Pharmacokinetics andPharmacodynamics of Biotech Drugs

Principles and Case Studies in Drug Development

Edited byBernd Meibohm

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Pharmacokineticsand Pharmacodynamicsof Biotech Drugs

Edited byBernd Meibohm

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Pharmacokinetics andPharmacodynamics of Biotech Drugs

Principles and Case Studies in Drug Development

Edited byBernd Meibohm

The Editor

Prof. Dr. Bernd MeibohmUniversity of TennesseeHealth Science CenterDepartment of Pharmaceutical SciencesCollege of Pharmacy874 Union Ave. Suite 5pMemphis, TN 38163USA

All books published by Wiley-VCH are carefully pro-duced. Nevertheless, authors, editors, and publisher donot warrant the information contained in these books,including this book, to be free of errors. Readers areadvised to keep in mind that statements, data, illustra-tions, procedural details or other items may inadver-tently be inaccurate.

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© 2006 WILEY-VCH Verlag GmbH & Co. KGaA,Weinheim, Germany

All rights reserved (including those of translation intoother languages). No part of this book may be repro-duced in any form – by photoprinting, microfilm, orany other means – nor transmitted or translated intoa machine language without written permission fromthe publishers. Registered names, trademarks, etc.used in this book, even when not specifically markedas such, are not to be considered unprotected by law.

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Printed in the Federal Republic of GermanyPrinted on acid-free paper

ISBN-13: 978-3-527-31408-9ISBN-10: 3-527-31408-3

�

Foreword

Pharmacokinetics and pharmacodynamics (PK/PD) have become essential disci-plines in drug research and development. Rational use of PK/PD allows for betterdecision making and streamlines dose optimization. In the past, PK/PD conceptshave been primarily been applied to the development of small drug molecules.However, in recent years more and more drug candidates come form the field ofbiotechnology and are larger molecules. Pharmacokinetics and Pharmaco-dynamics of Biotech Drugs gives an excellent overview of the state of the art of ap-plying PK/PD concepts to large molecules.

After a comprehensive introduction, the basic PK/PD properties of peptides,monoclonal antibodies, antisense oligonucleotides and gene delivery vectors arereviewed. In the second part, the book covers a number of challenges and oppor-tunities in this field such as bioanalytical methods, bioequivalence and pulmonarydelivery. The text finishes with a detailed presentation of some real-life examplesand case studies which should be of particular interest to the reader and integratemany of the concepts presented earlier in the text.

The book was written by a group of international expert scientists in the field. Itis well-structured and easy to follow. The book is of great value for everybodyworking in this area.

Hartmut Derendorf, Ph.D.Distinguished Professor and ChairmanDepartment of PharmaceuticsUniversity of Florida

V

Preface

In recent years, biotechnologically-derived drugs (biotech drugs) including pro-teins, peptides, monoclonal antibodies and antibody fragments, as well as anti-sense oligonucleotides and DNA preparations for gene therapy, have been a majorfocus of research and development (R&D) efforts in the pharmaceutical industry,and biotech drugs constitute already a sizable fraction of the medications used inclinical practice.

Pharmacokinetic (PK) and pharmacodynamic (PD) concepts impact every stageof the drug development process starting from lead optimization to the design ofPhase III pivotal trials. PK and PK/PD evaluations are widely considered corner-stones in the development of new drug products and are usually deeply embeddedin the discovery and development plan. The widespread application of PK/PD con-cepts in all phases of drug development has repeatedly been promoted by indus-try, academia, and regulatory authorities, most recently through FDA’s CriticalPath to New Medical Products initiative and the concept of integrated model-based drug development.

An understanding of PK and PD and the related dose-concentration-effect rela-tionship is crucial to any drug – including biotech products – since it lays thefoundation for dosing regimen design and rational clinical application. While gen-eral PK and PD principles are just as applicable to biotech agents as they are totraditional small molecule drugs, PK and PK/PD analyses of biotech agents fre-quently pose extra challenges related to factors such as their similarity to endogen-ous molecules and/or nutrients and their immunogenicity.

This textbook provides a comprehensive overview on the PK and PD of biotech-derived drug products, highlights the specific requirements and challenges relatedto PK and PK/PD evaluations of these compounds and provides examples of theirapplication in preclinical and clinical drug development. The impetus for this pro-ject originated from the notion that at the time of its initiation there was no com-prehensive publication on the market that specifically addressed this topic.

Following a short introduction, the book is structured into three sections: The‘Basics’ section discusses individually the pharmacokinetics of peptides, monoclo-nal antibodies, antisense oligonucleotides and gene delivery vectors. The subse-quent ‘Challenges and Opportunities’ section includes more detailed considera-tions on selected topics, including technical challenges such as bioanalytical

VII

methodologies, noncompartmental data analysis and exposure-response assess-ments. It furthermore discusses biopharmaceutical challenges as exemplified bythe delivery of oligonucleotides and of peptides and proteins to the lung, and pro-vides insights into the opportunities provided by chemical modification of biotechdrugs and the regulatory challenges related to follow-on biologics. The third andfinal section provides examples for the ’Integration of Pharmacokinetic and Phar-macodynamic Concepts into the Biotech Drug Development Plan’, including thepreclinical and early clinical development of tasidotin, and the clinical develop-ment programs for cetuximab and pegfilgrastim.

The book addresses an audience with basic knowledge in clinical pharmacology,PK and PD, and clinical drug development. It is intended as a resource for gradu-ate students, postdocs, and junior scientists, but also for those more experiencedpharmaceutical scientists that have no experience in the PK and PD evaluation ofbiotech drugs and wish to gain knowledge in this area.

I would like to express my gratitude to all contributors of this project for provid-ing their unique array of expertise to this book project which allowed us to com-pile a wide variety of viewpoints relevant to the PK and PK/PD evaluation of bio-tech drugs and derived products. In addition, I would like to thank Dr. RomyKirsten and Dr. Andrea Pillmann at Wiley-VCH for their assistance in producingthis book and Ms. Faith Barcroft for her invaluable text editing.

Finally I would like to dedicate this book to my family for their patience, encour-agement and support during this project.

Memphis, Summer 2006 Bernd Meibohm

VIII Preface

Contents

Foreword VPreface VIIList of Contributors XIX

Part I: Introduction

1 The Role of Pharmacokinetics and Pharmacodynamics in theDevelopment of Biotech Drugs 3Bernd Meibohm

1.1 Introduction 31.2 Biotech Drugs and the Pharmaceutical Industry 41.3 Pharmacokinetics and Pharmacodynamics in Drug Development 61.4 PK and PK/PD Pitfalls for Biotech Drugs 91.5 Regulatory Guidance 101.6 Future 101.7 References 12

Part II: The Basics

2 Pharmacokinetics of Peptides and Proteins 17Lisa Tang and Bernd Meibohm

2.1 Introduction 172.2 Administration Pathways 182.2.1 Administration by Injection or Infusion 182.2.2 Inhalational Administration 232.2.3 Intranasal Administration 242.2.4 Transdermal Administration 252.2.5 Peroral Administration 252.3 Administration Route and Immunogenicity 272.4 Distribution 28

IX

2.5 Elimination 292.5.1 Proteolysis 322.5.2 Gastrointestinal Elimination 322.5.3 Renal Elimination 322.5.4 Hepatic Elimination 342.5.5 Receptor-Mediated Endocytosis 352.6 Interspecies Scaling 362.7 Conclusions 372.8 References 38

3 Pharmacokinetics of Monoclonal Antibodies 45Katharina Kuester and Charlotte Kloft

3.1 Introduction 453.2 The Human Immune System 463.2.1 The Cellular Immune Response 473.2.2 The Humoral Immune Response 473.3 Physiological Antibodies 483.3.1 Classes of Antibodies 483.3.1.1 Immunoglobulin G 483.3.1.2 Immunoglobulins A, D, M, and E 493.3.2 Chemical Structure of Antibodies 503.4 Therapeutic Antibodies 523.4.1 Therapeutic Polyclonal Antibodies 523.4.2 Therapeutic mAbs 533.4.2.1 Murine mAbs 533.4.2.2 Chimeric mAbs 553.4.2.3 Humanized mAbs 553.4.2.4 Human mAbs 553.4.2.5 Further Species of mAbs 563.5 Effector Functions and Modes of Action of Antibodies 583.5.1 Biological Effector Functions of mAbs 583.5.2 Modes of Action of mAbs 593.5.2.1 Antibody-Dependent Cellular Cytotoxicity (ADCC) 593.5.2.2 Complement-Dependent Cytotoxicity 603.5.2.3 Blockage of Interaction between (Patho)Physiological Substance

and Antigen 613.5.2.4 Conjugated Unlabeled mAbs 613.5.2.5 Radioactively Labeled mAbs 613.6 Prerequisites for mAb Therapy 623.6.1 The Patient 623.6.2 The Antibody 633.6.3 The Target Cell 633.6.4 The Antigen 633.7 Issues in the Bioanalysis of Antibodies 64

X Contents

3.8 Catabolism of Antibodies 653.8.1 Proteolytic Degradation 653.8.2 Neonatal Fc Receptor (Fc-Rn) 653.9 Pharmacokinetic Characteristics of mAbs 683.9.1 Absorption 683.9.2 Distribution 713.9.2.1 Transport 713.9.2.2 Volume of Distribution 723.9.2.3 Types of Binding 743.9.3 Elimination 763.9.3.1 Clearance 763.9.3.2 Proteolysis 763.9.3.3 Binding to Antigen 773.9.3.4 Binding to Anti-Idiotype Antibodies 773.9.3.5 Drug Interaction Studies 783.9.4 Comparison of Pharmacokinetics of mAbs and Traditional

Small-Molecule Drugs 783.10 Pharmacokinetic Modeling of mAbs 793.10.1 Noncompartmental Pharmacokinetic Analysis 793.10.2 Individual Compartmental Pharmacokinetic Analysis 803.10.3 Population Pharmacokinetic Analysis 813.10.3.1 Structural Submodel 823.10.3.2 Statistical Submodel 853.10.3.3 Covariate Submodel 853.11 Pharmacodynamics of mAbs 863.12 Conclusions 903.13 References 91

4 Pharmacokinetics and Pharmacodynamics of AntisenseOligonucleotides 93Rosie Z. Yu, Richard S. Geary, and Arthur A. Levin

4.1 Introduction 934.2 Pharmacokinetics 964.2.1 Plasma Pharmacokinetics Across Species 974.2.2 Tissue Distribution 1004.2.3 Metabolism 1024.2.4 Elimination and Excretion 1054.3 Pharmacodynamics 1084.3.1 Pharmacological Endpoint: Reduction of Target mRNA

and Protein 1094.3.2 Pharmacological Endpoint: Downstream Effects 1134.3.3 Relationship between ASO Pharmacokinetics and Clinical Outcome 1134.4 Summary 1154.5 References 115

XIContents

5 Pharmacokinetics of Viral and Non-Viral Gene Delivery Vectors 121Martin Meyer, Gururaj Rao, Ke Ren, and Jeffrey Hughes

5.1 General Overview of Gene Therapy 1215.2 Anatomical Considerations 1225.3 Naked DNA 1225.4 Non-Viral Vectors 1245.4.1 Polymer-Based Vectors 1265.4.1.1 Introduction 1265.4.1.2 Influence of Charge and Size 1275.4.1.3 Biodistribution and Gene Expression 1285.4.2 Lipid-Based Vectors 1315.4.2.1 Introduction 1315.4.2.2 Influence of Physico-Chemical Properties 1335.4.2.3 Biodistribution and Gene Expression 1345.5 Viral Vectors 1365.5.1 rAAV: Properties 1365.5.2 rAAV Serotype and Biodistribution 1385.6 Summary 1395.7 References 139

Part III: Challenges and Opportunities

6 Bioanalytical Methods Used for Pharmacokinetic Evaluationsof Biotech Macromolecule Drugs: Issues, Assay Approaches,and Limitations 147Jean W. Lee

6.1 Introduction 1476.2 Bioanalytical Methods for Macromolecule Drug Analysis: Common

Considerations 1486.2.1 Sample Integrity and Analyte Stability 1486.2.2 Surface Adsorption 1496.2.3 Process of Method Development and Validation of Bioanalytical

Methods for Macromolecule Drug Analysis 1506.2.4 Reference Standards 1516.2.5 Drug Compounds that Exist Endogenously 1526.2.6 Validation Samples, Quality Controls, and Assay Range 1536.2.7 Protein Binding Problems 1536.3 The Bioanalytical Method Workhorses 1546.3.1 Ligand-Binding Assays: Immunoassays 1576.3.1.1 Common Method Approach 1576.3.1.2 Advantages of Immunoassays 1586.3.1.3 Issues and Limitations of Immunoassays 1586.3.2 HPLC-ESI-MS/MS Methods 162

XII Contents

6.3.2.1 Common Method Approach 1626.3.2.2 Advantages of HPLC-ESI-MS/MS Methods 1626.3.2.3 Issues and Limitations of LC-ESI-MS/MS Methods 1626.4 Case Studies 1676.4.1 Development and Validation of an ELISA Method for an Antibody

Drug 1676.4.2 Development and Validation of a Sandwich Immunoradiometric

Method Using Commercial Kits for a Recombinant Peptide Drug 1696.4.3 Development and Validation of LC-MS/MS Method for a Peptide

Drug 1716.5 Future Perspectives: Emerging Quantitative Methods 1736.5.1 Sample Clean-Up 1736.5.2 Innovations in MS Instruments 1736.5.3 Quantification using Signature Hydrolytic Peptides 1746.5.4 Advances in Ligand Reagents Design and Production 1756.6 Conclusions 1756.7 References 176

7 Limitations of Noncompartmental Pharmacokinetic Analysisof Biotech Drugs 181Arthur B. Straughn

7.1 Introduction 1817.2 The Concept of Volume of Distribution 1827.3 Calculation of Vss 1837.4 Pitfalls in Calculating Vss 1857.5 Results and Discussion 1877.6 Conclusions 1887.7 References 188

8 Bioequivalence of Biologics 189Jeffrey S. Barrett

8.1 Introduction 1898.2 Prevailing Opinion: Science, Economics, and Politics 1918.3 Biologics: Time Course of Immunogenicity 1938.4 Pharmaceutical Equivalence 1968.4.1 How Changes in Quality Might Affect Safety and Efficacy 1978.5 Bioequivalence: Metrics and Methods for Biologics? 1988.6 Case Study: Low-Molecular-Weight Heparins 2008.7 Conclusions 2058.8 References 206

XIIIContents

9 Biopharmaceutical Challenges: Pulmonary Delivery of Proteinsand Peptides 209Kun Cheng and Ram I. Mahato

9.1 Introduction 2099.2 Structure and Physiology of the Pulmonary System 2119.2.1 Airway Epithelium 2129.2.2 Alveolar Epithelium 2149.3 Barriers to Pulmonary Absorption of Peptides and Proteins 2149.4 Strategies for Pulmonary Delivery 2159.4.1 Intratracheal Instillation 2159.4.2 Aerosol Inhalation 2159.4.2.1 Aerosol Deposition Mechanisms 2169.4.2.2 Devices for Pulmonary Drug Delivery 2169.5 Experimental Models 2209.5.1 Isolated Perfused Lung Model 2209.5.2 Cell Culture Models 2209.6 Pulmonary Delivery of Peptides and Proteins 2219.6.1 Mechanisms of Peptide Absorption after Pulmonary Delivery 2219.6.2 Mechanisms of Protein Absorption after Pulmonary Delivery 2229.6.3 Pulmonary Delivery of Peptides and Proteins 2239.6.3.1 Insulin 2239.6.3.2 Salmon Calcitonin 2279.6.3.3 Luteinizing Hormone-Releasing Hormone (LHRH) Agonists/

Antagonists 2299.6.3.4 Vasopressin 2309.6.3.5 Granulocyte Colony-Stimulating Factor (G-CSF) 2319.6.3.6 Interferons 2329.6.3.7 TSH, FSH, and HCG 2339.6.3.8 Elastase Inhibitors 2339.7 Limitations of Aerosol Delivery 2349.8 Summary 2359.9 References 235

10 Biopharmaceutical Challenges: Delivery of Oligonucleotides 243Lloyd G. Tillman and Gregory E. Hardee

10.1 Introduction 24310.2 ASOs: The Physico-Chemical Properties 24410.3 Local Administration 24610.3.1 Ocular Delivery 24610.3.2 Local Gastrointestinal Delivery 24710.3.2.1 Rectal Dosing 24710.3.2.2 Oral Dosing 24810.3.3 Pulmonary Delivery 24910.3.3.1 Formulation Considerations 251

XIV Contents

10.3.3.2 Deposition and Uptake 25110.3.4 Delivery to the Brain 25310.3.5 Topical Delivery 25310.3.6 Other Local Delivery Approaches 25410.4 Systemic Delivery 25510.4.1 Parenteral Routes 25510.4.1.1 Sustained-Release Subcutaneous Formulations 25610.4.2 Oral Delivery 25710.4.2.1 Permeability 25810.4.2.2 Systemic Bioavailability 26010.5 Conclusions 26510.6 References 266

11 Custom-Tailored Pharmacokinetics and Pharmacodynamicsvia Chemical Modifications of Biotech Drugs 271Francesco M. Veronese and Paolo Caliceti

11.1 Introduction 27111.2 Polymers Used in Biotechnological Drug PEGylation 27211.3 Advantages of PEG as Drug Carrier 27311.4 Chemical Aspects Critical for the Pharmacokinetics of Drug

Conjugates 27411.5 Insulin 27911.6 Interferons 28211.7 Avidin 28511.8 Non-Peptide Drug Conjugation 28811.8.1 Amphotericin B 28911.8.2 Camptothecins 29011.8.3 Cytosine Arabinoside (Ara-C) 29111.9 Concluding Remarks 29211.10 References 292

12 Exposure–Response Relationships for Therapeutic BiologicProducts 295Mohammad Tabrizi and Lorin K. Roskos

12.1 Introduction 29512.2 Overview of Pharmacokinetics and Pharmacodynamics 29512.2.1 Pharmacokinetics 29512.2.1.1 Absorption 29612.2.1.2 Distribution 29612.2.1.3 Elimination 29612.2.1.4 Immunogenicity 29812.2.2 Pharmacodynamics 29812.3 Hormones 30012.3.1 Insulin 301

XVContents

12.3.2 Parathyroid Hormone 30212.4 Cytokines 30312.4.1 Interleukin-2 30512.5 Growth Factors 30612.5.1 Epoetin-� 30712.6 Soluble Receptors 30812.6.1 Etanercept 30812.7 Monoclonal Antibodies (mAbs) 31012.7.1 Therapeutic Antibodies in Inflammatory Diseases 31112.7.1.1 Anti-TNF-� Antibodies 31412.7.1.2 Efalizumab 31612.7.1.3 Omalizumab 31712.7.2 Therapeutic Antibodies in Oncology 31712.7.2.1 Rituximab 31812.7.2.2 Bevacizumab 31912.7.2.3 Trastuzumab 32012.8 Conclusions 32112.9 References 321

Part IV: Examples for the Integration of Pharmacokinetic andPharmacodynamic Concepts Into the Biotech Drug Development Plan

13 Preclinical and Clinical Drug Development of Tasidotin,a Depsi-Pentapeptide Oncolytic Agent 331Peter L. Bonate, Larry Arthaud, and Katherine Stephenson

13.1 Introduction 33113.2 The Dolastatins 33113.3 Discovery and Preclinical Pharmacokinetics of Tasidotin 33313.4 Preclinical Pharmacology of Tasidotin and ILX651-C-Carboxylate 33413.5 Toxicology of Tasidotin 33413.6 Clinical Pharmacology and Studies of Tasidotin in Patients with Solid

Tumors 33513.7 Clinical Pharmacology of ILX651-C-Carboxylate 34113.8 Exposure–Response Relationships 34213.9 Discussion 34313.10 Summary 34913.11 References 349

XVI Contents

14 Clinical Drug Development of Cetuximab, a Monoclonal Antibody 353Arno Nolting, Floyd E. Fox, and Andreas Kovar

14.1 Introduction 35314.2 Specific Considerations in Oncologic Drug Development 35414.3 Introduction to the Clinical Pharmacokinetics of Cetuximab 35614.4 Early Attempts to Characterize the PK of Cetuximab 35614.5 PK of Cetuximab Following Pooling of Data Across All Studies 35714.5.1 Comparison of Single-Dose PK Parameters at Various Dose Levels 35714.5.1.1 Maximum Serum Concentration 35714.5.1.2 Area Under the Concentration-Time Curve 35914.5.1.3 Clearance 36014.5.1.4 Elimination Half-Life 36114.5.1.5 Volume of Distribution 36114.5.2 Drug Metabolism and in-vitro Drug–Drug Interaction Studies 36214.5.3 Comparison of Single- and Multiple-Dose PK at the Approved Dosing

Regimen 36214.6 Characterization of Cetuximab PK by a Population PK Approach 36414.7 Drug–Drug Interaction Studies 36614.8 Conclusions 36914.9 References 370

15 Integration of Pharmacokinetics and Pharmacodynamics Into the DrugDevelopment of Pegfilgrastim, a Pegylated Protein 373Bing-Bing Yang

15.1 Introduction 37315.2 Overview of Filgrastim Pharmacokinetics 37415.3 The Making of Pegfilgrastim 37515.4 Preclinical Pharmacokinetics and Pharmacodynamics of

Pegfilgrastim 37615.5 Pharmacokinetic and Pharmacodynamic Modeling 37915.6 Clinical Pharmacokinetics and Pharmacodynamics of

Pegfilgrastim 38115.7 Basis for the Fixed-Dose Rationale 38515.8 Clinical Evaluation of the Fixed Dose 38915.9 Summary 39115.10 References 391

Subject Index 395

XVIIContents

XIX

List of Contributors

Larry ArthaudDepartment of PharmacokineticsGenzyme Corporation4545 Horizon Hill Blvd.San Antonio, TX 78229USA

Jeffrey S. BarrettLaboratory for Applied PK/PDThe Children’s Hospital ofPhiladelphiaAbramson Research Center,Room 916 H34th Street and Civic Center Blvd.Philadelphia, PA 19104USA

Peter L. BonateDepartment of PharmacokineticsGenzyme Corporation4545 Horizon Hill Blvd.San Antonio, TX 78229USA

Paolo CalicetiDepartment of PharmaceuticalSciencesSchool of PharmacyUniversity of PaduaVia Francesco Marzolo, 535131 PaduaItaly

Kun ChengDepartment of PharmaceuticalSciencesUniversity of Tennessee HealthScience Center26 S. Dunlap StreetMemphis, TN 38163USA

Floyd E. FoxClinical PharmacologyImClone Systems Inc.59 ImClone DriveSomerville, NJ 08876USA

Richard S. GearyPharmacokinetics and DrugMetabolismIsis Pharmaceuticals1896 Rutherford RoadCarlsbad, CA 92008USA

Gregory E. HardeeQuality AssuranceIsis Pharmaceuticals1896 Rutherford RoadCarlsbad, CA 92008USA

XX List of Contributors

Jeffrey R. HughesPharmaceutical SciencesCollege of PharmacyUniversity of FloridaBox 100494, JHMHCGainesville, FL 32610USA

Charlotte KloftDepartment of Clinical PharmacyFaculty of PharmacyMartin-Luther-UniversitätHalle-WittenbergWolfgang-Langenbeck-Strasse 406120 HalleGermany

Katharina KuesterDepartment of Clinical PharmacyInstitute of PharmacyFreie Universität BerlinKelchstrasse 3112169 BerlinGermany

Andreas KovarClinical Pharmacologyand PharmacokineticsMerck KGaAFrankfurter Strasse 25064293 DarmstadtGermany

Jean W. LeePharmacokinetics and DrugMetabolismProtein LabsAmgen Inc.One Amgen Center DriveThousand Oaks, CA 91320USA

Arthur A. LevinIsis Pharmaceuticals1896 Rutherford RoadCarlsbad, CA 92008USA

Ram I. MahatoDepartment of PharmaceuticalSciencesCollege of PharmacyUniversity of Tennessee HealthScience Center26 S. Dunlap StreetMemphis, TN 38163USA

Bernd MeibohmDepartment of PharmaceuticalSciencesCollege of PharmacyUniversity of Tennessee HealthScience Center874 Union Avenue, Suite 5pMemphis, TN 38163USA

Martin MeyerDepartment of PharmaceuticsCollege of PharmacyBox 100494, JHMHCUniversity of FloridaGainesville, FL 32610USA

Arno NoltingClinical Pharmacology andPharmacokineticsMerck KGaAFrankfurter Strasse 25064293 DarmstadtGermany

XXIList of Contributors

Gururaj RaoDepartment of PharmaceuticsCollege of PharmacyBox 100494, JHMHCUniversity of FloridaGainesville, FL 32610USA

Ke RenDepartment of PharmaceuticsCollege of PharmacyBox 100494, JHMHCUniversity of FloridaGainesville, FL 32610USA

Lorin K. RoskosPharmacokinetics and ToxicologyAmgen Inc.6701 Kaiser DriveFremont, CA 94555USA

Katherine StephensonDepartment of PharmacokineticsGenzyme Corporation4545 Horizon Hill Blvd.San Antonio, TX 78229USA

Arthur B. StraughnDepartment of PharmaceuticalSciencesCollege of PharmacyUniversity of Tennessee HealthScience Center874 Union Avenue, Suite 5pMemphis, TN 38163USA

Mohammad TabriziPharmacokinetics and ToxicologyAmgen Inc.6701 Kaiser DriveFremont, CA 94555USA

Lisa TangDepartment of PharmaceuticalSciencesCollege of PharmacyUniversity of Tennessee HealthScience Center874 Union Avenue, Room 105pMemphis, TN 38163USA

Lloyd G. TillmanPharmaceutical DevelopmentIsis Pharmaceuticals1896 Rutherford RoadCarlsbad, CA 92008USA

Francesco M. VeroneseDepartment of PharmaceuticalSciencesSchool of PharmacyUniversity of PaduaVia Francesco Marzolo, 535131 PaduaItaly

Bing-Bing YangPharmacokinetics and DrugMetabolismAmgen Inc.One Amgen Center DriveThousand Oaks, CA 91320USA

Rosie Z. YuDepartment of PharmacokineticsIsis Pharmaceuticals1896 Rutherford RoadCarlsbad, CA 92008USA

Part IIntroduction

1The Role of Pharmacokinetics and Pharmacodynamicsin the Development of Biotech Drugs

Bernd Meibohm

1.1Introduction

During the past two decades, advances in biotechnology have triggered the devel-opment of numerous new drug products. This group of so-called biotech drugsis a subset of the therapeutic group of biologics. Therapeutic biologic products,or biologics, are defined by the U.S. Food and Drug Administration (FDA) asany virus, therapeutic serum, toxin, antitoxin, or analogous product applicable tothe prevention, treatment or cure of diseases or injuries of man. Biologics are asubset of drug products distinguished by their manufacturing process. Whileclassical drugs are synthesized via a chemical process, biologics are manufac-tured utilizing biological processes and are typically derived from living material– human, plant, animal, or microorganism. Biotech drugs can be considered asthose biologics that are manufactured using biotechnology-based production pro-cesses.

The similarity in the drug development and evaluation process for biotechdrugs and conventional, chemically synthesized drugs has recently been acknowl-edged in the FDA’s 2003 decision to transfer certain product oversight responsibil-ities from the Center for Biologics Evaluation and Research (CBER) to the Centerfor Drug Evaluation and Research (CDER). The biologics for which oversight wastransferred include monoclonal antibodies for in vivo use, proteins intended fortherapeutic use, including cytokines (e.g., interferons), enzymes (e.g., thromboly-tics), growth factors, and other novel proteins that are derived from plants, ani-mals, or microorganisms, including recombinant versions of these products, andother non-vaccine and non-allergenic therapeutic immunotherapies. Classical bio-logics such as blood, blood components and vaccines remain under the regulatoryauthority of the CBER. Even under this new structure, however, the biologic pro-ducts transferred to the CDER will continue to be regulated as licensed biologics –that is, a Biologic License Application (BLA) must be submitted to obtain market-ing authorization as compared to a New Drug Application (NDA) which is usedfor traditional, chemically manufactured drug products.

3

For the purpose of this book, biotech drugs include not only therapeuticallyused peptides and proteins, including monoclonal antibodies, but also oligonu-cleotides and DNA preparations for gene therapy. Although oligonucleotides are,due to their chemically defined production process, classified by the FDA as classi-cal drugs requiring an NDA prior to marketing authorization, and DNA prepara-tions for gene therapy are regulated by the CBER, they are both included in theclass of biotech drugs as their therapeutic application relies heavily on the princi-ples of molecular biology and they are considered by analysts as biotech com-pounds.

1.2Biotech Drugs and the Pharmaceutical Industry

In parallel with the development of the discipline of biotechnology during thepast two decades, an increasing fraction of pharmaceutical R&D has been devotedto biotechnology-derived drug products. It has been estimated that more than250 million patients have benefited from already approved biotechnology medi-cines to treat or prevent heart attacks, stroke, multiple sclerosis, leukemia, hepati-tis, rheumatoid arthritis, breast cancer, diabetes, congestive heart failure, kidneycancer, cystic fibrosis and other diseases [1]. This number is expected to increasesignificantly with the introduction of new biotech drugs into the marketplace.According to a survey by the Pharmaceutical Research and Manufacturers ofAmerica (PhRMA) in 2004, 324 biotechnology medicines were in development foralmost 150 diseases. These include 154 medicines for cancer, 43 for infectious dis-eases, 26 for autoimmune diseases, and 17 for AIDS/HIV and related conditions.These potential medicines – all of which were at the time of the survey either inhuman clinical trials or under review by the FDA – will enlarge the list of 108 bio-technology medicines already approved and available to patients (Fig. 1.1) [1].

Biotech and genomic companies currently perform almost one-fifth of all phar-maceutical R&D, and this figure is set to double during the next 10 years [2]. Ithas been suggested that over half of all the New Active Substances developed dur-ing the next 10–15 years will result from research into antibodies alone. Biotech-nology products accounted for more than 35% of the 37 New Active Substancesthat were launched in 2001 [2]. This success in drug development is underlinedby the fact that several biotech drugs have achieved blockbuster status, earningmore than US$ 1 billion in annual sales, including Epoetin-� (Epogen/Procrit/Eprex), interferon-�2b (IntronA, PEG-Intron/Rebetron combination therapy), andfilgrastim (Neupogen) [3].

Since the development of biotech drugs generally rests on a fundamental under-standing of the related disease, their clinical development has also proven to bemore successful than for conventional, chemically derived small-molecule drugs.Only 8% of the new chemical entities that entered the clinical phases of drug de-velopment between 1996 and 1998 reached the market, compared to 34% of bio-tech drugs (Fig. 1.2). This means that biologics have, at the time of their first-in-

4 1 The Role of Pharmacokinetics and Pharmacodynamics in the Development of Biotech Drugs

51.2 Biotech Drugs and the Pharmaceutical Industry

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man studies, a fourfold greater chance than traditional, chemically defined drugsof making it into the marketplace. Thus, greater use of biologics will likely reducethe attrition rate at every stage of the clinical drug development process [2]. Basedon these facts, it can be predicted that biotech drugs will play a major – if notdominant – role in the drug development arena of the next decades.

1.3Pharmacokinetics and Pharmacodynamics in Drug Development

The general paradigm of clinical pharmacology is that administration of a dose orthe dosing regimen of a drug results in defined drug concentrations in variousbody compartments and fluids. These are, in turn, the driving force for the drug’sdesired and undesired effects on the human body that collectively constitute thedrug’s efficacy and safety profile. Based on this paradigm, the basis for the phar-macotherapeutic use of biotech drugs is similar to that of small molecules – a de-fined relationship between the intensity of the therapeutic effect and the amountof drug in the body or, more specifically, the drug concentration at its site of action(i. e., an exposure–response relationship). The relationship between the adminis-tered dose of a drug, the resulting concentrations in body fluids and the intensityof produced outcome may be either simple or complex, and thus obvious or hid-den. However, if no simple relationship is obvious, it would be misleading to con-clude a priori that no relationship exists at all rather than that it is not readily ap-parent [4, 5].

The dose–concentration–effect relationship is defined by the pharmacokinetic(PK) and pharmacodynamic (PD) characteristics of a drug. Pharmacokineticscomprises all processes that contribute to the time course of drug concentrations

6 1 The Role of Pharmacokinetics and Pharmacodynamics in the Development of Biotech Drugs

Fig. 1.2 Success rates for clinical drug development are much higher forbiologics than for traditional, chemically defined drug compounds.NCE: New chemical entity (modified from [2]).