquella sola palabra, que
traya alguna apariencia de bien.
Por tu uida, dixo Sireno, que
digas los uersos, que dizes que
yo le canté, pues los tomaste de
coro. Soy contento, dixo Syluano,
de esta manera dezian.
De merced tan extremada
ninguna deuda me queda,
pues en la misma moneda,
señora, quedays pagada.
Que si gozé estando alli
viendo delante de mi
rostro, y oyos soberanos:
vos tambien viendo en mis
manos
lo que en vuestros ojos vi.
Y esto no os parezca mal,
que de vuestra hermosura
vistes sola la figura,
y yo vi lo natural.
Vn pensamiento extremado,
jamas de amor subjetado,
mejor uee, que no el captiuo,
aunque el uno uea lo biuo,
y el otro lo debuxado.
Qvando esto acabó Sireno de oyr,

dixo contra Syluano: plega a Dios,
pastor, que el amor me dé
esperança de algun bien
impossible, si ay cosa en la vida
con que yo mas facilmente la
passasse que con tu
conuersacion, y si agora en
estremo no me pesa que Diana te
aya sido tan cruel, que siquiera no
mostrasse agradecimiento a tan
leales seruicios, y a tan verdadero
amor como en ellos has
mostrado. Syluano le respondio
sospirando. Con poco me
contentara yo, si mi fortuna
quisiera; y bien pudiera Diana, sin
offender á lo que a su honra, y a
tu fe deuia darme algun
contentamiento, mas no tan solo
huyó siempre de darmele, mas
aun de hazer cosa por donde
imaginasse que yo algun tiempo
podria tenelle. Dezia yo muchas
vezes entre mí: Aora esta fiera
endurescida no se enojaria algun
dia con Sireno, de manera que
por vengarse dél, fingiesse
favorescerme a mi? Que vn
hombre tan desconsolado, y falto
de fauores, aun fingidos los ternia
por buenos. Pues quando desta
tierra te partiste, pense
verdaderamente, que el remedio
de mi mal me estaua llamando a
la puerta, y que el oluido era la
cosa más cierta, que despues de
la ausencia se esperaua, y más
en coraçon de muger. Pero
quando despues vi las lagrimas
de Diana, el no reposar en la
aldea, el amar la soledad, los
continuos sospiros, Dios sabe lo
que senti. Que puesto caso que
yo sabia ser el tiempo vn medico
muy aprouado para el mal que la
ausencia suele causar, vna sola
hora de tristeza no quisiera yo
que por mi señora passara,
aunque della se me siguieran a
mí cien mil de alegria. Algunos
dias, despues que te fuyste, la vi
junto a la dehesa del monte,
arrimada a vna enzina, de pechos
sobre su cayado, y desta manera
estuuo gran pieça antes que me
viesse. Despues alçó los ojos, y
las lagrimas le estoruaron verme.
Deuia ella entonces imaginar en
su triste soledad, y en el mal que
tu ausencia le hazia sentir, pero
de ay a vn poco (no sin lagrimas,
acompañadas de tristes sospiros)
sacó vna çampoña, que en el
çurron traya; y la començo a tocar
tan dulcemente, que el valle, el
monte, el rio, las aues
enamoradas, y aun las sierras de
aquel espesso bosque quedaron
suspensas, y dexando la
çampoña al son que ella auia
tañido, començo esta cancion:
Cancion.
Ojos que ya no veys quien

os miraua,
(quando erades espejo en que
se via)
qué cosa podreys ver que os
dé contento?
Prado florido y verde, do algun
dia
por el mi dulce amigo yo
esperaua,
llorad comigo el graue mal que
siento.
Aqui me declaró su
pensamiento,
oyle yo cuytada,
mas que serpiente ayrada,
llamandole mil vezes atreuido.
Y el triste alli tendido[1220],
paresce que es ahora, y que lo
veo,
y aun esse es mi desseo,
¡ay si lo viesse yo, ay tiempo
bueno!
ribera vmbrosa, qué es del mi
Sireno?
Aquella es la ribera, este es
el prado,
de alli parece el soto y valle
vmbroso,
que yo con mi rebaño
repastaua.
Veys el arroyo dulce y
sonoroso,
a do pascia la siesta mi
ganado
quando el mi dulce amigo aqui
moraua.
Debaxo aquella haya verde
estaua,
y veys alli el otero
a do le vi primero,
y a do me vio: dichoso fue
aquel dia,
si la desdicha mia,
vn tiempo tan dichoso no
acabara.
O haya, o fuente clara,
todo está aquí, mas no por
quien yo peno.
Ribera vmbrosa, qu'es de mi
Sireno?
Aqui tengo un retrato que
me engaña,
pues veo a mi pastor quando
lo veo,
aunque en mi alma está mejor
sacado:
Quando de verle llega el gran
desseo
de quien el tiempo luego
desengaña,
a aquella fuente voy, que está
en el prado,
Arrimolo a aquel sauze y a
su lado
me assiento (ay amor ciego)
al agua miro luego,
y veo a mí y a él, tomo la via
quando él aqui viuia.
Esta inuencion vn rato me
sustenta,
despues caygo[1221] en la
cuenta
y dize el coraçon, de ansias
lleno:
ribera vmbrosa, qu'es d'el mi
Sireno?
Otras vezes le hablo, y no
responde
y pienso que de mí se esta
vengando,
porque algun tiempo no le
respondia,
Mas digole yo triste assi
llorando:
hablad, Sireno, pues estays
adonde
jamas ymaginó mi fantasia.
No veys, dezi, que estays n'el
alma mia?
Y él todavia callado
y estarse alli a mi lado:
en mi seso le ruego que me
hable:
¡qué engaño tan notable
pedir a una pintura lengua o
seso!
¡ay tiempo, que en un peso
está mi alma y en poder
ageno!
ribera umbrosa, qu'es del mi
Sireno?
No puedo jamas yr con mi
ganado,
quando se pone el sol, a
nuestra aldea,
ni desde ella uenir a la
majada,
Sino por donde, aunque no
quiera, uea
la choça de mi bien tan
desseado,
ya por el suelo toda derribada:
Allí me assiento un poco y
descuidada
do ouejas y corderos,
hasta que los uaqueros
me dan bozes diziendo: ha
pastora,
en que piensas aora,
y el ganado pasciendo por los
trigos?
mis ojos son testigos
por quien la yerua crece al
ualle ameno;
ribera umbrosa, qu'es d'el mi
Sireno?
Razon fuera, Sireno, que
hizieras
a tu opinion más fuerça en la
partida
pues que sin ella te entregué
la mia:
¿Mas yo de quién me quexo?
¡ay, perdida!
¿pudiera alguno hazer que no
partieras
si el hado o la fortuna lo
queria?
No fue la culpa tuya ni podria

creer que tú hiziesses
cosa con que offendiesses
a este amor tan llano y tan
sencillo,
ni quiero presumillo,
aunque aya muchas muestras
y señales;
los hados desiguales
me an anublado vn cielo muy
sereno;
ribera vmbrosa, qu'es del mi
Sireno?
Cancion mira que vays
adonde digo,
mas quedate comigo,
que puede ser te lleue la
fortuna
a parte do te llamen
importuna.
Acabado[1222] Syluano la
amorosa cancion de Diana, dixo a
Sireno (que como fuera de si
estaua oyendo los uersos que
despues de su partida la pastora
auia cantado): quando esta
cancion cantaua la hermosa
Diana, en mis lagrimas pudieran
ver si yo sentia las que ella por tu
causa derramaua: pues que no
queriendo yo della entender que
la auia entendido, dissimulando lo
mejor que pude (que no fue poco
podello hazer) llegueme adonde
estaua. Sireno entonces le atajó
diziendo: Ten punto, Syluano;
¿que vn coraçon, que tales cosas
sentia pudo mudar fe? O
constancia, o firmeza, y quantas
pocas uezes hazeis assiento
sobre coraçon de hembra, que
quanto mas subiecta está á
quereros, tanto mas
propuesta[1223] para oluidaros. Y
bien creya yo que en todas las
mugeres auia esta falta, mas en
mi señora Diana, jamas pensé
que naturaleza auia dexado cosa
buena por hazer. Prosiguiendo
pues Syluano por su historia
adelante, le dixo: Como yo me
llegase más adonde Diana
estaua, vi que ponia los ojos en la
clara fuente, adonde prosiguiendo
su acostumbrado officio, començó
a dezir. Ay ojos y quanto más
presto se os acabaran las
lagrimas que la ocasion de
derramabas; ay mi Sireno, plega
a Dios que antes que el desabrido
inuierno desnude el verde prado
de frescas y olorosas flores, y el
ualle ameno de la menuda yerua,
y los arboles sombrios de su
uerde hoja, uean estos ojos tu
presencia tan desseada de mi
anima, como de la tuya deuo ser
aborrecida. A este punto alçó el
diuino rostro, y me uido: trabajó
por disimular el triste llanto, mas
no lo pudo hazer, de manera que
las lagrimas no atajassen el
passo a su disimulacion.
Leuantose a mi, diziendo:
Sientate aqui, Syluano, que asaz
vengado estás, y a costa mia.
Bien paga esta desdichada lo que
dizes que a su causa sientes si es
uerdad que es ella la causa. Es
possible, Diana, (le respondi) que
eso me quedaua por oyr? En fin,
no me engaño en dezir, que nasci
para cada dia discubrir nueuos
generos de tormentos, y tú para
hazerme más sinrazones, de las
que en tu pensamiento pueden
caber. Aora dudas ser tú la causa
de mi mal? Si tú no eres la causa
d'el, quién, sospechas que
mereciesse tan gran amor? O qué
coraçon auria en el mundo si no
fuesse el suyo, a quien mis
lagrimas no vuiessen ablandado?
E a esto añadi otras muchas
cosas, de que ya no tengo
memoria. Mas la cruel enemiga
de mi descanso, atajó mis
razones, diziendo: Mira, Syluano,
si otra vez tu lengua se atreue a
tratar de cosa tuya y a dexar de
hablarme en el mi Sireno, a tu
plazer te dexaré gozar de la clara
fuente donde estamos sentado. Y
tú no sabes que toda cosa que en
mi pastor no tratare, me es
aborrescible y enojosa? y que a la
persona que quiere bien, todo el
tiempo que gasta en oyr cosa
fuera de sus amores le parece
mal empleado? Yo entonces, de
miedo que mis palabras no
fuessen causa de perder el
descanso que su vista me
offrescia, puse silencio en ellas, y
estuue alli vn gran rato gozando
de ver aquella hermosura
sobrehumana, hasta que la noche
se dexó venir (con mayor
presteza de lo que yo quisiera) y
de alli nos fuymos los dos con
nuestros ganados al aldea. Sireno
sospirando, le dixo: grandes
cosas me has contado (Syluano)
y todas en daño mio; desdichado
de mí, quán presto vine a
esperimentar la poca constancia
que en las mugeres ay. Por lo que
los deuo me pesa. No quisiera yo,
pastor, que en algun tiempo se
oyere dezir, que en vn vaso,
donde tan gran hermosura y
discrecion juntó naturaleza,
hubiera tan mala mixtura, como
es la inconstancia que comigo ha
usado. Y lo que más me llega al
alma, es que el tiempo le a de dar
a entender lo mal que comigo lo
ha hecho: lo qual no puede ser
sino a costa de su descanso.
¿Cómo le ua de contentamiento
despues de casada? Syluano le
respondió: dizenme algunos que
le ua mal, y no me espanto,
porque como sabes, Delio su
esposo, aunque es rico de los
bienes de fortuna, no lo es de los
de naturaleza, que en esto de la
disposicion ya ves quan mal le va.
Pues de otras cosas de que los
pastores nos preciamos, como
son tañer, cantar, luchar, jugar al
cayado, baylar con las mozas el
Domingo, paresce que Delio no
ha nascido para más que mirallo.
Aora pastor (dixo Sireno) toma tu
rabel y yo tomaré mi çampoña,
que no ay mal que con la musica
no se passe, ni tristeza que con
ella no se acresciente. Y
templando los dos pastores sus
instrumentos con mucha gracia y
suauidad començaron a cantar lo
siguiente.
SYLVANO
Sireno, en qué pensauas,

que mirandote
estaua desde el soto, y
condoliendome

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Physiologically Based Pharmacokinetic

(PBPK) Modeling and Simulations 2nd

Sheila Annie Peters

Limit of Liability/Disclaimer of Warranty

Library of Congress Cataloging-in-Publication Data

Cover Design: Wiley

Set in 9.5/11.5pt Times by Straive, Pondicherry, India

Preface to the Second Edition xix

SECTION I. PRINCIPLES, METHODS, AND

1 A REVIEW OF PHARMACOKINETIC AND PHARMACODYNAMIC

2 A REVIEW OF DRUG–DRUG INTERACTIONS 51

3 MODELING PHARMACOKINETICS, PHARMACODYNAMICS, AND

3.4.5 DDI Risk Assessment with PBPK vs Static Models 118

4 PHYSIOLOGICAL MODEL FOR ABSORPTION 129

5 PHYSIOLOGICAL MODEL FOR DISTRIBUTION 169

6 PHYSIOLOGICAL MODELS FOR DRUG METABOLISM AND

7 GENERIC WHOLE-BODY PHYSIOLOGICALLY BASED

8 PBPK MODELING OF BIOTHERAPEUTICS 225

8.3.9 Target-Mediated Drug Disposition and Receptor-Mediated

9 UNCERTAINTY AND POPULATION VARIABILITY 263

10 NONCLINICAL, CLINICAL, AND MODEL-INFORMED

10.3.5 Pediatric Assessment 306

SECTION II. APPLICATIONS IN THE PHARMACEUTICAL

11 OVERVIEW OF PBPK APPLICATIONS 325

12 APPLICATIONS OF HYPOTHESIS GENERATION AND TESTING

13 APPLICATIONS OF PHYSIOLOGICALLY BASED PHARMACOKINETIC

14 PBPK MODELING AND SIMULATIONS TO EVALUATE CLINICAL

14.4.2 Possible Regulatory Outcomes, Based on the Predictions from

15 DOSE EXTRAPOLATION ACROSS POPULATIONS (HEALTHY ADULT

16 DOSE EXTRAPOLATION ACROSS POPULATIONS: HEALTHY

16.5 Conclusions 425

17 ABSORPTION-RELATED APPLICATIONS OF PBPK MODELING 429

18 REGULATORY GUIDELINES ON THE REPORTING OF

19 RESOLVING THE CHALLENGES TO ESTABLISHING CONFIDENCE

19.3.2 Model Verification of Predicted Exposure and Validation of

SECTION III. CASE STUDIES OF PBPK APPLICATIONS IN

CASE STUDY 2 HYPOTHESIS TESTING (GASTRIC EMPTYING) 499

CASE STUDY 3 HYPOTHESIS TESTING (INTESTINAL LOSS) 505

CASE STUDY 4 PBPK/PD 509

CASE STUDY 5 DRUG–DRUG INTERACTION (INHIBITION) 515

CASE STUDY 6 DRUG–DRUG INTERACTION (INDUCTION) 521

CASE STUDY 7 GENETIC POLYMORPHISM 527

CASE STUDY 8 PEDIATRIC EXTRAPOLATION 535

CASE STUDY 9 PREGNANCY 541

CASE STUDY 10 HEPATIC IMPAIRMENT 547

CASE STUDY 11 RENAL IMPAIRMENT 555

CASE STUDY 12 ABSORPTION – IVIVC 561

Physiologically-based pharmacokinetic (PBPK) modelling has made rapid strides in the

This book is accompanied by a companion website

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Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulations: Principles,

1.5 Pharmacodynamic Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

1.2 PHARMACOKINETIC PRINCIPLES

1.2.1 Routes of Drug Administration

1.2.2 Intravenous Bolus

1.2.2.2 Clearance, Volume of Distribution, Half-life, and AUC. The first-order

Drug Concentration (mg/L)

Drug Concentration (mg/L)

Dose (mg) 1000

AUC (mg.h/L) 17.5

Taking natural logarithms on both sides,

Dose = CL × AUC (1.10)

Differentiating Equation 1.5 (A = A0 × e − kel × t ),