Principles of Biomedical Sciences and Industry Markus Hinder All Chapter

Principles of Biomedical Sciences and
Industry Markus Hinder

Visit to download the full and correct content document:
https://ebookmass.com/product/principles-of-biomedical-sciences-and-industry-marku
s-hinder/
Principles of Biomedical Sciences and Industry
Principles of Biomedical Sciences and
Industry
Translating Ideas into Treatments
Edited by
Markus Hinder
Alexander Schuhmacher
Jörg Goldhahn
Dominik Hartl
Editors All books published by WILEY-VCH are carefully
produced. Nevertheless, authors, editors, and
Prof. Dr. Markus Hinder publisher do not warrant the information
Novartis Global Drug Development contained in these books, including this book,
Chief Medical Office & Patient Safety to be free of errors. Readers are advised to keep
Postfach Forum 1 in mind that statements, data, illustrations,
4002 Basel procedural details or other items may
Switzerland inadvertently be inaccurate.
Prof. Dr. Alexander Schuhmacher Library of Congress Card No.: applied for
Technische Hochschule Ingolstadt
THI Business School British Library Cataloguing-in-Publication Data
Esplanade 10 A catalogue record for this book is available
85049 Ingolstadt from the British Library.
Germany
Bibliographic information published by the
Prof. Dr. Jörg Goldhahn Deutsche Nationalbibliothek
ETH Zürich The Deutsche Nationalbibliothek lists
Institute for Translational Medicine this publication in the Deutsche
HCP H15.3 Leopold-Ruzicka-Weg 4 Nationalbibliografie; detailed bibliographic
ETH-Hönggerberg data are available on the Internet at
8093 Zürich <http://dnb.d-nb.de>.
Switzerland
© 2022 WILEY-VCH GmbH, Boschstr. 12,
Prof. Dr. Dominik Hartl 69469 Weinheim, Germany
University Hospital Tübingen
Department of Pediatrics I All rights reserved (including those of
Hoppe-Seyler-Strasse 1 translation into other languages). No part of
72076 Tübingen this book may be reproduced in any form – by
Germany photoprinting, microfilm, or any other
means – nor transmitted or translated into a
machine language without written permission
from the publishers. Registered names,
trademarks, etc. used in this book, even when
not specifically marked as such, are not to be
considered unprotected by law.
Print ISBN: 978-3-527-34571-7

ePDF ISBN: 978-3-527-82399-4
ePub ISBN: 978-3-527-82400-7
oBook ISBN: 978-3-527-82401-4
Cover Design: ADAM DESIGN, Weinheim,

Germany, based on an idea by Alexander
Schuhmacher / frontcover: iStock /@ ko_orn
Typesetting Straive, Chennai, India
v
Contents
Foreword xvii
About the Editors xix
List of Abbreviations xxi
1 Biopharmaceutical Innovation at a Glance 1

Markus Hinder, Dominik Hartl, and Alexander Schuhmacher
Summary 1
1.1 Biopharmaceutical Innovation and Drug Development, the Past and
Present 2
1.2 Why We Wrote This Book and What Readers Can Expect to Gain from
Reading It 4
References 5
2 Pharmacology and Drug Targets – The Basis of

Therapeutics 7
Lena Hartl, Martin A. Fink, and Sandra Beer-Hammer
Summary 7
2.1 Introduction 8
2.2 Pharmacodynamics 10
2.3 Receptors and Ion Channels 11
2.3.1 G-protein-Coupled Receptors (GPCRs) 11
2.3.2 Ion Channels 12
2.3.3 Enzyme-Associated Receptors 12
2.3.4 Non-receptor-Mediated Effects 14
2.4 Receptor Agonism and Antagonism 15
2.5 Implications for Drug Development 18
2.6 Pharmacokinetics 19
2.6.1 Liberation and Administration 19
2.6.2 Absorption 21
2.6.3 Distribution 21
2.6.4 Metabolism/Biotransformation 22
2.6.5 Phase I Reaction 23
2.6.5.1 Oxidation 23
vi Contents
2.6.5.2 Reduction and Hydrolysis 24

2.6.5.3 Phase II Reaction 24
2.6.5.4 Phase III Reaction 25
2.6.6 Excretion 25
2.6.6.1 Renal Elimination 25
2.6.6.2 Biliary Elimination 27
2.6.6.3 Intestinal Elimination 27
2.6.6.4 Pulmonary Elimination 27
2.7 Quantitative Pharmacokinetics 27
2.7.1 Dosing Regimen 27
2.7.2 Clearance (CL) 27
2.7.3 Exposure as Area Under the Curve 28
2.7.4 Bioavailability 28
2.7.5 Cmax , Ctrough , and Peak-to-Trough-Ratio 28
2.7.6 Volume of Distribution 29
2.7.7 Half-Life 29
2.7.8 Accumulation and Loading Dose 29
2.7.9 Induction and Maintenance Dose 30
2.8 Pharmacokinetic Models 30
2.9 Implications for Drug Development 31
2.9.1 PK/PD Modelling 31
2.9.2 Characteristics of Pharmacokinetics in Age, Disease and Others 33
2.9.3 Dose Finding/Determination of Dosing Regimens 33
2.9.4 Individualized Dosing and Therapeutic Drug Monitoring 34
2.10 Conclusions 34
References 34
3 Principles and Methods of the Pharmaceutical Drug Discovery

Process – From Idea over Target to a Development
Candidate 37
Werner Kramer
Summary 37
3.1 What is the Purpose of Drug Discovery? 38
3.2 Phases of the Drug Discovery Process 38
3.3 Target Identification 40
3.3.1 What is a Pharmaceutical Target? 40
3.3.2 Sources for Target Identification 41
3.3.2.1 An Extensive Inquiry of All Published Data on a Particular Target and Its
Pathway(s) 41
3.3.2.2 (Pharmaco)-Genetic Links to a Phenotype 41
3.3.2.3 Phenotypic Screening 41
3.3.3 Target Validation 42
3.3.3.1 Genetic Target Validation 42
3.3.3.2 Chemical Target Validation (‘Chemical Genomics’) 42
3.4 Strategies to Modulate Biological Targets 43
Contents vii
3.4.1 Preventing Formation of the Target Protein 43

3.4.2 Targeting the Ligand Binding Site of the Protein 44
3.4.3 Targeting Protein–Protein Interactions (PPI) 44
3.4.4 Masking Proteins 44
3.5 The Lead Identification Process 44
3.6 Strategies to Identify Lead Compounds 45
3.6.1 High-Throughput Screening (HTS) 45
3.6.1.1 Assay Criteria for Screening Approaches 47
3.6.1.2 Structure-Based Rational Drug Design 49
3.6.1.3 Phenotypic Screening 51
3.6.2 Chemical Libraries 52
3.6.2.1 Criteria for the Compounds in a Chemical Library 53
3.6.2.2 DNA-Encoded Chemical Libraries (DEL Libraries) 54
3.7 Drug Candidates 55
3.7.1 Lead Optimization and Candidate Selection 56
3.8 Outlook 59
References 60
4 Biomarkers: Definitions and Utility for Drug Development 63

Dominik Hartl
Summary 63
4.1 Introduction 64
4.2 Biomarker Modalities 69
4.2.1 Molecular Biomarkers 71
4.2.2 Imaging Biomarkers 72
4.2.3 Digital Biomarkers 73
4.3 Biomarkers in Drug Development 73
4.4 Biomarker Use Cases 75
4.5 Outlook 78
References 78
5 Toxicology in Drug Development – Understanding a Drug’s

Toxicity and Managing Safety and Risks 81
Elisabeth Rosner
Summary 81
5.1 Introduction to Toxicology and Definitions 82
5.2 The General Toxicological Framework 83
5.3 The Concept of the Therapeutic Index 84
5.4 The International Regulatory Framework for Safety Evaluations 85
5.4.1 The Data Package Required for First in Human (FIH) Trials 86
5.4.2 The Data Package Required for Studies Beyond FIH 87
5.4.2.1 The Data Package Required for Studies Beyond FIH for Large
(Bio)molecules and Oncology Compounds 87
5.5 Animal Species Selection 89
5.6 Basic Concepts for Non-clinical Studies to Support Clinical Trials 89
viii Contents
5.7 What Activity at Which Stage of Development? 92

5.8 Estimating the Safe Starting Dose in FIH Trials 93
5.8.1 Anti-cancer Drugs 93
5.9 Toxicological Evaluations During Late-Stage Drug Development 94
5.10 Outlook 96
References 97
6 Introduction to Chemistry Manufacturing and Controls – From

Compound and Development Candidate to Drug 99
Thomas Eichinger
Summary 99
6.1 CMC Introduction and Background 100
6.2 Some Basic Thoughts 100
6.2.1 Transition from Research to Development 100
6.2.2 Some Fundamentals About Physico-chemical Characteristics 101
6.2.3 The Biopharmaceutical Classification System (BCS) 102
6.2.4 Stability Investigations 104
6.2.5 The Physical Appearance: Morphology and Polymorphism 105
6.3 Preclinical Development and the Clinical Phase 1 from a CMC
Perspective 107
6.3.1 The Active Pharmaceutic Ingredient (API) 107
6.3.2 The Drug Product 108
6.3.3 Analytical Development 109
6.3.4 Regulatory Green Light for FIH Study 110
Perspective 110
6.4.1 The Active Pharmaceutic Ingredient (API) 111
6.4.2 The Drug Product 111
6.4.3 Analytical Development 111
Perspective 111
6.6 The Compilation and Authoring of the Submission Dossier for
Marketing Authorization 112
6.7 The NDA Submission and the Steps to Product Launch 116
References 117
7 Translational Medicine – The Bridging Discipline. Role and

Tools in the Drug Development Process 119
Markus Hinder and Dominik Hartl
Summary 119
7.1 Translational Medicine, Definitions and History 120
7.2 The Translational Gap 122
7.2.1 Failed Translation: Why It Happens and Why We Need to Avoid It 122
7.2.2 Predictivity of Models and the Translatability Gap 123
7.2.3 The Learning and Confirming Paradigm 124
Contents ix
7.3 Paths of Translation 126

7.3.1 Forward vs Reverse/Back-Translation 126
7.4 Translational Medicine in Drug Development 129
7.4.1 Bench to Bedside and Back or Forward and Backward Translation 129
7.4.1.1 Examples of Classical Forward Translation 129
7.4.1.2 Examples of Bedside to Bench or Backward Translation 130
7.5 Serendipity 132
7.5.1 Serendipity Examples: Sildenafil and the SGLT2 inhibitors 133
7.6 Conclusions 134
References 136
8 Decision-Making: What are the Key Drivers Around

Decision-Making in Drug Development? 139
Nigel McCracken
Summary 139
8.1 Background 140
8.1.1 Drug Development Process 140
8.1.2 Target Product Profile 141
8.2 Key Decision Points 142
8.3 Moving Towards ‘Go IND Enabling’ 143
8.4 Moving Towards Go/No Go First in Human (FIH) 144
8.5 Moving Towards Go/No Go Phase 2 146
8.6 Moving Towards Go Confirmatory Development 148
8.7 Concluding Remarks 150
References 150
9 Clinical Drug Development – Clinical Characterization for

Regulatory Approval 151
Werner Seiz
Summary 151
9.1 Clinical Drug Development, Definition, and Framework 152
9.2 The Different Stages of Clinical Development 153
9.3 The Basic Framework and Elements for Clinical Trials 155
9.4 The Clinical Study Protocol 156
9.5 Written Subject Information 156
9.6 Graphical Study Design and Schedule of Activities 156
9.7 Definition of Patient Population and Sample Size Calculation 160
9.8 Study Design 161
9.9 General Methods and Statistical Tools 163
9.9.1 Analysis Populations 163
9.9.2 Clinical Operations 163
9.10 Target Product Profile, Clinical Development Plan, and Other
Documents During Development 166
9.11 Changing Environment: Sensors, Digitalization, and COVID-19
Pandemic 166
x Contents
9.12 Key Studies During Clinical Development 167

9.12.1 First-In-Human Study 167
9.12.2 Mechanistic Study 169
9.12.3 Clinical Proof-of-Concept 169
9.12.4 Dose-Ranging Studies 170
9.12.5 Efficacy Studies 171
9.12.6 Specific Approaches – Adaptive Trial Designs 171
9.12.7 Oncology Trials 173
9.12.8 Basket, Umbrella, and Platform Trials 173
9.13 Advisory Boards, Steering Committees, Data and Safety Monitoring
Boards 174
9.13.1 Advisory Boards 174
9.13.2 Steering Committees 174
9.13.3 Endpoint Adjudication Committees 174
9.13.4 Data Safety and Monitoring Boards/Data Monitoring Committee 174
9.14 Summary of Information 175
References 175
10 Regulatory Affairs – Communicating with Health

Authorities 177
Hans-Juergen Fuelle and Valerie Lanctin
Summary 177
10.1 Regulatory Environment – Getting Started 178
10.2 The Role of Regulatory Affairs in Early Drug Development 180
10.3 The Common Technical Document 182
10.4 Investigational New Drug 184
10.5 Clinical Trial Application 184
10.6 Early Consultations with Health Authorities 185
10.7 Regulatory Requirements for Paediatric Diseases 186
10.8 Regulatory Pathways for Drug Development for Orphan/Rare
Diseases 187
10.9 Accelerated Pathways for Expedited Clinical Development and
Regulatory Review 188
10.10 The Role of Regulatory Affairs in Late-Stage Drug Development 190
10.11 The Role of Regulatory Affairs Before, During and After
Registration 194
10.12 Pre-submission Meetings with Health Authorities 195
10.13 Additional Submission-Enabling Regulatory Affairs Activities 196
10.14 Health Authority Review of Registration Dossiers 196
References 200
Contents xi
11 Regulatory Affairs in Device Development – How to Design

Medical Devices Capable to Enter the Market 203
Dietmar Schaffarczyk
Summary 203
11.1 Introduction 204
11.2 Product Commercialization 206
11.3 Ten Things to Know and Consider When Developing a Device 208
11.4 Obtaining Qualified Input from Interested Parties 212
11.5 Planning and Executing All Important Development Milestones 216
11.6 Design and Development Verification: Did I MAKE the Product
Right? 218
11.7 Design and Development Validation: Did I MAKE the Right
Product? 219
References 222
12 Market Entry and Reimbursement: Making Drugs Available for

Patients After Drug Approval 225
Ahmad Bechara and Rola Haroun
Summary 225
12.2 Healthcare Challenges 226
12.3 What Does Market Access Mean? 227
12.4 Market Access Gatekeepers 228
12.5 Drug Purchasing 228
12.6 Payers and Value Assessment 229
12.7 Health Economics as a Decision Tool for Market Access 231
12.7.1 What Is Health Economics? 232
12.7.2 What Is the Aim of a HTA? 232
12.7.3 HTA Process 233
12.8 Setting the Right Price 234
12.8.1 Pricing Policy 234
12.8.2 Therapeutic Reference Pricing (Internal) 234
12.8.3 International/External Reference Pricing 235
12.8.4 Value-Based Pricing 235
12.8.5 Overview of the Pricing and Reimbursement Process in Key European
Markets 236
12.9 How Does the Pharma Industry Prepare for Market Entries? 237
12.10 Early Patient Access 240
12.11 Managed Entry Agreements 240
12.12 Market Access Trends 242
xii Contents
12.12.1 USA and Canada 242

12.12.2 Europe 242
12.13 Future Market Access Challenges 243
References 243
13 Pricing in Germany – Key Learnings for Optimizing Price

Potential After the Introduction of AMNOG 247
Jacqueline Jones
Summary 247
13.2 Structure of the Pricing and Reimbursement Process in Germany 249
13.3 Analysis of Effects of the AMNOG Process on Drug Prices in
Germany 251
13.4 Learnings from AMNOG to Ensure Success in the German Market 253
13.5 Study Design 254
13.6 Dossier Preparation 254
13.7 Pre-launch Strategy 254
13.8 Post-launch 255
13.9 Price Negotiation 255
13.10 Post-negotiation 255
13.11 Key Takeaways 256
Key Resources 256
References 256
14 Project, Risk, and Portfolio Management – Managing R&D

Projects Today 257
Alexander Schuhmacher and Markus Hinder
Summary 257
14.2 The Phases of the Pharma R&D Process 259
14.3 Projects and Project Management 263
14.4 Project Life Cycle and Project Phases 270
14.5 Risk Management 272
14.6 Portfolio Management 274
References 279
15 Intellectual Property – How to Protect Innovation in the

Biopharmaceutical Industry 281
Charles E. Jeffries and Karen D. Larbig
Summary 281
15.1 Introduction to Intellectual Property Rights 282
15.2 Patent Rights 284
15.2.1 What is a Patent? 284
15.2.2 Patentability Criteria 285
15.2.3 Why and How to Apply for a Patent? 286
Contents xiii
15.2.4 Patenting Procedure 287

15.2.4.1 From Invention Harvesting to Patent Filing 287
15.2.4.2 Patent Prosecution and Grant Procedure 288
15.2.5 Value and Use of Patent Rights 291
15.3 The ‘Freedom to Operate’ Principle 292
15.4 Intellectual Property Protection in the Biopharmaceutical Industry 294
15.4.1 Patent Protection for a Pharmaceutical Drug Product 296
15.4.2 Life Cycle Management 298
15.4.3 Patent Term Extensions 298
15.4.4 Regulatory Data Protection 299
15.4.5 Loss of Exclusivity 299
15.4.6 FTO Issues in the Biopharmaceutical Industry 300
15.4.7 Role of an In-house Intellectual Property Department 301
15.5 Conclusion 302
Key Resources 302
16 Patents in the Biomedical Sciences and Industry – The Case of

the Swiss Life Science Company Prionics 305
Martin A. Bader and Oliver Gassmann
Summary 305
16.1 Patents in the Biomedical Sciences and Industry 306
16.2 The Swiss Life Science Company Prionics 309
16.3 Success Factors and Failures 312
16.4 Consequences and Insights 313
Key Resources 314
References 314
17 Pharmaceutical Business Development and

Licensing – Overview of a Cross-Functional and Multifaceted
Role and Its Key Elements in Biopharmaceutical Industry 317
Monika Schuessler
Summary 317
17.2 Types of Collaborations 318
17.3 Licensing Agreements 319
17.4 Commercial or Distribution Partnerships 320
17.5 Research Collaborations 321
17.6 Other Types of Agreements 321
17.7 Tech Transfer Agreements 322
17.8 Structured Approach – How to Start a Transaction? 322
17.9 Evaluation Process 324
17.10 Due Diligence 327
17.11 Letter of Intent and Term Sheet 329
17.12 Negotiation and Contract Closure 330
17.13 Alliance Management 331
xiv Contents
17.14 Conclusions 332

References 332
18 The Entrepreneur’s Guide Through the Galaxy of Biotech

Funding 333
Mathias Schmidt
Summary 333
18.2 Seed Funding – from a Research Concept to Validation of a Business
Idea 335
18.3 Getting Serious – Series A 336
18.3.1 Valuation 338
18.3.2 Building the Team 338
18.3.3 Alternatives to Venture Financing 338
18.4 Getting more Serious – Series B 339
18.5 Venture Debt as an Alternative to a Series B 341
18.6 Getting most Serious – Series C 341
18.7 Exit Options 342
18.8 Closing Remarks 343
Reference 343
19 Medical Technologies – Key Learning from Two Case

Studies 345
Günter Lorenz and Andreas Schüle
19.1 Case Study 1 – Medical Grade Plastics (MPG) 345
19.1.1 Consistency of Formulation 347
19.1.2 Security of Supply 348
19.1.3 Appendix – ISO 10993 349
19.2 Case Study 2 – Vitrectomy Using Fast Pneumatic-Driven Cutter
Systems 350
19.3 Innovative Valve Technology 352
19.4 Integration Technology 353
20 Laboratory Diagnostics – Tools for Clinical Decision-Making

and Clinical Trial Endpoints 357
Bhuwnesh Agrawal
Summary 357
20.1 Definition of Diagnostics, Why Diagnostics, Importance of Diagnostics,
Sample Types 358
20.2 The Diagnostics Industry – Key Figures and Key Players 361
20.3 Brief History of Diagnostics 362
20.4 Elements of the Laboratory Workflow (Pre-analytics, Analytics, and
Post-analytics) 362
20.5 Various Types of Diagnostic Tests in the Laboratory 363
20.5.1 Clinical Chemistry 363
Contents xv
20.5.2 Immunology 364

20.5.3 Haematology and Coagulation 364
20.5.4 Microbiology 365
20.5.5 Molecular Diagnostics 365
20.5.6 Histopathology 366
20.6 Place of Diagnostics in the Clinical Workflow 366
20.7 Quality Management 367
20.7.1 Commercial Tests 367
20.7.2 Laboratory-Developed Tests (LDTs) 367
20.7.3 Test Performance Characteristics 369
20.8 Regulatory Approval of Diagnostics 370
20.9 The Diagnostics R&D Process – Stage Gate and Agile Development
Processes 373
20.9.1 The Stage-Gate Process 373
20.9.2 The Agile Development Process 373
20.10 The Future of Diagnostics – Key Technologies and Trends, Personalized
Diagnostics 375
20.10.1 Automation 375
20.10.2 Molecular Testing 375
20.10.3 Personalized/Precision Medicine 375
20.10.4 Point of Care Testing 375
20.10.5 Digitization and Artificial Intelligence 376
20.11 Conclusions 376
References 376
21 Vaccination: Towards an Improved Influenza Vaccine 377

Pierre A. Morgon
Summary 377
21.1 Influenza – A Deadly Disease with a Long History 378
21.2 The Annual Challenge 383
21.3 Mechanisms of the Immune Response 384
21.4 Antigen Content 385
21.5 Although Influenza Vaccine Formulation Evolves to Reflect the
Circulating Strains, Innovation is Rare 386
21.6 Medical Rationale for Intradermal Administration (ID) 386
21.7 Search for Greater Acceptability 387
21.8 Acceptability of the New Device 389
21.9 Acceptability in Real Life 391
21.10 Outlook and Trends 393
References 394
Index 397
xvii
Foreword
This book with many critically important chapters is addressing key topics in
biopharmaceutical research & development and innovation. It aims at explaining
new modalities to diagnose, prevent, and treat human diseases. It also provides
real examples (case-in-points) of prototypes of innovative approaches that are
tested in biological systems of increasing size, complexity, and relevance where
the early phase spans from individual receptors over cell, organ systems to first
therapeutic exploration in small and well-defined patient populations. It debates
the latest know-how and the common commitment to the vision of a revitalized and
impactful biopharmaceutical development as well as other characters such as reg-
ulatory and health technology agencies instrumental to completing the journey of
medicines development, i.e. delivering to the respective patient population. This is a
recognition of the current environment where patient advocacy groups demanding
equitable access to affordable, quality products in reasonable timeframes.
The editors’ vision of recognizing the science of decision-making or ‘decision
science’ as an important process in medicines development is commendable. This
is often neglected in books addressing the process of medicines development. The
quality decision-making process as an integral part of medicines development has
a much higher chance of leading to quality outcomes. It can be argued that a poor
quality or bad decision-making process could lead to a good outcome; however,
this could only happen by chance. For example, applying quality decision-making
process by incorporating validated methodologies for benefit-risk assessment into
guidance for regulatory review. Such approaches are all twenty first century best
practices, which will have the outcomes of improved predictability, accountability,
consistency, and transparency of a public health focused, science-based medicines
development.
The book’s editors are active or former pharmaceutical executives who have
been lecturing biopharmaceutical innovation, pharmacology, and pharmaceutical
medicine over decades and who have brought together 27 experts in medicines
development to write the 21 chapters addressing development of biopharmaceuti-
cals/pharmaceuticals from molecule to market place. The chapters have focused
on the evaluation of many aspects of pre-clinical and clinical development very
helpful to students in biopharmaceutical sciences, pharmaceutical medicine, and
life science management. These chapters also provide insights that can be of benefit
xviii Foreword
to not only those engaged in biomedical postgraduate studies but also to those
early career researchers involved in medicines development. Undoubtedly, this
comprehensive body of work will improve scientific, regulatory, and reimbursement
processes and more efficiently facilitate access to quality versions of needed medical
products.
It is my hope that this book and the research it contains will provide significant
insight into pre-clinical and clinical development of biopharmaceuticals as well
as fostering innovation and quality decision-making practices applied to key
milestones of medicines development. I believe the roadmap provided in this book
could be considered as a blueprint for other health technology innovations, whether
a new active substance or an incremental innovation.
Professor Sam Salek, PhD, RPh, FFPM, GFMD, FRPS, FESCP, MCMS
Professor of Pharmacoepidemiology
Head – Public Health and Patient Safety Research Group
School of Life and Medical Sciences
University of Hertfordshire, UK
Visiting Professor – Estate of Hessen, Germany

Vice-President, PharmaTrain Federation
xix
About the Editors
Prof. Dr. Markus Hinder studied medicine at the

Universities of Heidelberg, Paris, and Zürich and
obtained a doctoral degree in pharmacology from
Heidelberg University. After graduation, he trained
in clinical pharmacology, cardiology, and emergency
medicine and underwent postgraduate training in
clinical trial methodology and statistics at the Uni-
versities of Basel and Brussels. Markus joined the
pharmaceutical industry more than 20 years ago and
held senior leadership positions in clinical pharma-
cology, translational medicine, clinical development,
medical affairs, drug safety and project management.
He has been lecturing pharmacology and pharma-
Photo: Markus Hinder.
ceutical R&D since 2004. In 2010, he was appointed
professor at Cardiff University/Hochschule Fresenius. He serves as a reviewer for
several journals and as an associate editor for the Journal of Translational Medicine.
Prof. Dr. Alexander Schuhmacher graduated in

biology from the University of Konstanz (Germany),
in pharmaceutical medicine at the University of
Witten/Herdecke (Germany) and did a Ph.D. in
molecular biology at the University of Konstanz; he
is also a graduate of the Executive MBA program at
the University of St. Gallen (Switzerland). Alexander
holds a full professorship in Life Science Manage-
ment at the THI Business School (Germany). His
research focus is on biopharmaceutical innovation
management with a specialization on R&D effi-
ciency, artificial intelligence, and open innovation.
Prior to that, Alexander worked 9 years as professor
at Reutlingen University (Germany) and 14 years
Photo: Alexander
in various senior R&D leadership positions in the
Schuhmacher.
pharmaceutical industry.
xx About the Editors
Prof. Dr. Jörg Goldhahn received his M.D. in 1997

from the Friedrich-Schiller University in Jena, Ger-
many, finished a postgraduate course (MAS) in Med-
ical Physics and Biomechanics at the ETH Zürich in
2000, received the postdoctoral lecture qualification
(Habilitation) in 2008, and became a faculty member
of the department for health sciences and technol-
ogy (D-HEST) as adjunct professor 2014. He worked
as a translational medicine expert at the Novartis
Institutes for Biomedical Research (NIBR) in Basel
in addition to more than 15 years in clinical research.
He is currently the head of the Institute for Transla-
Photo: Jörg Goldhahn. tional Medicine and medical director of the bachelor
in medicine at ETH in Zurich, Switzerland.
Prof. Dr. Dominik Hartl studied Medicine at the

Universities of Regensburg, Munich, and Melbourne
and obtained his doctoral degree in Immunology
from Munich/LMU University. He is board certified
in Pediatrics and Infectious Diseases and worked as
Physician Scientist/Post-Doc Scholar at Yale Univer-
sity. He joined the pharmaceutical industry more
than seven years ago and gained extensive experi-
ence in his positions in Drug Discovery, Transla-
tional Medicine, Biomarkers, Clinical Development
and Precision Medicine/Personalized Healthcare in
Biotech and Big Pharma. In addition to working in
Photo: Dominik Hartl. the pharmaceutical industry, Dominik is a Professor
for Pediatric Immunology/Infectious Diseases at the
University of Tübingen.
xxi
List of Abbreviations
More than
Abbreviations Meaning one meaning
AAALAC Association for Assessment and Accreditation of

Laboratory Animal Care
ACE Angiotensin-converting enzyme
ADH Autosomal dominant hypercholesterolaemia
ADME Absorption, distribution, metabolism and
excretion
ADMET Absorption, distribution, metabolism, excretion,
toxicity
AEMPS Spanish Agency for Drugs and Medical Products
AI Artificial intelligence
AIDS Acquired immunodeficiency syndrome
AIFA Italian Medicines Agency
AIS Arztinformationssystem
AMNOG Arzneimittelmarkt Neuordnungsgesetz
AMPA α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid (receptor)
AP Angina pectoris
API Active pharmaceutical ingredient
AR Assessment report
ASMF Active substance master file
ASMR Amélioration du Service Médical Rendu
ATC Anatomical therapeutic chemical
ATMP Advanced therapy medicinal product
ATP Adenosine triphosphate
AUC Area under the curve
BA Bioavailability
BBB Blood-brain barrier
xxii List of Abbreviations
More than
BCS Biopharmaceutical classification system

BEST Biomarker, endpoints and other tools
BLA Biologics license application
BMP Bone morphogenetic protein
BNP Brain natriuretic peptide
BPCA Best Pharmaceuticals for Children Act
BQP Biomarker qualification program
BSE Bovine spongiform encephalopathy
CA Competent authority
CAP College of American Pathologists
CAPA Corrective and preventive action
CAR-T Chimeric antigen receptor T-cell (therapy)
CAS Chemical abstract service (registration number)
CAT Committee for advanced therapies
CBA Cost–benefit analysis
CBER Center for Biologics Evaluation and Research
CD4 Cluster of differentiation 4 (cell)
CDA Confidentiality agreement
CDER Center for Drug Evaluation and Research
CDP Clinical development plan
CDRH Center for Devices and Radiological Health
CE Conformité Européenne
CEA Cost-effectiveness analysis
CED Coverage with evidence development
CEO Chief executive officer
CEREP Inhibitory activity and selectivity of compounds on
the PDE superfamily
CETP Cholesteryl-ester-transfer-protein
cGMP Cyclic guanosine monophosphate
CJD Creutzfeldt–Jakob disease
CKD-EPI Chronic kidney disease epidemiology
collaboration equation
CKL Clearance
CLIA Clinical Laboratory Improvement Act
clogP Partition coefficient between n-octanol and water
CMA Critical material attributes or cost-minimization
analysis
CMC Chemistry, manufacturing, and control
CNS Central nervous system
COGs Cost of goods
COMP Committee for orphan medicinal products
List of Abbreviations xxiii
More than
CP Centralized procedure
CPP Critical process parameters
CQA Critical quality attributes
CRO Contract research organization
CRP C-reactive protein
CSE Cystathionine-γ-lyase
CSP Clinical study protocol
CT Computed tomography
CTA Clinical trial application
CTD Common technical document
CUA Cost–utility analysis
CYP Cytochrome P450
CyTOF Cytometry by time-of-flight
DCDS Development core data sheet
DD Due diligence
DDI Drug–drug interaction
DDP Drug development pathway or design and 1
development plan
DEL DNA-encoded chemical libraries
DLTs Dose-limiting toxicities
DMC Data monitoring board
DMF Drug master file
DMSO Dimethyl sulphoxide
DNA Deoxyribonucleic acid
DoH Declaration of Helsinki
DP Drug product or decentralized procedure 1
DRF Dose-range finding
DSMB Data safety monitoring board
EAC Endpoint adjudication committee
EAP Early access program
EC Ethics committee
ECG Electrocardiogram
ECHA European Chemical Agency
ED Exectile dysfunction
ED50 50% of the test objects show the expected effect
EDMF European drug master file
EFD Embryofetal development
EGF Epidermal growth factor
ELISA Enzyme-linked immunosorbent assay
EMA European Medicines Agency
EoP End-of-phase
xxiv List of Abbreviations
More than
EPC European Patent Convention

EPO European Patent Office
EQA External quality assurance
ERA Environmental risk assessment
ERK Extracellular signal-regulated kinase
ERP External reference pricing
ESTs Expressed sequence tags
eTOC Electronic table of content
EUDAMED European Database for Medical Devices
EUnetHTA European Network for Health Technology
Assessment
FACS Fluorescence-activated cell sorting
Fas FS-7-associated surface antigen
FDA (American) Food and Drug Administration
FEED Fertility and early embryonic development
FGF Fibroblast growth factor
FIBC Fully integrated Biopharmaceutical Company
FIH First in human
FIM First in men
FISH Fluorescence in situ hybridization
Flunet Flue network
FPE First pass effect
FRET Fluorescence resonance energy transfer
FTE Full-time employee
FTO Freedom to operate
GABA Gamma aminobutyric acid
G-BA Germany, Federal Joint Committee
GC Gas chromatography
GCP Good clinical practice
GDP Guanosine diphosphate or gross domestic product 1
GDPR General Data Protection Regulation
GFR Glomerular filtration rate
GHTF Global Harmonization Task Force
GI Gastrointestinal
GIRK G-protein-coupled inwardly rectifying K+ channel
GKV-SV Umbrella Organization of the Statutory Health
Insurers
GLP Good laboratory practice
GMP Good manufacturing practice
GPCR G-protein-coupled receptor
GTMP Gene therapy medicinal product
List of Abbreviations xxv
More than
GTP Guanosine triphosphate

GxP Good …practice
HA Hemagglutinin
HAV Hepatitis A virus
HbA1c Hemoglobin A1c
HCP Health care providers
HCV Hepatitis C virus
HED Human equivalent dose
hERG human ether-a-go-go-related gene (channel)
HI Hemagglutination inhibition
HIV Human immunodeficiency virus
HMG-CoA Hydroxy-methyl-glutaryl-coenzyme-A
HNSTD Highest non severely toxic dose
HPLC High-performance liquid chromatography
HR Human resources
HTA Health technology assessment
HTS High-throughput screening
HV Health volunteer
i.p. Intraperitoneal
i.v. Intravenous
IB Investigator’s brochure
IC50 Half maximal inhibitory concentration
ICANN Internet Corporation for Assigned Names and
Numbers
ICER Incremental cost-effectiveness ratio or Institute for 1
Clinical and Economic Review
ICH International Conference on Harmonization
ID Intradermal administration
IDP Integrated development plan
IFCC International Federation of Clinical Chemistry and
Laboratory Medicine
IGF Insulin-like growth factor
Il-6 Interleukin 6
IMDRF International Medical Device Regulators Forum
IMP Investigational medicinal product
IMPD Investigational medicinal product documentation
IND Investigational New Drug
INN International non-proprietary name
INTERACT INitial Targeted Engagement for Regulatory
Advice on CBER producTs
xxvi List of Abbreviations
More than
IP Intellectual property
IPI Swiss Federal Institute of Intellectual Property
IPO Initial public offering
IPR Intellectual property right(s)
IPRP International preliminary report on patentability
iPS (cell) Induced pluripotent stem cells
IQVIA Company name, formerly Quintiles and IMS
Health, Inc.
IQWiG Institut für Qualität und Wirtschaftlichkeit im
Gesundheitswesen
IRB Institutional Review Board
ISO International Organization for Standardization
ISP Indication-specific pricing
ISR Injection site reactions
ITT Intent-to-treat population
IVD In vitro diagnostics
IVDR In vitro Diagnostic Device Regulation
JAK Just another kinase (Janus kinase)
JNK c-Jun N-terminal kinases
KCNQ Potassium channel, voltage-gated, KQT-like
subfamily
Kir-channel Inwardly rectifying K+ channel
Km Michaelis constant
KOL Key opinion leader
LADME Liberation/absorption/distribution/
metabolism/elimination
LCM Life Cycle Management
LD Loading dose or lead discovery 1
LD50 Lethal dose for 50% of the animals
LDL Low-density lipoprotein
LDT Lab developed test
LO Lead optimization
LoE Loss of exclusivity
LoI Letter of intent
LRV Lower reference value
MA&P Market access and pricing team
MAA Marketing authorization application
mAb Monoclonal antibody
MABEL Minimum anticipated biological effect level
MAD Multiple ascending doses
MALDI-TOF Matrix-associated laser desorption/ionization
List of Abbreviations xxvii
More than
MAP-kinase Mitogen-activated protein kinase

MD Medical device
MDG Medical grade plastics
MDR Medical Device Regulation
MDRD Modification of diet in renal disease
MEA Managed entry agreements
MedDRA Medical Dictionary for Regulatory Activities
MHLW (Japanese) Ministry of Health, Labour, and Welfare
MIC90 Minimum inhibitory concentration
mM Millimolar
MoA Mechanism/mode of action
MRI Magnetic resonance imaging
mRNA Messenger ribonucleic acid
MRSA Methicillin-resistant Staphylococcus aureus
MTA Material transfer agreement
MTD Maximum tolerated dose
NA Neuraminidase
NADPH Nicotinamide adenine dinucleotide phosphate
NAT N-acetyltransferase
NB Notified body
NBTS Non-binding term sheet
NCA Non-compartmental analysis
NDA New drug application or non-disclosure agreement 1
NeeS Non-eCTD electronic submission format
NEP Nuclear export protein
NICE National Institute for Health and Care Excellence
NIH National Institutes of Health (US)
NMDA N-methyl-D-aspartate
NME New molecular entity
NMPA National Medical Products Administration (China)
NNT Numbers-needed-to-treat
NO Nitric oxide
NOAEL No-observed-adverse-effect level
NPV Net-present value or negative predictive values 1
NRTL Nationally Recognized Testing Laboratory
NSAID Non-steroidal anti-inflammatory drug
NTEL No toxic effect level
OAT Organic anion transporter
OBA Outcomes-based agreement
OCT Organic cation transporter
OD Orphan drug
xxviii List of Abbreviations
More than
ODA Orphan Drug Act

OECD Organisation for Economic Co-operation and
Development
OGTT Oral glucose tolerance test
OOPD Office of Orphan Products Development
OSHA Occupational Safety and Health Administration’s
PAH Pulmonary arterial hypertension
PAI Pre-approval inspection
PAS Patient access scheme
PBB Polybrominated biphenyls
PBDE Polybrominated diphenyl ether
PBM Pharmacy Benefit Manager
PBPK Physiologically based PK
PC Paris convention
PCR Polymerase chain reaction
PCSK9 Proprotein convertase subtilisin/kexin type 9
PCT Patent Cooperation Treaty
PD Pharmacodynamics
PDCO Paediatric Committee
PDE5 Phosphodiesterase type 5
PDGF Platelet-derived growth factor
PE Polyethylene
PET Positron-emission tomography
Ph. Eur. EU Pharmacopeia
PI Principal investigator
PIP Paediatric investigation plan
PK Pharmacokinetics
pKa pKa is the negative log of the acid dissociation
constant
PKPD Pharmacokinetic––Pharmacodynamic
PMDA Pharmaceuticals and Medical Devices Agency
PMI Project Management Institute
PoC Proof of concept (study)
PoCT Point of care testing
PoM Proof-of-mechanism
PopPK Population PK
PoS Probability of success
PP Per-protocol
PPB Plasma protein binding
PPI Protein–protein interaction
PPND Peri- and postnatal development
List of Abbreviations xxix
More than
PPQ Process performance qualification

PPV Positive predictive value
PREA Pediatric Research Equity Act
PRIME (EMA’s) Priority medicines
PRN Pro re nata
PRO Patient-reported outcomes
PSP Paediatric study plan
PSUR Periodic safety update reports
PTE Patent term extensions
PTRS Probability of technical and regulatory success
QALY Quality-adjusted life year
QbD Quality by design
QDM Quantitative decision making
QED quod erat demonstrandum
QIV Quadrivalent influenza vaccine
QMS Quality management system
QSE Quality, safety efficacy (requirements)
QSP Quantitative systems pharmacology
QTPP Quality target product profile
R&D Research and development
RA Regulatory affairs
RAPS Regulatory Affairs Professionals Society
RDP Regulatory data protection
REACH Registration, evaluation, authorization, and
restriction of chemicals
RIP Receptor-interacting protein
RMAT Regenerative medicine advanced therapy
RMS Reporting member state
RNA Ribonucleic acid
rNPV Risk adjusted net present value
ROC Receiver-operating characteristics (curve)
RohS Restriction of certain hazardous substances
ROI Return of investment
RP2D Recommended phase 2 dose
RUO Research use only
RWE Real-world evidence
s.c. Subcutaneous
SAD Single ascending doses
SAR Structure–activity relationship
SBDD Structure-based drug design
SC Steering committee
xxx List of Abbreviations
More than
scRNAseq Single-cell RNA sequencing

SCTMP Somatic cell therapy medicinal product
SE Substantially equivalent
SGLT Sodium-glucose linked transporter
siRNA Small interfering RNA
SISH Silver in situ hybridization
SLC Solute carrier
SME Small- and medium-sized enterprises
SmPC Summary of product characteristics
SNP Single-nucleotide polymorphism
SoC Standard of care
SOP Standard operating procedure
SP Safety population
SPA Special Protocol Assessment
SPC Supplemental protection certificate
SPECT Single-photon emission computed tomography
STAT Signal transducers and activators of transcription
STD10 Severely toxic dose in 10% of the rodent
STDI Sexually transmitted infectious diseases
STI Sexually transmitted infection
SVHC Substances of very high concern
T2D Type 2 diabetes
TEP Tissue-engineered product
TET2 Tet methylcytosine dioxygenase 2
TGA Therapeutic Goods Administration (Austria)
TGF Transforming growth factor
TI Therapeutic index or target identification 1
TIV Trivalent influenza vaccine
TM Translational medicine
TMP Target marketing profile
TNF Tumor necrosis factor
TOP Target out-licensing profile
TPP Target product profile
TRADD TNF (tumor necrosis factor) R1 (receptor type
1)-associated death domain
TRAF TNF receptor-associated factor
TRF Time-resolved fluorescence
TRP Therapeutic reference pricing
TRV Target reference value
TS Term sheet
TV Target validation
List of Abbreviations xxxi
More than
UGE Urinary glucose excretion

UGT UDP-glucuronosyltransferase
UPOV Convention of the International Union for the
Protection of New Varieties of Plants
US PI US packaging insert
USP United States Pharmacopeia or unique selling 1
point (context dependent)
USPTO United States Patent and Trademark Office
UV Ultra violet (radiation)
VBP Value-based pricing
VDI Association of German Engineers
VEGF Vascular endothelial growth factor
VFA Verband der forschenden Pharma-Unternehmen
VHP Voluntary harmonization process
VN Virus neutralization
VoC Voice of customer
WBS Work breakdown structure
WIPO World Intellectual Property Organization
WoCBP Women of childbearing potential
WR Written request
1
Biopharmaceutical Innovation at a Glance

Markus Hinder 1 , Dominik Hartl 2 , and Alexander Schuhmacher 3
1
Novartis, Global Drug Development, Chief Medical Office & Patient Safety, Forum 1, CH-4002, Basel,
Switzerland
2
Eberhard Karls Universität Tübingen, Universitätsklinik für Kinder- und Jugendmedizin, Department of
Pediatrics I, Hoppe-Seyler-Straße 1, 72076, Tübingen, Germany
3
Technische Hochschule Ingolstadt, THI Business School, Esplanade 10, D-85049, Ingolstadt, Germany
Summary
Biopharmaceutical Research & Development (R&D) aims at finding new modalities

to diagnose, prevent, and treat human diseases. Prototypes of innovative approaches
are tested in biological systems of increasing size, complexity, and relevance. The
early phase spans from individual receptors over cell, organ systems to first therapeu-
tic exploration in small and well-defined patient populations. This exploratory phase
ends once clinical proof of concept (PoC) is established. Subsequently, large clinical
programs are undertaken to confirm the efficacy and (if applicable) superiority of
the new approach by means of long clinical programs. Health authorities around the
world play a key role in this process. During the clinical test phase, together with the
biopharmaceutical companies, they surveil and ensure the scientifically sound and
safe conduct of clinical trials. In a second step, health authorities review the entire
data set that has been generated during both the exploratory and the confirmatory
phases. If, based on these data, they come to conclude that the benefits conferred
to the patients outweigh the risks, authorization to market the drug in the respec-
tive country is conferred. In order to get reimbursed, approved new drugs need to
undergo an economic review process. There the decision is made if the new drug
confers enough clinical benefits to justify its price. The drug approval process and
the economic evaluation/reimbursement process are two distinct processes carried
out by different institutions.
Although R&D leverages a number of academic disciplines like epidemiology,
genetics, biology, chemistry, bioinformatics, pharmacology, toxicology, pharmacy,
and medicine, it is not primarily an academic discipline and cannot be studied in one
program at a university. It is difficult to find coherent overarching information on
Principles of Biomedical Sciences and Industry: Translating Ideas into Treatments, First Edition.
Edited by Markus Hinder, Alexander Schuhmacher, Jörg Goldhahn, and Dominik Hartl.
© 2022 WILEY-VCH GmbH. Published 2022 by WILEY-VCH GmbH.
2 1 Biopharmaceutical Innovation at a Glance
concepts generally applicable to the industry beyond individual company processes.

Thus, this book attempts to bridge this gap and provide an overview and concepts
and reliable details which apply across the industry and are valuable for everyone
working in or with the biopharmaceutical industry.
Tools
● Pharmacology
● Pharmacokinetics
● Toxicology
● Clinical studies
● Project and portfolio management
● IP management
Regulatory framework
● National and regional drug approval regulations
● International Conference on Harmonization (ICH)
● Declaration of Helsinki (DoH)
Risks
● Strategic risks, such as enormous R&D investments
● External risks, such as drug approval regulations
● Internal risks, such as degree of predictivity of early trials for late-stage development
Success factors
● Understanding molecular mechanisms
● Disease understanding
● Biomarkers
1.1 Biopharmaceutical Innovation and Drug

Development, the Past and Present
‘Définissez les termes, vous dis-je, ou jamais nous ne nous entendrons’.

Voltaire (François-Marie Arouet 1694–1778)
If you wish to converse with me, define your terms.
To alleviate or even cure human disease has always been an area of paramount
interest and activity of mankind. Documentation from around the globe (e.g. Middle
East, India, China, America) indicates that since ancient times people observed and
collected information about techniques to treat human disease. The oldest available
documents are approximately 4000 years old and date from approximately 2000
1.1 Biopharmaceutical Innovation and Drug Development, the Past and Present 3
B.C. (papyrus Ebers (1500 BC) and papyrus Kahun (1800 BC)). From ancient times
up to the Middle Ages, the key source to finding ways to treat human disease were
trial and observation and in many cases folk memory to preserve useful knowledge.
Thus, the first treatments were rather found by chance than actively discovered.
Pharmacology as a scientific discipline, which deals with the discovery and char-
acterization of xenobiotics to treat diseases, is a relatively young discipline and had
to wait until physics, chemistry, and biology had established themselves as sciences
and laid the foundations for a scientific understanding of human health and disease.
Until the 1950s, classical (forward) pharmacology dominated the scientific
approach to find new medicines. During this time, most of the discoveries focused
mainly on medications providing symptomatic amelioration or relief as opposed to
changing long-term prognosis of patients suffering from a disease or treatment of
risk factors (Drews 2000).
Drug approval in the early days was often restricted to small series of clinical tests
demonstrating that the desired effects were detectable. Systematic testing in broad
populations of interest and a systematic approach to investigating a drug’s preclinical
and clinical safety only became a prerequisite on both sides of the Atlantic after two
drug disasters became public (1930 Sulfanilamide and 1960 Thalidomide) (Paine
2017; Silverman 2002). Subsequently, more and more processes and standards
which were related to drug discovery and more importantly drug approval became
standardized and regulated – thus today’s notion of a highly regulated industry.
In 1990, the Japanese Ministry of Health, Labour and Welfare (MHLW), the
American Food and Drug Administration (FDA), and the European Medicines
Evaluation Agency (EMEA, today EMA) agreed on common procedures and
standards that apply to the investigation approval of new drugs in all three countries
and regions. These standards are laid down in the documents of the ‘International
Council for Harmonisation of Technical Requirements for Pharmaceuticals for
Human Use’, often just called ICH (ICH, n.d.). From the 1990s on, some researchers
started to discuss a ‘productivity crisis’ in the biopharmaceutical industry. Since
these times, productivity, determined as the number of new drugs approved, and
efficiency, determined as the ratio of investments needed by the number of new
drugs approved, are figures that are constantly watched by decision makers inside
and outside of the biopharmaceutical industry. Recent analyses indicate that
discovering and bringing a new drug to the market need investments in the range
of US$ 5–10 billion (Schuhmacher et al. 2016).
The more drugs became available to treat a specific condition and the more
drugs were used as chronic or preventive treatments, the more long-term clinical
safety became a focus area. Altered benefit/risk assessments in this context led to
marketing withdrawals for numerous approved drugs from nearly all therapeutic
areas. Prominent examples include some fluoroquinolone antibiotics, some per-
oxisome proliferator-activated receptor agonists, cyclooxygenase 2 inhibitors and
anti-histaminics and ant-psychotics, just to name a few. Based on these experiences,
health authorities started to require prior to approval of a new medicine an active
risk exclusion approach. In other words, the long accepted ‘no difference approach’
to demonstrate clinical safety was abandoned by an active process able to rule out
a certain degree of hazard (Brass et al. 2006).
The core responsibility of a pharmaceutical company towards society is to discover
and develop solutions which help patients to lead a better and longer life. In order
to generate the necessary cash flow which can be invested in R&D, many companies
have focused in the past on the so-called blockbuster model, i.e. on products with
worldwide sales in excess of US$ 1 billion/year. Traditionally, these were products
at relatively low daily dosage cost in highly prevalent diseases and thus large world-
wide populations. Triggered by an improved mechanistic understanding of diseases
and genetics enhancing the identification of new drug targets, the biopharmaceuti-
cal sector has developed in recent years more and more medicines to treat so-called
orphan diseases which by definition affect less than 1 in 2000 people (Trusheim et al.
2007). By today, orphan drugs represent around one-eighth of worldwide prescrip-
tion drug sales indicating the importance of this new market segment (Waters and
Urquhart 2019).
With more and more competitive drugs entering the market and the availability of
a plethora of therapeutic options in the highly prevalent diseases, the question arises,
how to best invest scarce healthcare resources. As a reaction, payors around the globe
have at different pace and to different extent started to ask the ‘value for money’
question. This has led to a situation, where a new drug today needs to conform or
exceed the quality, safety efficacy (QSE) requirements set forth by health authorities
to gain marketing authorization on the one hand. On the other hand, these new
medicinal products need to demonstrate their cost-effectiveness before they can be
reimbursed by national health insurers and other payors.
1.2 Why We Wrote This Book and What Readers Can

Expect to Gain from Reading It
Biopharmaceutical sciences and pharmaceutical innovation belong to the highly
innovative, cost-intense, high tech endeavours which can provide important
progress to both the individual and the society.
Finding and developing a new medicine is a complex undertaking which requires
many diverse scientific disciplines with different scientific languages and ways of
thinking to collaborate effectively and efficiently towards a common goal over many
years.
The editors of this book realized through own experience as academicians and
as associates in the biopharmaceutical industry, as well as university lecturers that
becoming a drug hunter or developer is a year-long, often unstructured process and
that biopharmaceutical innovation and the art and science of drug development are
not yet established as an academic university discipline. Universities are home to
excellent disciplines wh are an essential part of the pharmaceutical value chain. As
academic institutions, their scope is broader and contributions to pharmaceutical
innovation often are a more peripheral aspect of their overall work. Equally
important, the integrating, connective band between the multiple critical academic
References 5
disciplines is frequently not established. Accordingly, it is challenging to gather

coherent overarching information on concepts generally applicable to the industry
beyond individual company processes.
This book aims to provide a comprehensive and coherent insight into pharmaceu-
tical R&D and related functions, such as business development and market entry.
In general, biopharmaceutical R&D relies on external innovation and on qualified
academics transitioning from basic and clinical research into pharmaceutical indus-
try. Drug discovery and development in biopharmaceutical companies, however,
usually is an internally focused process and easily perceived by industry outsiders as
a ‘black-box’ without insights into strategies and operations, making it difficult for
academics to consider and prepare for a career in R&D in pharmaceutical industry.
Based on feedback from industry-internal and academic-external colleagues and
stakeholders, we identified the clear unmet need to map out the different phases
and frameworks of drug discovery, drug development, business development, and
market access within the pharmaceutical industry. Pharmaceutical R&D makes
intensive use of a broad number of academic disciplines, including epidemiol-
ogy, genetics, biology, chemistry, biochemistry, bioinformatics, pharmacology,
toxicology, pharmacy, veterinary medicine, and medicine.
This book covers all relevant disciplines along the pharmaceutical value chain,
introduces key success-critical concepts to find, select, and develop new drugs,
as well as introduces the reader into basic concepts and the technical jargon
of integrated drug developers. All book authors are recognized experts in their
respective areas. They know the ins and outs of their disciplines from a theoretical
perspective, they all know from own practical work which parts of the theory are
critically important and wrote their respective chapters with the reader and future
application of knowledge in mind. The chapters include comprehensive referencing
for readers who want to get down to the primary sources and in many cases contain
practical examples and illustrations.
The editors believe that this book can bridge and close the existing knowledge gap
and therefore provides a comprehensive overview on different components, phases,
and frameworks of biopharmaceutical R&D, with broad relevance across pharma-
ceutical industries and valuable for a broad readership working either in, together
with or interested in joining the biopharmaceutical industry.
References
No author (1550 BC). Papyrus Ebers. University library Leipzig https://papyrusebers.de/

en/ (accessed 3 October 2020).
No author (1800 BC). Papyrus Lahun. University College London library https://www
.ucl.ac.uk/museums-static/digitalegypt/med/birthpapyrus.html (accessed 3 October
2020).
Brass, E.P., Lewis, R.J., Lipicky, R. et al. (2006). Risk assessment in drug development
for symptomatic indications: a framework for the prospective exclusion of
unacceptable cardiovascular risk. Clin. Pharmacol. Ther. 79 (3): 165–172.
Drews, J. (2000). Drug discovery: a historical perspective. Science 287 (5460): 1960–1964.
ICH (n.d.). International Council for Harmonisation of Technical Requirements for
Pharmaceuticals for Human Use (ICH). https://www.ich.org/ (accessed 3 October
2020).
Paine, M.F. (2017). Therapeutic disasters that hastened safety testing of new drugs. Clin.
Pharmacol. Ther. 101 (4): 430–434.
Schuhmacher, A., Gassmann, O., and Hinder, M. (2016). Changing R&D models in
research-based pharmaceutical companies. J. Transl. Med. 14 (1): 105.
Silverman, W.A. (2002). The schizophrenic career of a “monster drug”. Pediatrics 110
(2 Pt 1): 404–406.
Trusheim, M.R., Berndt, E.R., and Douglas, F.L. (2007). Stratified medicine: strategic
and economic implications of combining drugs and clinical biomarkers. Nat. Rev.
Drug Discovery 6: 287–293.
Waters, R. and Urquhart, L. (2019). Evaluate Pharma. World Preview, Outlook to 2024.
https://www.evaluate.com/thought-leadership/pharma/evaluatepharma-world-
preview-2019-outlook-2024 (accessed 27 September 2020).
7
Pharmacology and Drug Targets – The Basis of Therapeutics

Lena Hartl 1 , Martin A. Fink 2 , and Sandra Beer-Hammer 3
1
University of Tübingen, Department of Pediatrics, Hoppe-Seyler-Strasse 1, 72072, Tübingen, Germany
2
Novartis Pharma AG, Novartis Campus, CH-4056, Basel, Switzerland
3
University of Tübingen, Institute for Experimental and Clinical Pharmacology and Toxicology, Department
of Pharmacology and Experimental Therapy, Hoppe-Seyler-Strasse 1, 72072, Tübingen, Germany
Summary
This chapter covers (i) basics of pharmacology such as dosage forms, routes of
administration, delivery to the target site, (ii) pharmacodynamics (PD), and (iii)
pharmacokinetics (PK) and provides (iv) examples of its use in drug discovery
and development. In particular, basic principles of drug–target receptor inter-
actions, agonistic and antagonistic mechanisms of action (MoA), liberation/
absorption/distribution/metabolism/elimination (LADME) phases of PK, dosage
forms, PK/PD modelling, drug–drug interactions (DDIs), drug transporters, aspects
of clinical pharmacology, therapeutic window/index calculations, and illustrative
examples of how these tools are utilized in drug discovery and development are
provided.
Tools
● In vitro systems
● In vivo systems
● Genetics
● Screening
● Modelling
Regulatory framework
● ICH
(Continued)
Principles of Biomedical Sciences and Industry: Translating Ideas into Treatments, First Edition.
Edited by Markus Hinder, Alexander Schuhmacher, Jörg Goldhahn, and Dominik Hartl.
© 2022 WILEY-VCH GmbH. Published 2022 by WILEY-VCH GmbH.
8 2 Pharmacology and Drug Targets – The Basis of Therapeutics
(Continued)
Risks
● Limited understanding of pathophysiology
● Target validation/reproducibility
● Lack of appropriate models
Success factors
● Translating pre-clinical compounds into drugs for patients
2.1 Introduction
After human health was believed to be determined solely by God and fate for long
times, the theory of humourism (also known as the four humours) developed
in antiquity under the influence of important Greek savants as Hippocrates and
Galen dominated Western medicine until modern times. In his works, Galen wrote
numerous texts on the composition and manufacture of medicines and gave his
name to the Galenic formulation of medicines. In the sixteenth century, the famous
savant Paracelsus also included chemical substances in drug therapy. Under his
influence, the pharmacy laboratory also gained more importance. During the course
of the industrialization in the nineteenth century, pharmaceutical industry evolved
from pharmacies specialized on the manufacturing of pharmaceuticals and the
tar and paint industry. At that time, the prevailing teaching of humoral pathology
was replaced by the research of the physician Rudolf Virchow and based on it the
so-called cellular pathology and formed the fundament for science-based medicine.
Pharmacology (greek for ‘pharmacon’: drug and ‘-logos’: doctrine/knowledge of)
explores interactions between compounds and organism and describes it in a quan-
titative and qualitative manner (Tozer and Rowland 2016; Simmons 2011). The term
pharmacon describes the active element of a drug and is non-judgemental; e.g. it
contains no statement if the substance is harmful (poison) or healing (drug).
The interaction between drug and organism can be classified in three phases:
1. Pharmaceutical phase
The pharmaceutical phase includes administration and drug release. This is
decisively determined by the type of administration (e.g. oral, intravenous
(iv), intramuscular, subcutaneous, inhalative, epicutaneous, sublingual, and
rectal) and the galenics (composition and manufacture of drugs). Together with
so-called adjuvants, the drug becomes a dosage form. Galenics can be used, for
example, to influence the duration of action, the concentration of the active
substance in the blood and sometimes even the site of action.
2. Pharmacokinetics (PK)
Pharmacokinetics deals with the concentrations of a drug in the body and is
affected by all processes to which a drug is exposed to in the body. Pharma-
cokinetics includes absorption, distribution, metabolism and excretion of a
compound (ADME).
2.1 Introduction 9
3. Pharmacodynamics (PD)
Pharmacodynamics describes the effect of the drug on the organism. Here, bind-
ing to a target (e.g. receptors, ion channels, enzymes, and bacterial metabolism)
and the resulting biological effect play a major role. The pharmacological effect
of a substance can be divided into desirable and undesirable effects (side effects).
Pharmacodynamics: Effect of the Drug on the Organism. The pharmacological

effect of a substance can be divided into desirable (potency) and undesirable
effects (side effects).
Pharmacokinetics: Effect of the Organism on the Drug. Concentrations of a
drug in the body, affected by all processes to which a drug is exposed to, includ-
ing absorption, distribution, metabolism, and excretion of a compound (ADME).
The pharmacology differs between individuals – for instance higher weight

subjects often show lower concentrations. Diseases may need different concen-
tration levels for efficacy but might also influence the pharmaceutical phase and
the PK. There are many factors that influence the interaction between drug and
organism (Figure 2.1) – and all these aspects influence the dose and regimen (i.e.
frequency) that provide an optimal benefit–risk relationship for the individual
patient.
Studying the pharmacology of a compound during drug development is essential
to learn about the influencing factors on the pharmacokinetics and pharmacody-
namics and, if necessary, provide information in the drug label on adjusting the dose
or regimen accordingly (Rosenbaum 2016).
In this chapter, we describe general concepts mainly related to small molecules
(low molecular weight compounds) and monoclonal antibodies. Of note, there exist
newer therapeutic approaches, like cell and gene therapies (e.g. CAR-T therapies or
Drug/
Disease
formulation
Demographics Co-medication
Individual
dose/
regimen
Efficacy
Safety (risk)
(benefit)
Figure 2.1 Factors influencing the interaction between a drug and an organism. Source:
Book editors based on Hartl, Fink, and Beer-Hammer.
adeno-associated virus vector therapies) which can show different dynamics over
time and are not covered here even though the basic concepts of pharmacology
still hold.
2.2 Pharmacodynamics
Pharmacodynamics is the science of biochemical and physiological drug effects on

animal or human organisms as well as microorganisms and parasites.
Pharmacodynamics:
● Type of action (profile and quality)
● Mechanisms of action (MoA)
● Place of action
● Potency
● Efficacy
Specific substances interact with defined endogenous target molecules that are
structurally proteins such as receptors, transporters, and enzymes, DNA, RNA, or
lipids. They already act in low dosages or concentrations, and their effect depends on
the chemical structure and thus on the shape, size, and stereochemical arrangement
of the molecule. The specific effect also means that a drug affects as selectively as
possible on the target structures.
Two main classes of molecules used as therapeutics:

a) Small molecules
● low molecular weight compounds
● chemically produced
● defined by exact chemical structure
● usually oral drugs
b) Large molecules/biomolecules
● recombinant proteins or monoclonal antibodies
● produced in genetically modified cells
● usually intravenous (IV) or subcutaneously (SC) administered drugs
Small molecules are mostly less specific in their action than biomolecules or mon-
oclonal antibodies; they can bind to receptors other than the target (off-target bind-
ing) which can result in unwanted side effects (off-target toxicity, which is compound
specific). Strong inhibition of a pathway by on-target binding can also induce adverse
effects (on-target toxicity, which is target-specific), for instance, immunosuppressive
drugs often lead to higher infection risks. At the molecular pharmacological level,
specificity implies that the drug binds to its target with sufficient affinity and has the
ability to enhance or inhibit its function as a result of this binding.
Unspecific substances are characterized by the fact that they do not react specif-
ically with endogenous compounds and that they do not change their effect if the
chemical modification is not too profound.
Most pharmacological effects can be attributed to a few MoA:
● Interaction with membrane receptors (stimulation or inhibition)
● Opening or blockade of voltage-dependent or ligand-controlled ion channels
● Regulation of gene transcription by binding to intracellular receptors
● Influence of transmembrane or intracellular transporters
● Inhibition or activation of enzymes
2.3 Receptors and Ion Channels
Pharmacological receptors are characterized as intracellular or membrane receptors,

which upon binding of an endogenous or exogenous ligand to a specific binding site
elicit direct or indirect effects (E). With this definition, the basic equation is ligand
(L)–receptor (R) interaction: L + R ↔ [LR] →→ E. Thus, a (pharmacological) recep-
tor has a dual role: (i) signal recognition through interaction with the ligand and
formation of the ligand–receptor complex and (ii) direct or indirect triggering of an
effect. Receptors can be found intracellularly or bound to membranes. Intracellu-
lar receptors, which act as transcription factors, include the receptors of (i) steroid
hormones, (ii) retinoids, and (iii) thyroid hormones. The membrane receptors can be
divided into (i) G-protein-coupled receptors (GPCRs), (ii) ion channels (voltage- and
ligand-controlled), and (iii) receptor protein kinases (enzyme-associated receptors).
2.3.1 G-protein-Coupled Receptors (GPCRs)

With 800 genes, GPCRs are not only the largest group within the family of mem-
brane receptors in the human genome, but also the group with the highest diversity.
Various extracellular stimuli induce intracellular signalling cascades via the intra-
cellularly coupled Guanine-nucleotide-binding proteins (G-protein). This receptor
group includes numerous neurotransmitter receptors that are particularly important
for drug therapy, such as adenosine-, adrenergic, ATP- (P2Y-), dopamine-, GABAB -,
metabotropic glutamate-, histamine-, muscarinergic, opioid- and serotonin (except
5-HT3 ) receptors. In GPCRs, signal transmission takes place via the G-protein.
Activation of GPCRs by an agonist results in dissociation of the heterotrimeric G
protein into the Gα- and Gβγ-subunit after exchange of GDP bound to the α-subunit
for guanosine triphosphate (GTP). According to the various functions of GPCRs,
there is a multitude of different G proteins, e.g. cyclase stimulating (Gs proteins),
cyclase inhibiting (Gi proteins) or phospholipase C-activating G proteins (Gq
proteins).
2.3.2 Ion Channels

Ion channels are in third place after the GPCRs and protein kinases and play impor-
tant roles in a variety of biological processes, e.g. formation of action potentials, car-
diac, skeletal and smooth muscle constrictions, epithelial transport, T-cell activation
or insulin secretion. Ion channels are integrated in the cell membrane and consist
of several subunits. These subunits form a channel pore that is opened or closed by
conformational changes. Due to their selective permeability for distinct ions, they
are named sodium-, potassium-, calcium-, and chloride channel. The inflow and
outflow of the respective ions is controlled by the concentration gradient between
extracellular and intracellular space and by the membrane potential. The extent of
the ion flow depends on the number of open channels, the duration of opening and
the permeability of the corresponding ions of the so-called conductivity. There are
two kinds of receptors distinguished:
● Ligand-controlled ion channels or ionotropic receptors: (e.g. ATP- (P2X-),
GABAA -, glutamate- (NMDA- and AMPA-), glycine-, 5-HT3 - and nicotine recep-
tors, and K+ (ATP-sensitive, Ca2+ /calmodulin-activated, Gi -protein-regulated
‘GIRK’), where opening and closing of the channel is controlled by extracellular
binding of a ligand. For example, binding of acetylcholine or nicotine to the
α-subunit of the nicotinic receptor leads to the opening of the channel, thus
releasing an action potential through the influx of sodium ions.
● Voltage-controlled channels: (e.g. Na+ -, Ca2+ - [L-type, N-type, T-type, P/Q-type]
and K+ - [Kγ, hERG-, KCNQ-, Kir-] channels) that are opened or closed by mem-
brane depolarization or hyperpolarization. For example, the influx of Na+ ions
into a myocardial cell allows rapid membrane depolarization, which is necessary
to open L-type Ca2+ channels. The incoming calcium ions now lead to Ca2+ release
from the endoplasmic reticulum and allow the initiation of the contraction of car-
diomyocytes. K+ channels, which are also activated by depolarization, repolarize
the cell membrane and allow previously inactivated Na+ - and Ca2+ channels to
revert to the activatable state by conformational change and thus be available
again for subsequent excitation.
2.3.3 Enzyme-Associated Receptors

This group of receptors belong (i) receptors with tyrosine kinase activity, (ii) recep-
tors with associated tyrosine kinases, (iii) receptors with guanylyl cyclase-activity,
(iv) receptor serine/threonine kinases as well as (v) tumour necrosis factor (TNF)
receptors, which mediate apoptosis.
Tyrosine kinase receptors are characterized to have a ligand binding site
extracellularly and a domain with the property of a tyrosine kinase on the cytosolic
protein part and thus exert both the function of a receptor and that of an enzyme.
Mitogen-activated protein kinases (MAP kinases) are involved in further signal
transduction. Since they regulate a variety of cellular activities such as gene
expression, mitosis, differentiation, and apoptosis/necrosis, they are of great
importance for the whole organism. Notably, their proliferative effect is critical for
signal transduction of most oncogenes. MAP kinases are divided into four groups:
extracellular signal-regulated kinases (ERK), c-Jun N-terminal kinases (JNK), p38
kinases, and as a special ERK form ERK5. The signalling cascade of ERK is mainly
stimulated by growth factors, JNK and p38 kinases are active in the presence of
stress stimuli such as cytokine release, UV radiation, heat or osmotic shock. ERK5,
on the other hand, is activated by both growth factors and stress stimuli. Receptors
with tyrosine kinase activity include the receptors of insulin, insulin-like growth
factor (IGF-1), as well as various other growth factors (e.g. vascular endothelial
cell factor [VEGF], epidermal growth factor [EGF], fibroblast growth factor [FGF],
and platelet-derived growth factor [PDGF]). Insulin and IGF-1 each consist of two
α- and β-subunits, which are linked by disulphide bridges. The other growth factors,
however, are monomeric proteins that dimerize only after ligand binding. The
dimerization leads to autophosphorylation of tyrosine residues in the cytosolic part
of the receptor. This generates docking sites for signalling proteins that bind to the
phosphorylated residues of the receptor. In this way, receptor tyrosine kinases are
coupled to the Ras signalling cascade, which controls cell growth and proliferation.
Receptors with associated tyrosine kinases, like the growth factor receptors,
are monomeric membrane proteins with a transmembraneous region, which in turn
dimerize after ligand binding, but the receptor group does not possess its own tyro-
sine kinase domain. This group of receptors includes numerous cytokine receptors
as well as growth hormone, prolactin, and erythropoietin receptors. Upon activa-
tion and dimerization, just another kinase (JAK) proteins dock and phosphorylate
tyrosine residues of the receptor. As a result, signal transducers and activators of
transcription (STAT) proteins associate with the phosphorylated receptor domains.
The associated STAT proteins are then also phosphorylated by JAK kinases. Finally,
the phosphorylated STAT proteins dimerize, are translocated into the nucleus and
activate transcription of specific genes.
Receptors with guanylyl cyclase activity (membrane-bound guanylyl cyclase)
in particular comprise the receptors for natriuretic peptides and the intestinal hor-
mone guanylin. These monomeric transmembrane proteins, like the receptors with
tyrosine kinase activity, have an extracellular binding site for the activating ligand
and an intracellular enzyme domain. When a ligand binds to receptors with guanylyl
cyclase activity, their guanylyl cyclase domain is activated. As a consequence, GTP is
formed into cyclic guanosine monophosphate (cGMP) which, as second messenger,
triggers further reactions, e.g. the relaxation of smooth muscle cells or the secretion
of chloride in the intestinal lumen.
Receptor serine/threonine kinases include the receptors of transforming
growth factor-β (TGF-β), of which two types, TGF-β-R-I and TGF-β-R-II, exist. Also,
the cytokine bone morphogenetic protein 2 (BMP2) unfolds its action by means
of such a receptor type. TGF-β is a local cytokine which acts via TGF-β receptors
and is associated with healing processes but also fibrosis of tissue, e.g. diabetic
nephropathy, renal and pulmonary fibrosis, as well as cardiac remodelling after
myocardial infarction. Angiotensin converting enzyme (ACE) inhibitors reduce the
release of TGF-β. The transduction mechanism of TGF-β receptors is the following:
initially, TGF-β binds to TGF-β-R-II and then forms a heterodimer together with
TGF-β-R-I. In the next step, a transphosphorylation of TGF-R-II to TGF-R-I occurs,

which triggers the actual signal transduction. The activated receptor complex
then triggers gene expression via so-called Smad proteins, which migrate into the
nucleus in an active form.
TNF receptors, also called death receptors, include 29 different receptor subtypes.
They are integrated into the membrane of most cells. Important representatives
are the TNF receptor 1 and FAS. The binding of TNF to its receptor results in
homotrimerization and recruitment of an adapter protein (e.g. TRADD, TRAF,
and RIP) to the so-called ‘death domains’ of the three subunits. The nature of the
associated adapter protein determines which signalling pathways (e.g. apoptosis
and inflammation) are induced by the stimulation of the TNF receptor. In the case
of programmed cell death, apoptosis, the resulting complex activates the caspase
cascade, which leads to inactivation of enzymes and degradation of structural
proteins as well as fragmentation of genomic DNA.
2.3.4 Non-receptor-Mediated Effects

Beside of receptor-mediated effects, there are also drug effects mediated by trans-
porters or enzymes. The transport of small organic molecules or ions through
the cell membrane often occurs with the help of transport molecules when the
molecules to be transferred are too polar to overcome the membrane alone. In
addition to the transporters for neurotransmitters in terminal nerve endings
(neurotransmitter-specific transporters, e.g. for norepinephrine, serotonin, or
GABA), which serve to resume the secreted transmitter in the presynaptic neuron,
and the transporters for electrolytes (e.g. Na+ /K+ /2Cl− – and Na+ /Cl− – symporter),
which predominantly occur in epithelia with secretory function (among others
in renal tubules, bronchial epithelium, and intestinal mucosa), there are also
transporters for glucose and amino acids.
In particular, the transporters for neurotransmitters and electrolytes represent
targets for important drugs such as antidepressants, diuretics, cardiac glycosides,
and proton pump inhibitors. Antidepressants inhibit the active (re-)transport of
norepinephrine and/or serotonin. Diuretics are to be characterized as selective elec-
trolyte transport inhibitors: Furosemide-type loop diuretics block the Na+ /K+ /2Cl+
and thiazides the Na+ /Cl− symporter. Cardiac glycosides inhibit the outward trans-
port of sodium ions from the intracellular space into the extracellular space as well
as the inward transport (extracellular/intracellular) of potassium ions by blocking
the sodium–potassium pump (Na+ /K+ ATPase). The proton pump inhibitors used
as antiulcer drugs suppress the production of hydrochloric acid in the stomach by
inhibiting the proton potassium pump (H+ /K+ ATPase).
Numerous effects of drugs are due to the inhibition or (less common) of the
activation of enzymes. Similar to the pharmacon receptor interaction, it first
comes to the formation of a drug–enzyme complex and thereby, depending on
the nature of the drug, to enzyme inhibition or enzyme activation. At constant
enzyme concentration, the reaction rate depends on the substrate concentration.
The more the substrate there is, the more the enzymes can be occupied and cause
the reaction.
2.4 Receptor Agonism and Antagonism 15
Substrate saturation: From a certain substrate concentration, all enzymes are

present in enzyme–substrate complexes, and thus the maximum velocity V max
for this amount of enzyme is reached.
Substrate excess: If more substrate molecules are present than can be bound by the
enzymes, the reaction rate is no longer increased.
The substrate concentration K m , which is half of the maximum reaction rate, is

called Michaelis constant (K m ). It is a measure of the affinity of an enzyme for its
substrate, i.e. the smaller the K m , the higher the enzyme–substrate affinity, because
the less substrate it takes to occupy half of all binding sites of the enzymes. The value
of the maximum velocity (V max ) depends on the enzyme concentration. The more
the enzymes are present, the more the enzyme–substrate complexes can be formed,
which is why a higher maximum speed can be achieved. Also, the half-maximal
velocity is larger and is still reached at the substrate concentration K m (the affinity
is independent of the enzyme concentration).
Drug-induced enzyme inhibition may be competitive or non-competitive.
Competitive inhibition occurs when the drug reversibly competes with the sub-
strate for its binding site. In non-competitive inhibition, the drug reacts irreversibly
with the active site or suppresses the formation of the substrate–enzyme complex
following reaction and not the binding of the substrate to the enzyme. Impor-
tant examples of enzyme blocking drugs are the monoamine oxidase inhibitors,
non-steroidal anti-inflammatory drugs (NSAID) as inhibitors of cyclooxygenase,
anticoagulants as xanthine oxidase inhibitors, indirect parasympathicomimetics as
choline esterase blocker, hydroxy-methyl-glutaryl-coenzyme-A reductase inhibitors
(HMG-CoA reductase inhibitors, CSE inhibitors, and statins), phosphodiesterase
inhibitors, ACE inhibitors, and tyrosine kinase inhibitors. Many anti-infective
agents also exert their effect by selective enzyme inhibition in microorganisms,
e.g. penicillins and other beta-lactam antibiotics by inhibiting transpeptidases,
gyrase inhibitors by interacting with DNA gyrase, azole antifungals by blocking
lanosterol dimethylase or antiviral HIV by interacting with viral polymerases or
proteases.
Enzyme activation is usually effected by second messengers such as cAMP,
cGMP, or Ca2+ . Nitrates catalyse the soluble guanylyl cyclase via nitric oxide (NO).
The effect of some coagulation factors on blood clotting is based on the fact that
they convert inactive into active proteases. Fibrinolytic convert plasminogen to
plasmin, also a protease.
2.4 Receptor Agonism and Antagonism
As physiological ligands drugs can interact as exogenous ligands with the receptor.
The prerequisite for this is a drug (D)–receptor (R) complex. This is dependent on the
affinity of the drug to the receptor. The higher the affinity, the higher the tendency
that the drug forms a complex with the receptor. Hereby, the receptor can exist in
two conformations, in an inactive (R) and in an active (R*) state. Both conformations
are in dynamic equilibrium, which in the absence of an endogenous or exogenous

ligand is usually shifted to the inactive side. Receptors, which are active even without
a ligand, are called constitutively active receptors.
Agonist: Substances that both bind to and stimulate the receptor

Inverse agonists: Substances which bind to a constitutively active receptor,
shift their equilibrium to the inactive state and reduce the proportion of consti-
tutively active receptors even more than at basal levels.
Antagonist: Substances which reduce or completely abolish a receptor-
mediated effect
Substances that both bind to and stimulate the receptor are agonists (Figure 2.2).
Substances which reduce or completely abolish a receptor-mediated effect are
antagonists.
Substances which bind to a constitutively active receptor shift their equilibrium to
the inactive state and reduce the proportion of constitutively active receptors even
more than at basal levels are called inverse agonists.
Agonists possess affinity as well as intrinsic activity. The intrinsic activity is
usually indicated as relative intrinsic activity α. This is proportional to the quotient
of the effect EA triggered by the agonist and the maximum possible effect Em in the
biological system. The maximum relative intrinsic activity is evident as α = EA /Em .
Agonists with an intrinsic activity of 1 are named as full agonists. Agonists with
an intrinsic activity >0 and <1 are named partial agonists. Partial agonists are
Signal
+ Agonist Effect
Receptor transduction
Agonist
Competitive No signal
+ No effect
antagonist transduction
Receptor
Figure 2.2 Illustration of drug–receptor intercations leading to activation or inhibition of

signal transduction and an effect. Source: Book editors based on Hartl, Fink, and
Beer-Hammer.
Another random document with
no related content on Scribd:
go, or what I shall do when I leave Sothernbay. I have only one
distinct idea.”
“What is that?”
“Merely to go away—the further the better,” he replied, with a sort
of reckless despondency that startled Cicely; “to be forgotten,
doubtless; to forget if I can.”
Once or twice during the interview a thought had occurred to
Cicely which explained Mr. Guildford’s unexpected behaviour. Now it
gathered strength; his last words especially seeming to confirm it. A
sudden impulse seized her to test its correctness.
“Mr. Guildford,” she exclaimed. “You are not at all like yourself this
morning. You are generally far too sensible to talk so. You know very
well we are not the least likely to forget you—we are not so
ungrateful; and if I believed that you mean what you said, I should be
very angry with you for saying you would forget us if you could. But
you don’t mean it. Something is wrong with you, and I believe,” she
went on slowly, “I believe I know what it is.”
“You cannot. It is impossible,” he said hastily.
“Has it not something to do with my cousin Geneviève?” asked
Cicely quietly.
“Certainly not,” he replied promptly. “Not directly, that is to say.
She certainly helped me to find it out—for which I suppose I should
be very much obliged to her—” he gave a bitter little laugh; “but in no
other way has she anything to do with my wish to go away.”
“I thought you admired her so much,” said Cicely.
“So I do. I think she is marvellously pretty and charming, and I
dare say she is very amiable and sweet-tempered.”
“Yes, that is what you said of her before. Indeed you almost spoke
as if she were—as if she realised your ideal woman,” said Cicely
with an attempt at playfulness.
But Mr. Guildford did not smile.
“You have a good memory, Miss Methvyn,” he said rather coldly.
“If you remember so much, don’t you remember a little more? By
what you call my ideal woman, you mean the sort of woman I should
choose for a wife; don’t you? But I have had a higher ideal woman—
a woman whom I would choose for a friend—don’t you remember my
telling you that?”
“Yes,” said Cicely with interest. “I remember. But what about it?”
“I have made a mistake—that’s all.” said the young man drearily.
“I have thought I was wiser than other men, and I find I am a greater
fool than any man I ever knew. My theories are all smashed. In plain
words, Miss Methvyn, I have come across such a woman as in my
wildest dreams I never dreamt of—a woman, whom any man would
be honoured by having as a friend, but whose friendship only will not
satisfy me. The sort of affection I used to picture myself as giving to
a wife—to my ‘ideal wife’ remember—seems to me now like the light
of a farthing candle beside that of the midday sun. Good God, what a
presumptuous fool I have been! I thought I was so strong, so
perfectly able to take care of myself—and see where I am now. At
this moment I care for nothing—all my studies, all my hopes seem to
have turned to ashes between my teeth—I have only one instinct left
—that of flight. Now, Miss Methvyn, will you forgive me?”
Cicely had sat in perfect silence, listening to his impetuous words.
When he stopped, she said softly, “I am very, very sorry for you.”
“You should not be sorry for me,” he said with a sort of reluctant
gentleness. “I have myself to thank for it. I think now,” he went on
slowly, “I think that my grand theories about women must have
arisen from an instinct in me that if ever I did come under an
overwhelming influence of the kind, it would go hard with me—very
hard indeed.”
“But,” said Cicely, speaking with an effort, yet earnestly, “I don’t
understand you. Do you mean that you are tearing yourself away
from the influence you tell me of?—a good and noble influence as far
as I can judge—simply because you have resolved that no woman
ever shall influence you strongly and entirely? How can you take
upon yourself so to thwart your best self? How do you know that this
woman, whoever she is, might not be all the truer a friend for being
your wife? If you are sacrificing yourself all for the sake of
consistency, I should respect you more if you were inconsistent.”
“I am not doing so,” replied Mr. Guildford sadly. “I cannot say
whether I think I should have acted as you suppose. I tell you all my
theories are put to confusion; I shall have hard work to gather them
together again. I have no choice; the longer I remain in this
neighbourhood, the worse it will be for me. It is a mere selfish instinct
of self-preservation that urges me to flight—a shadowy hope of
retaining some of the shreds of what used to be my interests in life.
Some day, I suppose—I have read of such things, though I never
understood them before—some day, I suppose, I shall find I have
outlived this after all, and then I may set to work again in the old way.
I can’t say, I don’t think I care. I only want you to give me back my
promise, Miss Methvyn, and to forgive me, and let me go.”
There was a despairing tone in the last few words which, coming
as they did from a man usually so self-contained, so resolutely
cheerful, so strong and manly, seemed, to Cicely, full of a strange
pathos. But she did not again say that she wa “very, very sorry” for
Mr. Guildford, nor did she at once answer his request. She looked up
timidly, and a faint colour rose in her cheeks. “Do you mean—do you
mean,” she said, “that you have no choice because you know
certainly that—she—does not care for you? Are you sure that you
are not letting false pride influence you, that you are not taking for
granted what may not be certain after all? Forgive me for saying it—I
am so reluctant for you to be unnecessarily unhappy—and in such
cases, lives are often ruined by some misapprehension.”
She spoke very gently. Mr. Guildford looked at her for a moment.
Then he rose from the chair where he had sat down, and walked a
few steps away.
“There is no misapprehension,” he said at last. “In no
circumstances could I have imagined it possible that—that I could
have been cared for in the only way that would have satisfied me.
But, as it happens—fortunately for me, I suppose—circumstances,
outward circumstances I mean, are dead against me. Socially even,
there could never have been a question of—of such a thing, and
besides that—”
He stopped abruptly. He had been standing near the window, at
some little distance from Cicely, not looking at her as he spoke.
Suddenly he turned, and came back again, close to the table by
which she was sitting. “Miss Methvyn,” he said, and his voice
sounded so strange that Cicely looked up quickly in affright, “Miss
Methvyn,” he repeated, “there is no use in beating about the bush.
Even if you despise me, and refuse ever to speak to me again, I
think it will be a relief to tell you the truth, if you have not already
guessed it. Don’t you know what has opened my eyes? Don’t you
know what Miss Casalis told me yesterday—about you—what I
never suspected before, blind fool that I was!—don’t you know what I
mean?”
“No,” said Cicely. But her voice was low and tremulous. She
hesitated a moment, “at least,” she added, “I don’t understand
altogether.”
She would rather not have said as much, but it seemed to her as
if the words were drawn from her against her will.
“Don’t you?” said Mr. Guildford, “are you sure you don’t?”
He was looking at her now, so earnestly that Cicely, who had
grown very pale, felt her cheeks burn with the consciousness of his
gaze. She could bear it no longer. She got up from her seat, and,
leaning one hand upon the table, spoke out bravely.
“Mr. Guildford,” she exclaimed, “you are trying me painfully. I am
very, very sorry for you, but—I think you may regret if you say any
more. I don’t know what my cousin told you yesterday—it is true that
I do not altogether understand what you mean, and I would rather
not understand. Let me tell you again how very sorry I am that you
should be troubled or pained; but—you are a man, Mr. Guildford; you
have life before you and great aims to live for. Whatever it is that is
troubling you now will pass away and leave no lasting traces. I won’t
insult you by supposing it could be otherwise. You are a man—some
things are harder to be borne by women than by men.”
She stifled a little sigh, and was moving away, but Mr. Guildford
stopped her.
“Miss Methvyn, you must listen to me. I want you to understand
me, if not you may think worse of me than I deserve. I had no
intention of troubling you, but I cannot bear you to think of me as I
see you do—as a foolish boy who has forgotten himself and his
place—” he hesitated a moment, then went on again, without
bitterness this time, but with a depth of restrained suffering in his
voice which touched Cicely to the quick. “I told you that I had to
thank Miss Casalis for bringing me to my senses,” he said. “It was
she who told me yesterday that you are shortly to be married to Mr.
Fawcett. She told it very abruptly. I had had no idea of it—not, of
course, that it could have made any difference to me—but it came
upon me very suddenly. People who have been blind, you know, are
startled when they first gain the use of their eyes. I am in that
condition. As I have told you, I am shaken to the very foundations. I
am a man, as you reminded me, not a boy; but, kind and good as
you are, you don’t know how a man can suffer. Miss Methvyn, I
cannot remain here. I am not really required. I entreat you to absolve
me from my promise, and let me go.”
Cicely had turned her face away while he was speaking. She
could not bear him to see the tears that were gathering in her eyes.
Now she only said gently, and it seemed to him coldly, “I would not
dream of preventing your going. It is very good of you to have asked
me to release you. Many people would have forgotten all about such
a promise.”
“Thank you,” he said. “Will you say good-bye to me, Miss
Methvyn?” he added. “I should like to think you have forgiven me.”
Then she turned towards him, and he saw that she was crying.
“That I have forgiven you,” she repeated. “What is there I could
possibly have to forgive? I cannot tell you how bitterly I regret that
your kindness to us should have brought suffering upon you. I
thought you so wise and clever, so above such things. I can hardly
even now believe that—that I can be the cause of your trouble. It is
not only that I have always thought of myself almost as if I were
already married, but I never associated you with such possibilities. I
never really believed you cared for Geneviève. I thought you were
wholly occupied with other thoughts—so above such things,” she
repeated. “Have I been to blame in any way?” she added
ingenuously.
“Only for believing my own account of myself—for taking me at
my own valuation,” he replied with a smile—a curious, bitter smile.
“‘Above such things!’ Yes, indeed, I deserve it all. Miss Methvyn,
good-bye, and thank you for your gentleness and goodness.”
He was turning away, when Cicely held out her hand. “Good-bye,”
she said, simply.
He took her hand, held it for an instant “I don’t think you will ever
see me again,” he said in a low voice. “Thank you for being sorry for
me;” then he was gone.
Cicely sat down by the table. She buried her face in her hands
and cried bitterly. “I am so sorry for him,” she said to herself over and
over again. “Why do things go wrong in this world always? I wish I
could think that Trevor cared for me as that man does.”
Mr. Guildford went upstairs to see Colonel Methvyn. He sat with
him for half an hour, talking as cheerfully as usual, intending, at least
once in every five minutes of that half-hour, to break to Cicely’s
father the news of his intended departure; but in the end he failed to
do so. Colonel Methvyn seemed nervous and depressed, and Mr.
Guildford’s courage played him false. He compromised matters at
last by promising to call again the next day. “To-morrow,” he said to
himself, as he walked slowly down the drive, “to-morrow I shall be
better able to talk of my leaving, quietly, so that no one can suspect
anything. But I must manage to avoid seeing her again. Oh, Cicely!
When I would give ten years of my life for a moment’s glimpse of
you! But she said goodbye, and she meant it.”
END OF VOL. II.
VOLUME III.
CHAPTER I.
DÉSILLUSIONNÉE.
“What made the Ball so fine?

Robin was there.
* * * * * *
But now thou’rt lost to me,
Robin Adair.
“CICELY,” said Mrs. Methvyn late that afternoon, “I want you to do

something to please me.”
“What, mother dear?” said the girl, looking up wearily from the
book she was trying to read, “what do you want me to do?”
She had felt very miserable all day. Her anxiety about her father
was by no means thoroughly allayed, and she knew that her chief
support had failed her; and the impression left upon her by her
strange interview with Mr. Guildford was still bewilderingly painful.
Her mother was struck by her pallor and depression.
“You don’t look well, Cicely,” she said anxiously; “is there anything
the matter?”
“I wish we were not going to Lingthurst,” said Cicely. “I cannot tell
you how I shrink from the thought of it.”
It was within a very few hours now of the happy moment which
Geneviève had been all day eagerly anticipating. “In four hours more
it will be time to dress,” she had reminded Cicely with delight, a few
minutes before. And Cicely had smiled and tried to think herself
“cross-grained and ill-humoured,” for not being able to sympathise
with her cousin’s enthusiasm. But it was no use. As the hours went
on, she grew more and more disinclined for the evening’s
amusement. “I cannot bear the thought of it,” she repeated to her
mother.
Mrs. Methvyn looked troubled. “You used to enjoy dancing, Cicely.
You used to be merry enough not so very long ago. What has
changed you so?”
“Nothing, mother dear,” exclaimed Cicely, ashamed of her
selfishness, “nothing truly. I am only rather dull and cross. Perhaps it
is true as some say, that it is not good for people to live so much by
themselves as we have done the last year or two.” She was silent for
a minute or two, then she looked up again. “It is not all crabbedness,
mother. It is partly that I can’t bear going to a ball when papa seems
less well than usual.”
“That is what I was going to speak to you about,” said Mrs.
Methvyn. “I don’t think your father is very well to-day. I don’t like
leaving him. What I wanted to ask you was, if you would very much
mind going without me.”
“Going without you,” exclaimed Cicely in surprise, “Geneviève and
I by ourselves! How could we?”
“You might go very early and be with Frederica before any one
comes, as if you were staying in the house,” replied Mrs. Methvyn. “I
can easily send a note to explain it. She will be quite pleased. And I
have no doubt she will ask you to stay till to-morrow, which will make
it all quite easy.”
Cicely’s face grew graver. “I don’t mind going without you,
mother,” she said. “Of course, I would much rather stay at home with
you, but there is no use repeating that—but please don’t ask me to
stay away till to-morrow. Let Parker go with us; she will be delighted
to see the fun, and she will take care to wrap us up and all the rest of
it. No one need know we are young women without a chaperone—
everybody will think we are staying in the house. Don’t say I am not
to come home to-night. I can’t bear the idea of it.”
She held up her face coaxingly for her mother to kiss. “Cis, what a
baby you are!” said Mrs. Methvyn fondly. “And yet you are so
sensible. What in the world will you do when the time comes for you
to—”
“Don’t talk about it, mother, please don’t,” interrupted Cicely. “If
you do, I shall begin to cry, and then what a fright I shall look to-
night!”
“You are not looking well,” said Mrs. Methvyn regretfully. “Indeed,
you look as if you had been crying already—have you, dear?”
“Don’t,” exclaimed Cicely, turning away her head to hide the tears
only too ready to spring again, “don’t, mother. Let us talk of
something cheerful. Geneviève, for instance. Did you ever see a little
mortal in such a state of delight as she is? She will look pretty
enough to do you credit any way, mother.”
“Yes,” said Mrs. Methvyn absently. “Well, then, Cicely,” she added,
“I will go and write my note to Frederica and send it at once; and
remember, dear, you must be ready very early.”
“Oh! yes,” replied Cicely, “we shall be sure to be in time. I think I
am much more likely to enjoy this evening, mother, knowing you are
at home with papa. It was partly the feeling of reluctance to leave
him alone that made me dull. It is so long, you know, since he has
had an evening by himself.”
She spoke more brightly than she felt. She resolved to dismiss
her depression and do her best to be cheerful, but it was hard work.
Her pretty ball dress seemed a mockery, Geneviève’s fluttering
excitement jarred upon her; over and over again she repeated to
herself, “Oh! how I wish this evening were over.” And when she went
to her father’s room to say good-night, and poor Colonel Methvyn
kissed her fondly, and told her he was pleased to see her in a ball
dress once more, she could hardly restrain the tears that had
seemed strangely near the surface all day.
“Did Mr. Guildford stay long with you this morning, papa?” she
asked, anxious to find out if the young man had said anything about
the change in his plans.
“Not very long,” replied her father, “he was rather hurried to-day,
but he is coming again to-morrow, or the next day. He says he is not
at all busy just now, and I am glad of it. I should quite miss his visits.”
“He has not told him,” thought Cicely, with a certain feeling of
relief, “he must be intending to do so the next time he comes. But I
can’t help feeling glad he did not tell papa to-day; he must have seen
he was not quite as well as usual.”
They reached Lingthurst very early, as had been arranged. They
had to wait by themselves for some little time, as Lady Frederica and
the visitors staying in the house had not yet made their appearance
in the drawing-room. At last Miss Winter, in a new and elegant
costume, came fluttering into the room, full of regrets and apologies.
Lady Frederica was so sorry, so very sorry to leave dear Miss
Methvyn and dear Miss Casalis so long alone, but the fact was, she
was not feeling very well and had gone to lie down a little after dinner
(evidently a ball at Lingthurst was an event!); and the other ladies
were dressing—she must run away again for a minute, dear Miss
Methvyn would excuse her she was sure—Lady Frederica was not
quite satisfied with her head-dress and she was altering it—she
would be back in five minutes, etc. etc., and then she fluttered out of
the room again.
“What are these for, Cicely?” said Geneviève, touching a basket
full of mysterious little white leaflets.
“Cards of the dances,” replied Cicely, glancing to see what she
was doing. “You may take one, Geneviève—look, you write down the
names of your partners at one side—so—and then you know whom
you are engaged to dance with.”
“Oh! how nice—what a good idea!” exclaimed Geneviève
gleefully. “But I am only engaged for one dance,” she went on
mournfully, “You Cicely, no doubt, are engaged for all.”
“Certainly not,” replied Cicely, laughing. “I am only engaged for
those I am going to dance with Trevor. You needn’t distress yourself,
Geneviève. You are sure to have plenty of partners.”
But Geneviève’s face did not clear. “You will dance the first with
Mr. Fawcett, I suppose?” she said.
“I suppose so,” answered Cicely.
“You mean it is of course, as you are his fiancée,” observed
Geneviève.
It seemed to Cicely that there was a slight sneer in her tone as
she made the remark. She looked at Geneviève in surprise, and as
she did so there recurred to her mind what Mr. Guildford had told her
of her cousin having been the source of his in formation.
“Why do you look so unhappy all of a sudden, Geneviève?” she
said quickly.
“I am not unhappy,” replied Geneviève hastily, the colour
mounting to her cheeks.
“Well, you seem annoyed, at least. I never know how to avoid
annoying you, Geneviève,” said Cicely regretfully. “Only yesterday
afternoon you spoke to me very strangely and unkindly for no reason
at all that I could find out. And that reminds me—Geneviève, how did
you come to be talking to Mr. Guildford about my—I mean about my
marriage?”
“Who said I had talked about you to him?” said Geneviève
defiantly—the scarlet settling into an angry spot on each cheek.
“He himself,” replied Cicely quietly. “He said that you had told him
about my marriage.”
“He knew it before,” said Geneviève evasively.
“No, he did not,” said Cicely. “I thought he did—I thought he had
always known it, but he never knew it till you told him. I am not
blaming you for telling it—it was no secret. I only want to know how
you came to be talking about me. Mr. Guildford was quite surprised
—he said you mentioned it so suddenly. How was it?”
She looked Geneviève full in the face as she asked the question.
At first Geneviève’s eyes fell; she seemed frightened and half
inclined to cry. But her glance happened to light on the little white
card she held in her hand, and her mood changed. She raised her
head, and her cheeks glowed with angry excitement. “I told him,” she
said, “because I thought it would vex him. I like him not. You think
everybody is in love with you, Cicely. It is not so. It is only that you
are rich. Some day you may find you have been too sure—you have
wanted too much. Some day perhaps you will not get what you want
—then you will no longer think you are to have all because you are
rich and I am poor!”
“Geneviève!” exclaimed Cicely. She could not trust herself to say
more. She turned away and began examining some books that lay
on a side-table, astonished, and wounded to the quick.
Another moment and Geneviève’s passion would have ended as
usual in a flood of tears, but there came a diversion. Mr. Fawcett
suddenly entered the room. He came in quickly, not expecting to see
any one there, and as he opened the door, the first object that met
his eyes was Geneviève. Geneviève in the full blaze of her beauty;
her loveliness enhanced by the excitement which had reddened her
cheeks and brightened her eyes, even though its source was
unlovely anger; Geneviève, dressed to perfection, as he had never
yet seen her, in a cloud of shimmering white, with crimson flowers in
her dark hair and pearls on her pretty neck—Trevor started as he
saw her, and a half smothered exclamation escaped him. And in an
instant Geneviève’s face was all smiles and blushes as she
hastened forward a step or two to meet him.
From her corner, Cicely, pale and silent and discomposed, saw it
all; saw Trevor’s start of unmistakable admiration, Geneviève’s pretty
self-consciousness, saw them shake hands and murmur a word or
two as if no such person as herself were in existence. She saw it,
but, with instinctive loyalty, before she had allowed herself to realise
the position, she forced herself to come forward.
“You did not expect to find any one here already, did you, Trevor?”
she said lightly. “Mother made us come at least an hour too soon
that we might be with Lady Frederica before any one else comes—
we are supposed to be staying in the house, you know.”
Before she had finished the last sentence, Mr. Fawcett had
perfectly recovered himself.
“I am so very sorry to hear your father is not as well as usual to-
day,” he said kindly, as he shook hands. “But I am glad it was not
bad enough to prevent you two coming. There is not much wrong, is
there?”
“No, at least I hope not,” replied Cicely. “I have not thought him as
well as usual for some time.”
She turned away and Trevor did not reply. Just then Lady
Frederica and a bevy of ladies rustled into the room, and a chatter of
greetings and introductions and regrets that “the poor Colonel was
not well and poor dear Mrs. Methvyn unable to leave him” began.
You are not looking well, dear Cicely,” said Trevor’s mother, in her
soft, plaintive voice, and somehow even these commonplace words
brought the tears into the girl’s eyes. “He never noticed that I looked
ill,” she thought, as she replied to Lady Frederica’s expressions of
sympathy, and there rushed through her mind in sharp and painful
contrast with Trevor’s indifference, the remembrance of how Mr.
Guildford’s firm cheery voice had grown gentle and anxious that
morning when he first remarked her paleness and agitation.
“And how perfectly lovely your cousin looks!” continued Lady
Frederica. “Pretty as I thought her, I had no idea till to-night how
lovely she was.”
“Yes,” said Cicely stoutly, “I think she looks as pretty as anything
one can imagine. Do you like our dresses, Lady Frederica? They are
from Madame Néret’s.”
“Geneviève’s is lovely, quite lovely,” answered Lady Frederica.
“And yours—ah! yes, it is very pretty, Chambéry gauze, I see,” she
remarked, putting up her eye glass and surveying Cicely’s draperies
with a critical air. “Yes, a beautiful material and everlasting wear—I
have had my Chambérys dyed black many a time—I was not sure if
yours was a new dress or not.”
“Yes, mother ordered both Geneviève’s and mine expressly for to-
night,” said Cicely.
“Ah! yes. Yes, I can see it is new now. Those good dresses, you
know, never do look quite so brilliant a white as more fragile
materials. And I was thinking of your trousseau, you know, my dear.
It is hardly worth while for you to get any more new dresses now.”
“No,” said Cicely quietly.
“What is Geneviève’s dress?” continued Lady Frederica,
“tarletane?”
“No, tulle, tulle over—” Cicely was beginning, but just then Mr.
Fawcett came up.
“Mother,” he said, “people are beginning to come. You mustn’t
stay any longer gossiping in that corner, do you hear, my lady?” Lady
Frederica laughed. “Impertinent boy!” she said, rising as she spoke.
“Where shall I find you, Cicely?” continued Trevor, “We must be
ready when the music begins, to set all the young people agoing.
Dances are events, at this season, and these country girls have no
idea of wasting time.”
“I shall stay here,” said Cicely, “I shall be ready when you come
for me.”
“All right,” replied Trevor, as he went off with his mother on his
arm.
Cicely remained in her corner, watching the guests as they began
to pour in. Now and then she came forward a little to shake hands
with such of her acquaintances as caught sight of her, or to introduce
her cousin, who was standing at a little distance, to some of her
parents’ more intimate friends who had not yet happened to meet
her.
“How lovely Miss Methvyn’s French cousin is! I did not think she
was that sort of girl. We heard she was the daughter of a poor
French pasteur,” an “how ill poor Miss Methvyn is looking herself!”
were the universal remarks on the appearance of the two cousins. “It
is the first time Miss Methvyn has been anywhere since the little
Forrester boy’s death, you know,” said some kind-hearted girl. Cicely
overheard the words, and after that it seemed to her that there was
unusual gentleness in the manners and voices of those whom she
spoke to, or to whose inquiries about her father she replied. She was
glad to think so.
“People are very kindly after all,” she said to herself. “I think I
have been growing morbid lately. It must be all my fancy that Trevor
is changed. I don’t believe he is. One grows exacting with living so
much alone.”
The thought cheered her. She looked brighter and less wearied
when Mr. Fawcett came to claim her.
“What has become of Geneviève?” she exclaimed, looking round,
as she took Trevor’s arm. “She was standing beside Miss Winter a
moment ago.”
Trevor laughed. “You must have been asleep, my dear child,” he
said. “Did you not see me introduce Dangerfield to her? There they
are. They are to be our vis-à-vis. I told Dangerfield she couldn’t
speak English at all, and he doesn’t know a syllable of anything else.
It will be great fun watching them.”
Cicely looked uneasy. “I am afraid Geneviève may not quite like
it,” she said rather timidly; “I don’t think she understands jokes,
Trevor. I wish you would tell Mr. Dangerfield that she can speak
English perfectly, for if he begins trying French she would think it
would be rude to speak English.”
“Nonsense,” said Trevor rather brusquely; “nonsense. Geneviève
understands a joke as well as any one. You don’t understand her
Cicely, as I have often told you. She knows all about it, and you will
see how she will take off Dangerfield.”
Cicely said no more, but already the little gleam of sunshine
seemed clouded over. She went through the quadrille languidly and
silently. Mr. Fawcett indeed seemed to have no leisure for talking to
his partner; his whole attention was absorbed by watching the way in
which his pretty vis-à-vis befooled her partner.
Now and then he turned to Cicely. “Do look at Dangerfield,” he
would say; “he has been five minutes over one word. Did you ever
see anything so mischievous as the way Geneviève looks up at him
in bewilderment?”
Cicely smiled faintly. “I did not know she could act so well,” she
said. Then she regretted the words and would have said something
to soften them, but Trevor did not seem to have caught their
meaning. He was in exuberant spirits, almost excitedly gay and
jocular, yet to Cicely it seemed that there was something forced in
his manner, and when he gave her his arm again after the quadrille
was over she fancied he was eager to avoid a téte-à-tête.
“I am afraid I must leave you here, Cicely,” he said, when he had
found a comfortable sofa in one of the drawing-rooms,“I have such a
terrible amount of introducing and all that to do between the dances.”
“Very well,” said Cecily. Her tone was rather cold, and Trevor,
glancing at her, observed for the first time how pale and fagged she
looked.
“Are you not well, dear?” he said kindly.
“Oh! yes. I am well enough,” she answered, brightening up at
once under the influence of his words; “but, Trevor,” she went on,
after a moment’s hesitation, “I am very dull about papa. I don’t think
he is well.”
Mr. Fawcett said nothing, but his blue eyes looked sympathy and
encouraged her to say more. “I did not like to make you dull,” she
went on, “you seem in such very good spirits, Trevor,” with the
slightest possible accent of reproach. “But you must not be vexed
with me for being rather stupid. I can’t help it.”
She looked up at him with tears in her eyes. “You are not vexed
with me, are you?” she whispered.
Mr. Fawcett’s face had grown grave. “Vexed with you,” he
repeated, “of course not. Why should I be? At least I am only vexed
with you for one thing. I hate all this—I detest it. I only wish you and I
had been married months ago; by this time we should have been
away somewhere by ourselves with no one to interfere with us. As it
is, I never seem to see you now, Cicely; I don’t know how it is.”
The sunshine seemed to have crept back again,—a somewhat
uncertain, tremulous light, but sunshine for all that. “Dear Trevor,”
said Cicely softly, “there is not really any change. It is only that I am
so much taken up at home, and you have been away so long. But if
you are not vexed with me, it will be all right. Sometimes lately I have
fancied I had grown dull and stupid and that you—”
She had laid her hand appealingly on Trevor’s arm, his eyes were
looking down upon her with an almost remorseful tenderness, some
eager words were on his lips, when a voice beside them—it was
Geneviève’s—made both him and Cicely start.
“Oh! Mr. Fawcett,” she exclaimed, “I want so much to tell you, ah!
is Cicely already tired?” with a curious change of tone from the
brightness of the first sentence. “I beg your pardon, I knew not that I
interrupted you,” she added timidly, making a little movement as if to
retire into the back ground.
“Interrupt! Nonsense,” exclaimed Trevor, laughing. “We have been
wondering how you got on with Dangerfield. Cicely, you must
remember which are your dances with me. Ours,” to Geneviève, as
he passed her, “is the next, you know.”
“Are you tired, Cicely?” inquired Geneviève somewhat awkwardly.
There was no time for a reply. Up came Lady Frederica, with a
gentleman to be introduced to Miss Casalis in humble hope of
finding she had still a dance to spare, in which he was not
disappointed. This happy person was followed by another and yet
another, till the vacant spaces on Geneviève’s card grow few. Then
the music begins again. Cicely catches a glimpse of Trevor’s tall
figure in the doorway; another moment, and Geneviève disappears
on his arm.
“Only the second dance—will the evening never be over?”
thought Cicely.
“Are you not dancing, my dear?” said Lady Frederica, coming up
to her.
“I don’t know, at least I forget. I think I am engaged for this
dance,” replied the girl indifferently. “Oh! yes,” consulting her card, “I
am engaged to Sir Arthur Vauxley; but he has not come for me. I
don’t care. I would rather not dance. Don’t you think it is rather cold,
Lady Frederica?”
“Cold, my dear!” repeated her hostess in astonishment, fanning
herself with a nearer approach to vigour than she was often in the
habit of exerting; “cold! Why we are in the greatest alarm that the
heat will be insufferable before supper; we cannot get all the
windows open till then. Cold! You must have got a chill.”
“Perhaps I have,” said Cicely, shivering a little and drawing back
further into her corner.
But she was not long allowed to remain there. Sir Arthur found her
out and claimed his dance. Then followed others, for which she was
likewise engaged; the evening began to pass a little more quickly
than at first; two dances more, and there would come her second
one with Trevor—a waltz this time. Cicely’s eyes brightened and a
little colour stole into her checks when at last the intervening dances
were over and the waltz music began.
“The ‘Zuleika,’” she said to herself, “that is one of Trevor’s
favourites. I wish he would come!”
Her feet beat time to the familiar strains, her eyes turned
impatiently towards the doorway in search of the pleasant, fair face
of her betrothed—again and again, but in vain. Cicely was only
twenty after all; she could not but own to herself that it was
disappointing.

Principles of Biomedical Sciences and Industry Markus Hinder All Chapter

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Principles of Biomedical Sciences and Industry Markus Hinder All Chapter

Uploaded by

Copyright:

Available Formats

Principles of Biomedical Sciences and

Industry Markus Hinder

Translating Ideas into Treatments

Print ISBN: 978-3-527-34571-7

Cover Design: ADAM DESIGN, Weinheim,

1 Biopharmaceutical Innovation at a Glance 1

2 Pharmacology and Drug Targets – The Basis of

2.6.5.2 Reduction and Hydrolysis 24

3 Principles and Methods of the Pharmaceutical Drug Discovery

3.4.1 Preventing Formation of the Target Protein 43

4 Biomarkers: Deﬁnitions and Utility for Drug Development 63

5 Toxicology in Drug Development – Understanding a Drug’s

5.7 What Activity at Which Stage of Development? 92

6 Introduction to Chemistry Manufacturing and Controls – From

7 Translational Medicine – The Bridging Discipline. Role and

7.3 Paths of Translation 126

8 Decision-Making: What are the Key Drivers Around

9 Clinical Drug Development – Clinical Characterization for

9.12 Key Studies During Clinical Development 167

10 Regulatory Affairs – Communicating with Health

11 Regulatory Affairs in Device Development – How to Design

12 Market Entry and Reimbursement: Making Drugs Available for

12.12.1 USA and Canada 242

13 Pricing in Germany – Key Learnings for Optimizing Price

14 Project, Risk, and Portfolio Management – Managing R&D

15 Intellectual Property – How to Protect Innovation in the

15.2.4 Patenting Procedure 287

16 Patents in the Biomedical Sciences and Industry – The Case of

17 Pharmaceutical Business Development and

17.14 Conclusions 332

18 The Entrepreneur’s Guide Through the Galaxy of Biotech

19 Medical Technologies – Key Learning from Two Case

20 Laboratory Diagnostics – Tools for Clinical Decision-Making

20.5.2 Immunology 364

21 Vaccination: Towards an Improved Inﬂuenza Vaccine 377

Visiting Professor – Estate of Hessen, Germany

About the Editors

Prof. Dr. Markus Hinder studied medicine at the

Prof. Dr. Alexander Schuhmacher graduated in

Prof. Dr. Jörg Goldhahn received his M.D. in 1997

Prof. Dr. Dominik Hartl studied Medicine at the

AAALAC Association for Assessment and Accreditation of

BCS Biopharmaceutical classification system

EPC European Patent Convention

GTP Guanosine triphosphate

MAP-kinase Mitogen-activated protein kinase

ODA Orphan Drug Act

PPQ Process performance qualification

scRNAseq Single-cell RNA sequencing

UGE Urinary glucose excretion

Biopharmaceutical Innovation at a Glance

Biopharmaceutical Research & Development (R&D) aims at finding new modalities

concepts generally applicable to the industry beyond individual company processes.

1.1 Biopharmaceutical Innovation and Drug

‘Déﬁnissez les termes, vous dis-je, ou jamais nous ne nous entendrons’.

1.2 Why We Wrote This Book and What Readers Can

disciplines is frequently not established. Accordingly, it is challenging to gather

No author (1550 BC). Papyrus Ebers. University library Leipzig https://papyrusebers.de/

Pharmacology and Drug Targets – The Basis of Therapeutics

Pharmacodynamics: Effect of the Drug on the Organism. The pharmacological

The pharmacology differs between individuals – for instance higher weight

Pharmacodynamics is the science of biochemical and physiological drug effects on

Two main classes of molecules used as therapeutics: