Drugs E-Book

Rick Ng

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 824

Veröffentlichungsjahr: 2015

Beschreibung

The third edition of this best-selling book continues to offer a user-friendly, step-by-step introduction to all the key processes involved in bringing a drug to the market, including the performance of pre-clinical studies, the conduct of human clinical trials, regulatory controls, and even the manufacturing processes for pharmaceutical products. Concise and easy to read, Drugs: From Discovery to Approval, Third Edition quickly introduces basic concepts, then moves on to discuss target selection and the drug discovery process for both small and large molecular drugs. The third edition incorporates the latest developments and updates in the pharmaceutical community, provides more comprehensive coverage of topics, and includes more materials and case studies suited to college and university use. Biotechnology is a dynamic field with changes across R&D, clinical trials, manufacturing and regulatory processes, and the third edition of the text provides timely updates for those in this rapidly growing field.

Leseprobe

CONTENTS

COVER

TITLE PAGE

PREFACE

CHAPTER 1: INTRODUCTION

1.1 AIM OF THIS BOOK

1.2 AN OVERVIEW OF THE DRUG DISCOVERY TO APPROVAL PROCESS

1.3 THE PHARMACEUTICAL INDUSTRY

1.4 ECONOMICS OF DRUG DISCOVERY AND DEVELOPMENT

1.5 TRENDS IN DRUG DISCOVERY AND DEVELOPMENT

1.6 CASE STUDY #1.1

1.7 CASE STUDY #1.2

1.8 SUMMARY OF IMPORTANT POINTS

1.9 REVIEW QUESTIONS

1.10 BRIEF ANSWERS AND EXPLANATIONS

1.11 FURTHER READING

CHAPTER 2: DRUG DISCOVERY: TARGETS AND RECEPTORS

2.1 DRUG DISCOVERY PROCESSES

2.2 MEDICAL NEEDS

2.3 TARGET IDENTIFICATION

2.4 TARGET VALIDATION

2.5 DRUG INTERACTIONS WITH TARGETS OR RECEPTORS

2.6 ENZYMES

2.7 RECEPTORS AND SIGNAL TRANSDUCTION

2.8 ASSAY DEVELOPMENT

2.9 CASE STUDY #2.1

2.10 CASE STUDY #2.2

2.11 SUMMARY OF IMPORTANT POINTS

2.12 REVIEW QUESTIONS

2.13 BRIEF ANSWERS AND EXPLANATIONS

2.14 FURTHER READING

CHAPTER 3: DRUG DISCOVERY: SMALL MOLECULE DRUGS

3.1 INTRODUCTION

3.2 IRRATIONAL APPROACH

3.3 RATIONAL APPROACH

3.4 ANTISENSE APPROACH

3.5 RNA INTERFERENCE APPROACH

3.6 CHIRAL DRUGS

3.7 CLOSING REMARKS

3.8 CASE STUDY #3.1

3.9 CASE STUDY #3.2

3.10 SUMMARY OF IMPORTANT POINTS

3.11 REVIEW QUESTIONS

3.12 BRIEF ANSWERS AND EXPLANATIONS

3.13 FURTHER READING

CHAPTER 4: DRUG DISCOVERY: LARGE MOLECULE DRUGS

4.1 INTRODUCTION

4.2 VACCINES

4.3 ANTIBODIES

4.4 CYTOKINES

4.5 HORMONES

4.6 GENE THERAPY

4.7 STEM CELLS AND CELL THERAPY

4.8 CASE STUDY #4.1

4.9 CASE STUDY #4.2

4.10 SUMMARY OF IMPORTANT POINTS

4.11 REVIEW QUESTIONS

4.12 BRIEF ANSWERS AND EXPLANATIONS

4.13 FURTHER READING

CHAPTER 5: DRUG DEVELOPMENT AND PRECLINICAL STUDIES

5.1 INTRODUCTION

5.2 PHARMACODYNAMICS

5.3 PHARMACOKINETICS

5.4 TOXICOLOGY

5.5 ANIMAL TESTS,

IN VITRO

ASSAYS, AND

IN SILICO

METHODS

5.6 FORMULATIONS AND DELIVERY SYSTEMS

5.7 NANOTECHNOLOGY

5.8 CASE STUDY #5.1

5.9 CASE STUDY #5.2

5.10 SUMMARY OF IMPORTANT POINTS

5.11 REVIEW QUESTIONS

5.12 BRIEF ANSWERS AND EXPLANATIONS

5.13 FURTHER READING

CHAPTER 6: CLINICAL TRIALS

6.1 DEFINITION OF CLINICAL TRIAL

6.2 ETHICAL CONSIDERATIONS

6.3 CLINICAL TRIALS

6.4 REGULATORY REQUIREMENTS FOR CLINICAL TRIALS

6.5 CLINICAL DATA MANAGEMENT

6.6 ROLE OF REGULATORY AUTHORITIES

6.7 GENE THERAPY CLINICAL TRIAL

6.8 ADAPTIVE CLINICAL TRIAL

6.9 META-ANALYSIS

6.10 CASE STUDY #6.1

6.11 CASE STUDY #6.2

6.12 SUMMARY OF IMPORTANT POINTS

6.13 REVIEW QUESTIONS

6.14 BRIEF ANSWERS AND EXPLANATIONS

6.15 FURTHER READING

CHAPTER 7: REGULATORY AUTHORITIES

7.1 ROLE OF REGULATORY AUTHORITIES

7.2 US FOOD AND DRUG ADMINISTRATION

7.3 EUROPEAN MEDICINES AGENCY

7.4 JAPAN'S PHARMACEUTICALS AND MEDICAL DEVICES AGENCY (PMDA)

7.5 CHINA FOOD AND DRUG ADMINISTRATION

7.6 INDIA's CENTRAL DRUGS STANDARD CONTROL ORGANIZATION

7.7 AUSTRALIA'S THERAPEUTIC GOODS ADMINISTRATION

7.8 CANADA'S HEALTH CANADA

7.9 OTHER REGULATORY AUTHORITIES

7.10 AUTHORITIES OTHER THAN DRUG REGULATORY AGENCIES

7.11 INTERNATIONAL CONFERENCE ON HARMONIZATION

7.12 WORLD HEALTH ORGANIZATION

7.13 PHARMACEUTICAL INSPECTION COOPERATION SCHEME

7.14 CASE STUDY # 7.1

7.15 CASE STUDY # 7.2

7.16 SUMMARY OF IMPORTANT POINTS

7.17 REVIEW QUESTIONS

7.18 BRIEF ANSWERS AND EXPLANATIONS

7.19 FURTHER READING

CHAPTER 8: REGULATORY APPLICATIONS

8.1 INTRODUCTION

8.2 UNITED STATES

8.3 EUROPEAN UNION

8.4 JAPAN

8.5 CHINA

8.6 INDIA

8.7 AUSTRALIA

8.8 CANADA

8.9 CASE STUDY #8.1

8.10 CASE STUDY #8.2

8.11 SUMMARY OF IMPORTANT POINTS

8.12 REVIEW QUESTIONS

8.13 BRIEF ANSWERS AND EXPLANATIONS

8.14 FURTHER READING

CHAPTER 9: GOOD MANUFACTURING PRACTICE: REGULATORY REQUIREMENTS

9.1 INTRODUCTION

9.2 UNITED STATES

9.3 EUROPE

9.4 INTERNATIONAL CONFERENCE ON HARMONIZATION (ICH)

9.5 PHARMACEUTICAL INSPECTION COOPERATION SCHEME (PIC/S)

9.6 SELECTED CORE ELEMENTS OF GMP

9.7 SELECTED GMP SYSTEMS

9.8 NEW GMP INITIATIVES

9.9 CASE STUDY #9.1

9.10 CASE STUDY #9.2

9.11 SUMMARY OF IMPORTANT POINTS

9.12 REVIEW QUESTIONS

9.13 BRIEF ANSWERS AND EXPLANATIONS

9.14 FURTHER READING

CHAPTER 10: GOOD MANUFACTURING PRACTICE: DRUG MANUFACTURING

10.1 INTRODUCTION

10.2 GMP MANUFACTURING

10.3 GMP INSPECTION

10.4 MANUFACTURE OF SMALL MOLECULE APIs (CHEMICAL SYNTHESIS METHODS)

10.5 MANUFACTURE OF LARGE MOLECULE APIs (RECOMBINANT DNA METHODS)

10.6 FINISHED DOSAGE FORMS

10.7 PRODUCT QUALITY REVIEW

10.8 MANUFACTURING VARIATIONS

10.9 CASE STUDY #10.1

10.10 CASE STUDY #10.2

10.11 SUMMARY OF IMPORTANT POINTS

10.12 REVIEW QUESTIONS

10.13 BRIEF ANSWERS AND EXPLANATIONS

10.14 FURTHER READING

CHAPTER 11: FUTURE PERSPECTIVES

11.1 PAST ADVANCES AND FUTURE CHALLENGES

11.2 SMALL MOLECULE PHARMACEUTICAL DRUGS

11.3 LARGE MOLECULE BIOPHARMACEUTICAL DRUGS

11.4 TRADITIONAL MEDICINE

11.5 PERSONALIZED MEDICINE

11.6 GENE THERAPY

11.7 CLONING AND STEM CELLS

11.8 OLD AGE DISEASES AND AGING

11.9 LIFESTYLE DRUGS

11.10 PERFORMANCE-ENHANCING DRUGS

11.11 CHEMICAL AND BIOLOGICAL TERRORISM

11.12 TRANSGENIC ANIMALS AND PLANTS

11.13 ANTIBIOTICS DRUG RESISTANCE

11.14 REGULATORY ISSUES

11.15 INTELLECTUAL PROPERTY RIGHTS AND MARKETING EXCLUSIVITIES

11.16 BIOETHICS

11.17 CONCLUDING REMARKS

11.18 CASE STUDY #11.1

11.19 CASE STUDY #11.2

11.20 FURTHER READING

APPENDIX 1: HISTORY OF DRUG DISCOVERY AND DEVELOPMENT

A1.1 EARLY HISTORY OF MEDICINE

A1.2 DRUG DISCOVERY AND DEVELOPMENT IN THE MIDDLE AGES

A1.3 FOUNDATION OF CURRENT DRUG DISCOVERY AND DEVELOPMENT

A1.4 BEGINNINGS OF MODERN PHARMACEUTICAL INDUSTRY

A1.5 EVOLUTION OF DRUG PRODUCTS

A1.6 FURTHER READING

APPENDIX 2: CELLS, NUCLEIC ACIDS, GENES, AND PROTEINS

A2.1 CELLS

A2.2 NUCLEIC ACIDS

A2.3 GENES AND PROTEINS

A2.4 FURTHER READING

APPENDIX 3: SELECTED DRUGS AND THEIR MECHANISMS OF ACTION

APPENDIX 4: A DHFR PLASMID VECTOR

APPENDIX 5: VACCINE PRODUCTION METHODS

APPENDIX 6: VACCINES APPROVED BY FDA

APPENDIX 7: PHARMACOLOGY/TOXICOLOGY REVIEW FORMAT

APPENDIX 8: EXAMPLES OF GENERAL BIOMARKERS

APPENDIX 9: TOXICITY GRADING

APPENDIX 10: HEALTH SYSTEMS IN SELECTED COUNTRIES

ACRONYMS

GLOSSARY

INDEX

END USER LICENSE AGREEMENT

List of Tables

Chapter 01

TABLE 1.1 Global Pharmaceutical Sales by Region, 2012

TABLE 1.2 The Top 10 Best-selling Products, 2012

TABLE 1.3 The Top 10 Best-selling Biopharmaceuticals, 2013

TABLE 1.4 The Top 10 Pharmaceutical Companies: Dec 18, 2013

TABLE 1.5 The Top 10 Biopharmaceutical Companies: 2012

TABLE 1.6 R&D Expenditures in R&D-Based Companies

TABLE 1.7 New Drugs Approved by FDA and EMA for Roche, Pfizer, and Novartis, 2012

Chapter 02

TABLE 2.1 Projected 2017 Drug Expenditures in Developed and Emerging Markets by Therapy Classes

TABLE 2.2 Classification of Enzymes

TABLE 2.3 Selected Drugs and Target Receptors

TABLE 2.4 Mechanisms of Action for Selected Drugs

TABLE 2.5 Molecular Targets of FDA-Approved Drugs

TABLE 2.6 Distribution of Drug Targets

Chapter 03

TABLE 3.1 Selected Examples of Promising Metabolic Targets for Cancer Therapy

TABLE 3.2 Selected Antisense Therapies That Have Reached Phase III Trials

Chapter 04

TABLE 4.1 Some Examples of Biologics and Their Uses

TABLE 4.2 Some Common Adjuvants and Their Mechanisms of Action

TABLE 4.3 Examples of Recent FDA-Approved Monoclonal Antibody Therapeutics

TABLE 4.4 Selected Interleukins

TABLE 4.5 Vectors for Gene Therapy

Chapter 05

TABLE 5.1 Half-Life Calculations

TABLE 5.2 Duration of Repeated Dose Toxicity Studies to Support Clinical Trials and Marketing Authorizations

TABLE 5.3 Conversion of Animal Doses to Human Equivalent Doses (HED) on the Basis of Body Surface Area

TABLE 5.4 Bioavailability of Oral Drugs

Chapter 06

TABLE 6.1 ICH Clinical Study Efficacy Guidelines

TABLE 6.2 Serum Tumor Markers

Chapter 07

TABLE 7.1 Selected Regulations from 21 CFR

TABLE 7.2 Selected International Regulatory Authorities

Chapter 08

TABLE 8.1 Content and Format of Chemistry, Manufacturing, and Controls Information

TABLE 8.2 FDA's Expedited Programs

TABLE 8.3 Review of Labeling

TABLE 8.4 Approval Times for NDAs and BLAs

TABLE 8.5 PDUFA Fees for FY 2014

TABLE 8.6 EMA Application Fees, 2014

TABLE 8.7 TGA Fees and Charges, 2014

TABLE 8.8 Module 2: Common Technical Document Summaries

TABLE 8.9 Module 3: Quality

TABLE 8.10 Module 4: Nonclinical Study Reports

TABLE 8.11 Module 5: Clinical Study Reports

TABLE 8.12 FDA NMEs/Biologics in 2013

TABLE 8.13 EMA New Medicines in 2013

Chapter 09

TABLE 9.1 Application of PIC/S GMP Guide Part II to API Manufacturing

TABLE 9.2 Airborne Environmental Cleanliness Requirements

TABLE 9.3 Recommended Limits for Microbial Contamination

TABLE 9.4 Stages of Process Validation

TABLE 9.5 The

US Pharmacopoeia

Specifications for Purified Water and Water for Injection

TABLE 9.6 Types of Cleaning Agents

TABLE 9.7 Storage Conditions for Evaluating Drug Stability

Chapter 10

TABLE 10.1 Deficiencies of Manufacturers of Medicinal Products and Starting Materials in EU and Third Countries During 1995 to 2005

TABLE 10.2 Finished Dosage Form Application

TABLE 10.3 Biologics Products Facing Biosimilars Challenge

Chapter 11

TABLE 11.1 Selected Drugs and Their Genetic Biomarkers

TABLE 11.2 List of Drugs Banned in Sports

TABLE 11.3 Leading Causes of Death in the World, 2012

Appendix 02

TABLE A2.1 The 20 Naturally Occurring Amino Acids

Appendix 02

TABLE A4.1 Restriction Endonucleases

List of Illustrations

Chapter 01

Figure 1.1 The stages from drug discovery to marketing approval.

Figure 1.2 R&D investments by research-based US pharmaceutical companies.

Figure 1.3 New drugs in development by regulatory phases, 2011.

Figure 1.4 Expenses and revenues curve for a new drug.

Chapter 02

Figure 2.1 Flow chart of drug discovery processes.

Figure 2.2 Microarray slides. 1) Thousands of short, single DNA strands containing specific genes are deposited onto glass slide at designated positions, 2) cDNAs from diseased cells are labeled with red fluorescent dye, 3) cDNAs from healthy cells are labeled with green fluorescent dye, 4) Pairing of diseased cDNAs with specific genes on glass slide, 5) Noncomplementary pairing of certain genes, 6) Pairing of healthy cDNAs with other specific genes. Fluorescence image of red and green intensities reveals genes involved in diseased and health cells. Refer to Exhibit 2.8.

Figure 2.3 Agonist binding to receptor initiates biochemical reactions.

Figure 2.4 Antagonist binding to receptor blocks biochemical reactions.

Figure 2.5 Signal transduction showing cascades of reaction occurring inside the cell.

Figure 2.6 A G-protein coupled receptor.

Figure 2.7 Signal cascade in GPCR.

Figure 2.8 A ligand-gated ion channel receptor. Ach, acetylcholine. The binding of Ach to the α subunits opens the ion channel, allowing Na

+

ions to flow through the channel into the cell.

Figure 2.9 A tyrosine kinase receptor.

Chapter 03

Figure 3.1 The basic steps of the irrational drug discovery process.

Figure 3.2 The basic steps of the rational drug discovery process.

Figure 3.3 Crystalline molecules in 3D. Unit cells are imaginary blocks used to represent the regular arrangement of molecules in 3D space.

Figure 3.4 Steps in X-ray structure determination. X-ray scattering by the crystal gives rise to a diffraction pattern. From the diffraction pattern, the molecular structure can be determined using Fourier transformation mathematical calculations.

Figure 3.5 Bioinformatics flow of information.

Figure 3.6 Docking simulations.

Figure 3.7 A ligand fitting into a binding site. Binding of inositol 1,4,5-trisphosphate (InsP3) with its receptor. The InsP3 receptor plays a key role in cellular and physiological processes.

Figure 3.8 Additions of amines (A) and carboxylic acids (B) in a 96-well plate.

Figure 3.9 Mode of action for antisense drugs. An example is Fomivirsen (Vitravene, Isis Pharmaceuticals), which is a 21-nucleotide phosphorothioate that binds to the complementary mRNA of cytomegalovirus and blocks the translation process. Cytomegalovirus is a virus that belongs to the herpes group.

Figure 3.10 siRNA Cellular Mechanism.

Figure 3.11 Chiral molecules. Black triangular bond projects out of the page, gray triangular bond projects into the page.

Chapter 04

Figure 4.1 Different classes of antibodies. IgG, IgD, and IgE are monomeric antibodies. IgA and IgM are polymeric antibodies.

Figure 4.2 IgG antibody molecule.

Figure 4.3 Different fragments of the antibody molecule.

Figure 4.4 Production of polyclonal antibodies from horse antisera.

Figure 4.5 Production of MAbs using the hybridoma technique.

Figure 4.6 Conjugate antibodies.

Figure 4.7 Bispecific antibody.

Figure 4.8 Interleukin 2 (IL-2) molecule.

Figure 4.9 Erythropoietin.

Figure 4.10 Human insulin molecule. Refer to Table A2.1 for the names of amino acids.

Figure 4.11 Basis of gene therapy.

Figure 4.12 Genesis of different stem cells.

Chapter 05

Figure 5.1 Dose–effect curve.

Figure 5.2 Dose–effect curve with logarithmic scale for dose.

Figure 5.3 Potency and effectiveness.

Figure 5.4 Therapeutic index.

Figure 5.5 Schematic representation of drug absorption, distribution, metabolism, and excretion.

Figure 5.6 Absorption of drugs in different pH environments.

Figure 5.7 Process of drug in the body.

Figure 5.8 Drug concentration in bloodstream versus time for a single dose.

Figure 5.9 Clearance of drug from the bloodstream.

Figure 5.10 Plasma concentration of drug after a single dose.

Figure 5.11 Multiple doses to maintain maximal effect.

Chapter 06

Figure 6.1 The four phases of clinical trials.

Chapter 08

Figure 8.1 Drug development process.

Figure 8.2 The IND process.

Figure 8.3 The NDA process.

Figure 8.4 Form 356 h (Page 1).

Figure 8.5 Approval process for generics.

Figure 8.6 Approval process for OTC drugs.

Figure 8.7 Marketing authorization procedures.

Figure 8.8 Centralized procedure.

Note:

Rapporteur – a person appointed to oversee the procedure, CHMP – Committee for Medicinal Products for Human Use

Figure 8.9 Drug approval process in Japan.

Figure 8.10 Manufacturing and distribution of drugs for overseas manufacturers.

Figure 8.11 Imported “Western” drug approval process in China.

Figure 8.12 Clinical trial process in China.

Figure 8.13 Drug approval process in Australia.

Figure 8.14 Clinical trial applications in Australia.

Figure 8.15 Common technical document.

Chapter 09

Figure 9.1 Cleanroom pressure scheme.

Note

: Two entrances and exits for Grade B environment; single entrance and exit for Grades A and B environments.

Figure 9.2 Production and in-process control mechanism.

Figure 9.3 Generation of purified water and water for injection.

Figure 9.4 Framework for specification and qualification of computerized systems.

Figure 9.5 Curves showing

D

and

Z

values.

Figure 9.6 Controls in manufacturing process.

Note

: Manufacturing includes controls on Building Management System (BMS) and Environment Management System (EMS).

Figure 9.7 Quality risk management process.

Chapter 10

Figure 10.1 Implementation of GMP in drug manufacture.

Figure 10.2 FDA inspection and action process.

Figure 10.3 Chemical synthesis of small molecule APIs.

Figure 10.4 Reaction vessel for the manufacture of an API – Schematic drawing.

Figure 10.5 Production of biopharmaceutical drug. Note: Ascites represents the old method of biopharmaceutical drug production.

Figure 10.6 Stages of cell growth.

Figure 10.7 Monitoring of cell growth over time. Note: Usually there are nutrient feeds that “kick start” the cell growth and the production of the MAb. This can be anything from a chemical inhibitor such as MTX or just as simple as changing the carbon substrate.

Figure 10.8 Production of tablets and capsules.

Figure 10.9 Drug recalls in US (2007 to 2013). Note: 2013* – second quarter data only.

Figure 10.10 Drug shortages in US (2005 to 2012).

Chapter 11

Figure 11.1 Patent term, extensions and exclusivities. Note: Top section for US, Bottom section for Europe. Top section – As NDA (orphan drug) is granted in Yr 9 of patent, the 14 year rule means a maximum PTR of 3 years can be approved. Generics can come into the market on Yr 23. If NDA is granted in Yr 11 of patent, the 14 year rule means a maximum PTR of 5 years can be approved. Generics can then only come into the market on Yr 25. Bottom section – Similar reasoning applies to Europe. A drug for pediatric indication will have an additional 6 months for SPC.

Figure 11.2 New molecular entities and biologics approved by FDA (1993 to 2013).

Figure 11.3 Challenges facing the pharmaceutical companies.

Appendix 02

Figure A2.1 Lipid bilayer cell membrane.

Figure A2.2 A prokaryote cell.

Figure A2.3 A human eukaryote cell.

Figure A2.4 Nucleoside and nucleotide. Circled areas show the presence and absence of oxygen atom in the ribose and deoxy ribose sugars.

Figure A2.5 Nucleic acid bases.

Figure A2.6 (a) Single strand nucleotide, (b) DNA in double helix formation, and (c) the pairing up of bases on two separate strands via hydrogen bonding to form the double helix.

Figure A2.7 Protein synthesis process.

Figure A2.8 Transcription from DNA to mRNA.

Figure A2.9 Formation of a peptide bond.

Figure A2.10 Protein structure: Human deoxyhemoglobin. (

Source

: Reprinted with permission from Protein Data Bank, Chatake T

et al

. 2007, ‘Protonated states of buried histidine residues in human deoxyhemoglobin revealed by neutron crystallography’,

Journal of the American Chemical Society

,, 129, pp. 14840–14841, http://www.rcsb.org/pdb/explore/explore.do?structureId=2DXM).

Figure A2.11 Protein structure: HIV-1 Protease complexed with a tripeptide inhibitor. (

Source

: Reprinted with permission from Protein Data Bank, Louis, JM, Dyda F, Nashed, F

et al

. 1998, ‘Hydrophilic peptides derived from the transframe region of Gag-Pol inhibit the HIV-1 protease’,

Biochemistry

, 37. pp. 2105, http://www.rcsb.org/pdb/explore/explore.do?structureId=1A30).

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DRUGS

From Discovery to Approval

Third Edition

RICK NG, PhD, MBA

TrainerNational University of Singapore Academy of GxP Excellence (NUSAGE)Singapore

Copyright © 2015 by John Wiley & Sons, Inc. All rights reserved

Published by John Wiley & Sons, Inc., Hoboken, New JerseyPublished simultaneously in Canada

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