ADME-Enabling Technologies in Drug Design and Development E-Book

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

Seitenzahl: 1820

Veröffentlichungsjahr: 2012

Beschreibung

A comprehensive guide to cutting-edge tools in ADME research

The last decade has seen tremendous progress in the development of analytical techniques such as mass spectrometry and molecular biology tools, resulting in important advances in drug discovery, particularly in the area of absorption, distribution, metabolism, and excretion (ADME).

ADME-Enabling Technologies in Drug Design and Development focuses on the current state of the art in the field, presenting a comprehensive review of the latest tools for generating ADME data in drug discovery. It examines the broadest possible range of available technologies, giving readers the information they need to choose the right tool for a given application, a key requisite for obtaining favorable results in a timely fashion for regulatory filings. With over thirty contributed chapters by an international team of experts, the book provides:

• A thorough examination of current tools, covering both electronic/mechanical technologies and biologically based ones

• Coverage of applications for each technology, including key parameters, optimal conditions for intended results, protocols, and case studies

• Detailed discussion of emerging tools and techniques, from stem cells and genetically modified animal models to imaging technologies

• Numerous figures and diagrams throughout the text

Scientists and researchers in drug metabolism, pharmacology, medicinal chemistry, pharmaceutics, toxicology, and bioanalytical science will find ADME-Enabling Technologies in Drug Design and Development an invaluable guide to the entire drug development process, from discovery to regulatory issues.

Leseprobe

Table of Contents

Cover

Title page

Copyright page

FOREWORD

PREFACE

CONTRIBUTORS

PART A: ADME: OVERVIEW AND CURRENT TOPICS

1 REGULATORY DRUG DISPOSITION AND NDA PACKAGE INCLUDING MIST

1.1 INTRODUCTION

1.2 NONCLINICAL OVERVIEW

1.3 PK

1.4 ABSORPTION

1.5 DISTRIBUTION

1.6 METABOLISM

1.7 EXCRETION

1.8 IMPACT OF METABOLISM INFORMATION ON LABELING

1.9 CONCLUSIONS

2 OPTIMAL ADME PROPERTIES FOR CLINICAL CANDIDATE AND INVESTIGATIONAL NEW DRUG (IND) PACKAGE

2.1 INTRODUCTION

2.2 NCE AND INVESTIGATIONAL NEW DRUG (IND) PACKAGE

2.3 ADME OPTIMIZATION

2.4 ADME OPTIMIZATION FOR CNS DRUGS

2.5 SUMMARY

3 DRUG TRANSPORTERS IN DRUG INTERACTIONS AND DISPOSITION

3.1 INTRODUCTION

3.2 ABC TRANSPORTERS

3.3 SLC TRANSPORTERS

3.4 IN VITRO ASSAYS IN DRUG DEVELOPMENT

3.5 CONCLUSIONS AND PERSPECTIVES

4 PHARMACOLOGICAL AND TOXICOLOGICAL ACTIVITY OF DRUG METABOLITES

4.1 INTRODUCTION

4.2 ASSESSMENT OF POTENTIAL FOR ACTIVE METABOLITES

4.3 ASSESSMENT OF THE POTENTIAL TOXICOLOGY OF METABOLITES

4.4 SAFETY TESTING OF DRUG METABOLITES

4.5 SUMMARY

5 IMPROVING THE PHARMACEUTICAL PROPERTIES OF BIOLOGICS IN DRUG DISCOVERY: UNIQUE CHALLENGES AND ENABLING SOLUTIONS

5.1 INTRODUCTION

5.2 PHARMACOKINETICS

5.3 METABOLISM AND DISPOSITION

5.4 IMMUNOGENICITY

5.5 TOXICITY AND PRECLINICAL ASSESSMENT

5.6 COMPARABILITY

5.7 CONCLUSIONS

6 CLINICAL DOSE ESTIMATION USING PHARMACOKINETIC/PHARMACODYNAMIC MODELING AND SIMULATION

6.1 INTRODUCTION

6.2 BIOMARKERS IN PK AND PD

6.3 MODEL-BASED CLINICAL DRUG DEVELOPMENT

6.4 FIRST-IN-HUMAN DOSE

6.5 EXAMPLES

6.6 DISCUSSION AND CONCLUSION

7 PHARMACOGENOMICS AND INDIVIDUALIZED MEDICINE

7.1 INTRODUCTION

7.2 INDIVIDUAL VARIABILITY IN DRUG THERAPY

7.3 WE ARE ALL HUMAN VARIANTS

7.4 ORIGINS OF INDIVIDUAL VARIABILITY IN DRUG THERAPY

7.5 GENETIC POLYMORPHISM OF DRUG TARGETS

7.6 GENETIC POLYMORPHISM OF CYTOCHROME P450s

7.7 GENETIC POLYMORPHISM OF OTHER DRUG METABOLIZING ENZYMES

7.8 GENETIC POLYMORPHISM OF TRANSPORTERS

7.9 PHARMACOGENOMICS AND DRUG SAFETY

7.10 WARFARIN PHARMACOGENOMICS: A MODEL FOR INDIVIDUALIZED MEDICINE

7.11 CAN INDIVIDUALIZED DRUG THERAPY BE ACHIEVED?

7.12 CONCLUSIONS

DISCLAIMER

CONTACT INFORMATION

8 OVERVIEW OF DRUG METABOLISM AND PHARMACOKINETICS WITH APPLICATIONS IN DRUG DISCOVERY AND DEVELOPMENT IN CHINA

8.1 INTRODUCTION

8.2 PK–PD TRANSLATION RESEARCH IN NEW DRUG RESEARCH AND DEVELOPMENT

8.3 ABSORPTION, DISTRIBUTION, METABOLISM, EXCRETION, AND TOXICITY (ADME/T) STUDIES IN DRUG DISCOVERY AND EARLY STAGE OF DEVELOPMENT

8.4 DRUG TRANSPORTERS IN NEW DRUG RESEARCH AND DEVELOPMENT

8.5 DRUG METABOLISM AND PK STUDIES FOR NEW DRUG RESEARCH AND DEVELOPMENT

8.6 STUDIES ON THE PK OF BIOTECHNOLOGICAL PRODUCTS

8.7 STUDIES ON THE PK OF TCMs

8.8 PK AND BIOAVAILABILITY OF NANOMATERIALS

PART B: ADME SYSTEMS AND METHODS

9 TECHNICAL CHALLENGES AND RECENT ADVANCES OF IMPLEMENTING COMPREHENSIVE ADMET TOOLS IN DRUG DISCOVERY

9.1 INTRODUCTION

9.2 “A” IS THE FIRST PHYSIOLOGICAL BARRIER THAT A DRUG FACES

9.3 “M” IS FREQUENTLY CONSIDERED PRIOR TO DISTRIBUTION DUE TO THE “FIRST-PASS” EFFECT

9.4 “D” IS CRITICAL FOR CORRECTLY INTERPRETING PK DATA

9.5 “E”: THE ELIMINATION OF DRUGS SHOULD NOT BE IGNORED

9.6 METABOLISM- OR TRANSPORTER-RELATED SAFETY CONCERNS

9.7 REVERSIBLE CYP INHIBITION

9.8 MECHANISM-BASED (TIME-DEPENDENT) CYP INHIBITION

9.9 CYP INDUCTION

9.10 REACTIVE METABOLITES

9.11 CONCLUSION AND OUTLOOK

ACKNOWLEDGMENTS

10 PERMEABILITY AND TRANSPORTER MODELS IN DRUG DISCOVERY AND DEVELOPMENT

10.1 INTRODUCTION

10.2 PERMEABILITY MODELS

10.3 TRANSPORTER MODELS

10.4 INTEGRATED PERMEABILITY–TRANSPORTER SCREENING STRATEGY

11 METHODS FOR ASSESSING BLOOD–BRAIN BARRIER PENETRATION IN DRUG DISCOVERY

11.1 INTRODUCTION

11.2 COMMON METHODS FOR ASSESSING BBB PENETRATION

11.3 METHODS FOR DETERMINATION OF FREE DRUG CONCENTRATION IN THE BRAIN

11.4 METHODS FOR BBB PERMEABILITY

11.5 METHODS FOR PGP EFFLUX TRANSPORT

11.6 CONCLUSIONS

12 TECHNIQUES FOR DETERMINING PROTEIN BINDING IN DRUG DISCOVERY AND DEVELOPMENT

12.1 INTRODUCTION

12.2 OVERVIEW

12.3 EQUILIBRIUM DIALYSIS

12.4 ULTRACENTRIFUGATION

12.5 ULTRAFILTRATION

12.6 MICRODIALYSIS

12.7 SPECTROSCOPY

12.8 CHROMATOGRAPHIC METHODS

12.9 SUMMARY DISCUSSION

ACKNOWLEDGMENT

13 REACTION PHENOTYPING

13.1 INTRODUCTION

13.2 INITIAL CONSIDERATIONS

13.3 CYP REACTION PHENOTYPING

13.4 NON-P450 REACTION PHENOTYPING

13.5 UGT CONJUGATION REACTION PHENOTYPING

13.6 REACTION PHENOTYPING FOR OTHER CONJUGATION REACTIONS

13.7 INTEGRATION OF REACTION PHENOTYPING AND PREDICTION OF DDI

13.8 CONCLUSION

14 FAST AND RELIABLE CYP INHIBITION ASSAYS

14.1 INTRODUCTION

14.2 CYP INHIBITION ASSAYS IN DRUG DISCOVERY AND DEVELOPMENT

14.3 HLM REVERSIBLE CYP INHIBITION ASSAY USING INDIVIDUAL SUBSTRATES

14.4 HLM RI ASSAY USING MULTIPLE SUBSTRATES (COCKTAIL ASSAYS)

14.5 TIME-DEPENDENT CYP INHIBITION ASSAY

14.6 SUMMARY AND FUTURE DIRECTIONS

15 TOOLS AND STRATEGIES FOR THE ASSESSMENT OF ENZYME INDUCTION IN DRUG DISCOVERY AND DEVELOPMENT

15.1 INTRODUCTION

15.2 UNDERSTANDING INDUCTION AT THE GENE REGULATION LEVEL

15.3 IN SILICO APPROACHES

15.4 IN VITRO APPROACHES

15.5 IN VITRO HEPATOCYTE AND HEPATOCYTE-LIKE MODELS

15.6 EXPERIMENTAL TECHNIQUES FOR THE ASSESSMENT OF INDUCTION IN CELL-BASED ASSAYS

15.7 MODELING AND SIMULATION AND ASSESSMENT OF RISK

15.8 ANALYSIS OF INDUCTION IN PRECLINICAL SPECIES

15.9 ADDITIONAL CONSIDERATIONS

15.10 CONCLUSION

16 ANIMAL MODELS FOR STUDYING DRUG METABOLIZING ENZYMES AND TRANSPORTERS

16.1 INTRODUCTION

16.2 ANIMAL MODELS OF DMEs

16.3 ANIMAL MODELS OF DRUG TRANSPORTERS

16.4 CONCLUSIONS AND THE PATH FORWARD

ACKNOWLEDGMENTS

17 MILK EXCRETION AND PLACENTAL TRANSFER STUDIES

17.1 INTRODUCTION

17.2 COMPOUND CHARACTERISTICS THAT AFFECT PLACENTAL TRANSFER AND LACTEAL EXCRETION

17.3 STUDY DESIGN

17.4 CONCLUSIONS

18 HUMAN BILE COLLECTION FOR ADME STUDIES

18.1 INTRODUCTION

18.2 PHYSIOLOGY

18.3 UTILITY OF THE BILIARY DATA

18.4 BILE COLLECTION TECHNIQUES

18.5 FUTURE SCOPE

ACKNOWLEDGMENT

PART C: ANALYTICAL TECHNOLOGIES

19 CURRENT TECHNOLOGY AND LIMITATION OF LC-MS

19.1 INTRODUCTION

19.2 SAMPLE PREPARATION

19.3 CHROMATOGRAPHY SEPARATION

19.4 MASS SPECTROMETRIC ANALYSIS

19.5 IONIZATION

19.6 MS MODE VERSUS MS/MS OR MSn MODE

19.7 MASS SPECTROMETERS: SINGLE AND TRIPLE QUADRUPOLE MASS SPECTROMETERS

19.8 MASS SPECTROMETERS: THREE-DIMENSIONAL AND LINEAR ION TRAPS

19.9 MASS SPECTROMETERS: TIME-OF-FLIGHT MASS SPECTROMETERS

19.10 MASS SPECTROMETERS: FOURIER TRANSFORM AND ORBITRAP MASS SPECTROMETERS

19.11 ROLE OF LC-MS IN QUANTITATIVE IN VITRO ADME STUDIES

19.12 QUANTITATIVE IN VIVO ADME STUDIES

19.13 METABOLITE IDENTIFICATION

19.14 TISSUE IMAGING BY MS

19.15 CONCLUSIONS AND FUTURE DIRECTIONS

20 APPLICATION OF ACCURATE MASS SPECTROMETRY FOR METABOLITE IDENTIFICATION

20.1 INTRODUCTION

20.2 HIGH-RESOLUTION/ACCURATE MASS SPECTROMETERS

20.3 POSTACQUISITION DATA PROCESSING

20.4 UTILITIES OF HIGH-RESOLUTION/ACCURATE MASS SPECTROMETRY (HRMS) IN METABOLITE IDENTIFICATION

20.5 CONCLUSION

21 APPLICATIONS OF ACCELERATOR MASS SPECTROMETRY (AMS)

21.1 INTRODUCTION

21.2 BIOANALYTICAL METHODOLOGY

21.3 AMS APPLICATIONS IN MASS BALANCE/METABOLITE PROFILING

21.4 AMS APPLICATIONS IN PHARMACOKINETICS

21.5 CONCLUSION

22 RADIOACTIVITY PROFILING

22.1 INTRODUCTION

22.2 RADIOACTIVITY DETECTION METHODS

22.3 AMS

22.4 INTRACAVITY OPTOGALVANIC SPECTROSCOPY

22.5 SUMMARY

ACKNOWLEDGMENTS

23 A ROBUST METHODOLOGY FOR RAPID STRUCTURE DETERMINATION OF MICROGRAM-LEVEL DRUG METABOLITES BY NMR SPECTROSCOPY

23.1 INTRODUCTION

23.2 METHODS

23.3 TRAZODONE AND ITS METABOLISM

23.4 TRAZODONE METABOLITE GENERATION AND NMR SAMPLE PREPARATION

23.5 METABOLITE CHARACTERIZATION

23.6 COMPARISON WITH FLOW PROBE AND LC-NMR METHODS

23.7 METABOLITE QUANTIFICATION BY NMR

23.8 CONCLUSION

24 SUPERCRITICAL FLUID CHROMATOGRAPHY

24.1 INTRODUCTION

24.2 BACKGROUND

24.3 SFC INSTRUMENTATION AND GENERAL CONSIDERATIONS

24.4 SFC IN DRUG DISCOVERY AND DEVELOPMENT

24.5 FUTURE PERSPECTIVE

25 CHROMATOGRAPHIC SEPARATION METHODS

25.1 INTRODUCTION

25.2 LC SEPARATION TECHNIQUES

25.3 SAMPLE PREPARATION TECHNIQUES

25.4 HIGH-SPEED LC-MS ANALYSIS

25.5 ORTHOGONAL SEPARATION

25.6 CONCLUSIONS AND PERSPECTIVES

26 MASS SPECTROMETRIC IMAGING FOR DRUG DISTRIBUTION IN TISSUES

26.1 INTRODUCTION

26.2 MSI INSTRUMENTATION

26.3 MSI WORKFLOW

26.4 APPLICATIONS OF MSI FOR IN SITU ADMET TISSUE STUDIES

26.5 CONCLUSIONS

27 APPLICATIONS OF QUANTITATIVE WHOLE-BODY AUTORADIOGRAPHY (QWBA) IN DRUG DISCOVERY AND DEVELOPMENT

27.1 INTRODUCTION

27.2 EQUIPMENT AND MATERIALS

27.3 STUDY DESIGNS

27.4  QWBA EXPERIMENTAL PROCEDURES

27.5 APPLICATIONS OF QWBA

27.6 LIMITATIONS OF QWBA

PART D: NEW AND RELATED TECHNOLOGIES

28 GENETICALLY MODIFIED MOUSE MODELS IN ADME STUDIES

28.1 INTRODUCTION

28.2 DRUG METABOLIZING ENZYME GENETICALLY MODIFIED MOUSE MODELS

28.3 DRUG TRANSPORTER GENETICALLY MODIFIED MOUSE MODELS

28.4 XENOBIOTIC RECEPTOR GENETICALLY MODIFIED MOUSE MODELS

28.5 CONCLUSIONS

29 PLURIPOTENT STEM CELL MODELS IN HUMAN DRUG DEVELOPMENT

29.1 INTRODUCTION

29.2 HUMAN DRUG METABOLISM AND COMPOUND ATTRITION

29.3 HUMAN HEPATOCYTE SUPPLY

29.4 hESCs

29.5 hESC HLC DIFFERENTIATION

29.6 iPSCs

29.7 CYP P450 EXPRESSION IN STEM CELL-DERIVED HLCs

29.8 TISSUE CULTURE MICROENVIRONMENT

29.9 CULTURE DEFINITION FOR DERIVING HLCs FROM STEM CELLS

29.10 CONCLUSION

30 RADIOSYNTHESIS FOR ADME STUDIES

30.1 BACKGROUND AND GENERAL REQUIREMENTS

30.2 RADIOSYNTHESIS STRATEGIES AND GOALS

30.3 PREPARATION AND SYNTHESIS

30.4 ANALYSIS AND PRODUCT RELEASE

30.5 DOCUMENTATION

30.6 SUMMARY

31 FORMULATION DEVELOPMENT FOR PRECLINICAL IN VIVO STUDIES

31.1 INTRODUCTION

31.2 FORMULATION CONSIDERATION FOR THE INTRAVENOUS ROUTE

31.3 FORMULATION CONSIDERATION FOR THE ORAL, SUBCUTANEOUS, AND INTRAPERITONEAL ROUTES

31.4 SPECIAL CONSIDERATION FOR THE INTRAPERITONEAL ROUTE

31.5 SOLUBILITY ENHANCEMENT

31.6 pH MANIPULATION

31.7 COSOLVENTS UTILIZATION

31.8 COMPLEXATION

31.9 AMORPHOUS FORM APPROACH

31.10 IMPROVING THE DISSOLUTION RATE

31.11 FORMULATION FOR TOXICOLOGY STUDIES

31.12 TIMING AND ASSESSMENT OF PHYSICOCHEMICAL PROPERTIES

31.13 CRITICAL ISSUES WITH SOLUBILITY AND STABILITY

31.14 GENERAL AND QUICK APPROACH FOR FORMULATION IDENTIFICATION AT THE EARLY DISCOVERY STAGES

32 IN VITRO TESTING OF PROARRHYTHMIC TOXICITY

32.1 OBJECTIVES, RATIONALE, AND REGULATORY COMPLIANCE

32.2 STUDY SYSTEM AND DESIGN

32.3 GOOD LABORATORY PRACTICE (GLP)-hERG STUDY

32.4 MEDIUM-THROUGHPUT ASSAYS USING PATCHXPRESS AS A CASE STUDY

32.5 NONFUNCTIONAL AND FUNCTIONAL ASSAYS FOR hERG TRAFFICKING

32.6 CONCLUSIONS AND THE PATH FORWARD

33 TARGET ENGAGEMENT FOR PK/PD MODELING AND TRANSLATIONAL IMAGING BIOMARKERS

33.1 INTRODUCTION

33.2 APPLICATION OF LC-MS/MS TO ASSESS TARGET ENGAGEMENT

33.3 LC-MS/MS-BASED RO STUDY DESIGNS AND THEIR CALCULATIONS

33.4 LEVERAGING TARGET ENGAGEMENT DATA FOR DRUG DISCOVERY FROM AN ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION (ADME) PERSPECTIVE

33.5 APPLICATION OF LC-MS/MS TO DISCOVERY NOVEL TRACERS

33.6 NONINVASIVE TRANSLATIONAL IMAGING

33.7 CONCLUSIONS AND THE PATH FORWARD

34 APPLICATIONS OF iRNA TECHNOLOGIES IN DRUG TRANSPORTERS AND DRUG METABOLIZING ENZYMES

34.1 INTRODUCTION

34.2 EXPERIMENTAL DESIGNS

34.3 APPLICATIONS OF RNAi IN DRUG METABOLIZING ENZYMES AND TRANSPORTERS

34.4 CONCLUSIONS

ACKNOWLEDGMENT

APPENDIX DRUG METABOLIZING ENZYMES AND BIOTRANSFORMATION REACTIONS

A.1 INTRODUCTION

A.2 OXIDATIVE ENZYMES

A.3 REDUCTIVE ENZYMES

A.4 HYDROLYTIC ENZYMES

A.5 CONJUGATIVE (PHASE II) DMEs

A.6 FACTORS AFFECTING DME ACTIVITIES

A.7 BIOTRANSFORMATION REACTIONS

A.8 SUMMARY

ACKNOWLEDGMENT

Index

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Library of Congress Cataloging-in-Publication Data:

ADME-enabling technologies in drug design and development / edited by Donglu

Zhang, Sekhar Surapaneni.

p. ; cm.

 Includes bibliographical references and index.

 ISBN 978-0-470-54278-1 (cloth)

 I. Zhang, Donglu. II. Surapaneni, Sekhar.

 [DNLM: 1. Drug Design. 2. Drug Evaluation, Preclinical. 3. Pharmaceutical

Preparations–metabolism. 4. Pharmacokinetics. 5. Technology,

Pharmaceutical–methods. QV 744]

 LC-classification not assigned

 615.1'9–dc23

2011030352

ISBN: 9780470542781

FOREWORD

The discovery, design, and development of drugs is a complex endeavor of optimizing on three axes: efficacy, safety, and druggability or drug-likeness. Each of these axes is a potential cause of attrition as a new molecular entity progresses through the many phases of drug development. Out of the 5000–10,000 compounds evaluated in discovery efforts, only 250 enter preclinical testing, 5 enter clinical trials, and only 1 is granted approval by the Food and Drug Administration at a cost that is estimated between US$1.3–1.6 billion [1]. Efforts to increase innovation, decrease attrition, and lower the cost of drug development are the focus of the pharmaceutical industry and regulatory agencies alike. Advances have been made in some disciplines such as drug metabolism and pharmacokinetics (PK), particularly in the area of absorption, distribution, metabolism, and excretion (ADME) studies. For example, a root cause analysis of clinical attrition [2] showed that unacceptable PK or bioavailability accounted for 40% of clinical attrition in the 1990s but within a decade had been reduced to less than 10%, in large part by the identification and mitigation of risks associated with ADME/PK properties earlier in the drug discovery process. This was enabled by the introduction of automated high- and medium-throughput screening of lead optimization candidates in the discovery space. While impressive, this improvement alone is not sufficient to reverse the rising costs and long development cycle times. It is, however, a step in the right direction. As the pharmaceutical industry has evolved, the focus of ADME studies has shifted from studies conducted primarily in support of regulatory submissions to playing a significant role in the earliest stages of the discovery phase of drug development. The engagement of ADME scientists in the discovery space has allowed drug candidates to progress in the development pipeline to the next milestone with greater probability of success because desirable characteristics, such as good aqueous solubility for absorption, high bioavailability, and balanced clearance, have been engineered into the molecules, and liabilities such as high first-pass metabolism and unacceptable drug–drug interactions potential have been engineered out.

The history of the discipline of drug metabolism and PK and ADME studies, with its roots in organic chemistry and pharmacology, has been well chronicled [3–8]. The rapid advancement of the discipline over the past 50 years is clearly linked to the development of ever-increasingly sophisticated analytical tools and the growth of the pharmaceutical industry. The vast number of tools at the disposal of drug metabolism scientists has transformed the study of xenobiotics from descriptive to quantitative, in vivo to the molecular levels, and from simply characterizing to predicting ADME properties.

It would be beyond the scope of this introduction to provide a historical accounting of the numerous advances of technology that have shaped the field. There are, however, three noteworthy milestones in the evolution of the discipline that merit mention: the use of radioisotopes in metabolism and distribution studies; the discovery of the superfamily of drug metabolizing enzymes, the cytochrome P450s; and the revolutionizing impact of mass spectrometry as both a qualitative and quantitative tool.

With the discovery of a new radioisotope of carbon, 14C, by Martin and Ruben [9], this powerful analytical tool enabled the first radiolabeled studies that elucidated the metabolic pathways and the disposition of xenobiotics in rats [10, 11]. The use of radiotracers went on to become an indispensable tool in biochemical pathway elucidation and in drug disposition studies. While 14C-labeled compounds are predominantly used in in vivo studies to fulfill regulatory requirement, the development of new reagents and techniques in tritium labeling now have allowed stereo- and site-selective synthesis with high specific activity, making these labeled molecule readily available for use in the earliest phases of drug discovery [12, 13].

The discovery of the cytochrome P450s and their role in the metabolism of endo- and xenobiotics opened a field of science that continues to grow and have a tremendous impact on the development of drugs and the practice of medicine. The pioneering research in this field has been well documented by Estabrook, a key contributor to our current understanding of this superfamily of enzymes [14]. The magnitude of research on the cytochrome P450s has exploded since 2003 (from greater than 2000 literature references to over 67,000 citations, as reflected by searching the PubMed database in 2011) The expanding knowledge of the cytochrome P450s has impacted early discovery efforts via assays for metabolic stability, species comparison in the selection of the most relevant species for toxicology studies, identification of the primary enzymes involved in the metabolism of a candidate drug, and potential polymorphic or drug–drug interaction liabilities of a candidate drug. The influence of the research on the cytochrome P450s also reaches into the clinical realm of drug development in the need for and design of clinical drug–drug interaction trials as well as in the regulatory guidance on drug interactions [15, 16].

No single analytical technique has had a more powerful effect on drug development than mass spectrometry, with an impact on multiple disciplines, such as chemistry, biology, and ADME [17]. An excellent review of mass spectrometry and its applications in drug metabolism and PK has recently been published [18] Mass spectrometry moved from the being a specialized tool largely used in structure identification to a “routine,” but albeit powerful, analytical technology used across the pharmaceutical industry and academia alike. The selectivity, sensitivity, and speed of mass spectrometry enabled much of the success seen with high-throughput screening and advances in bioanalytical analysis in a multitude of biological matrices in both PK and biotransformation studies.

The ADME scientist of today is fortunate to have an arsenal of tools at his or her disposal, many of which will be expanded upon in this book. The advances in technologies often have implications in adjacent technologies that further the discipline of drug metabolism and PK and allow an integrated approach to solving problems and advancing drug candidates through the phases of drug development.

LISA A. SHIPLEY

REFERENCES

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2. Kola I, Landis J (2004) Can the pharmaceutical industry reduce attrition rates? Nature Reviews. Drug Discovery 3:711–715.

3. Conti A, Bickel MH (1977) History of drug metabolism: Discoveries of the major pathways in the 19th century. Drug Metabolism Reviews 6(1):1–50.

4. Bachmann C, Bickel MH (1985) History of drug metabolism: The first half of the 20th century. Drug Metabolism Reviews 16(3):185–253.

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6. Murphy PJ (2008) The development of drug metabolism research as expressed in the publications of ASPET: Part 1, 1909–1958. Drug Metabolism and Disposition 36:1–5.

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9. Ruben S, Kamen MD (1941) Long-lived radioactive carbon: C14. Physical Review 59:349–354.

10. Elliott HW, Chang FNH, Abdou IA, Anderson HH (1949) The distribution of radioactivity in rats after administration of C14 labeled methadone. The Journal of Pharmacology and Experimental Therapeutics 95:494–501.

11. Morris HP, Weisburger JH, Weisburger EK (1950) The distribution of radioactivity following the feeding of carbon 14-labeled 2-acetylaminofluorene in rats. Cancer Research 10:620–634.

12. Saljoughian M (2002) Synthetic tritium labeling: Reagents and methodologies. Synthesis 13:1781–1801.

13. Voges R, Heys JR, Moenius T Preparation of Compounds Labeled with Tritium and Carbon -14, Chichester, U.K.: John Wiley and Sons, 2009.

14. Estabrook RW (2003) A passion for P450’s (remembrances of the early history of research on cytochrome P450). Drug Metabolism and Disposition 31:1461–1473.

15. Guideline on the Investigation of Drug Interactions (EMA/CHMP/EWP/125211/2010). (2010) http://www.ema.europa.eu/ema/pages/includes/document/open_document.jsp?webContentId=WC500090112.

16. Guidance for Industry: In Vivo Drug Metabolism/Drug Interaction Studies-Study Design, Data Analysis, and Recommendations for Dosing and Labeling. (1999) http://www.fda.gov/cder/guidance/index.htm.

17. Ackermann BL, Berna MJ, Eckstein JA, Ott LW, Chadhary AK (2008) Current applications of liquid chromatography/mass spectrometry in pharmaceutical discovery after a decade of innovation. Annual Review Of Analytical Chemistry 1:357–396.

18. Ramanathan R, ed. Mass Spectrometry in Drug Metabolism and Pharmacokinetics. Hoboken, NJ: John Wiley and Sons, 2009.

PREFACE

Understanding and characterizing absorption, metabolism, distribution, and excretion (ADME) properties of new chemical entities and drug candidates is an integral part of drug design and development. ADME is the discipline that is involved in the entire process of drug development, right from discovery, lead optimization, and clinical drug candidate selection through drug development and regulatory process. The complexity of ADME studies in drug discovery and development requires a drug metabolism scientist to know all available technologies in order to choose the right experimental approach and technology for solving the problems in a timely manner. During the last decade, tremendous progress has been made in wide array of technologies including mass spectrometry and molecular biology tools, and these enabling technologies are widely employed by ADME scientists. The generation of ADME data to support discovery and development teams is a gated process and timely generation of data to make right decisions is of paramount importance. Given the complexity of the drug discovery and development process, right techniques and tools should be used to generate timely data that is useful for decision making and regulatory filing. This requires an understanding of not only the breadth and depth of ADME technologies but also their limitation and pitfalls so scientists can make appropriate choices in employing these tools. A book on integrated enabling technologies will not only be useful to drug metabolism scientists but also could be a very helpful reference for scientists from the fields of pharmacology, medicinal chemistry, pharmaceutics, toxicology, and bioanalytical sciences in academia and industry.

This book is divided into four main sections. Part A provides the reader with an overview of ADME concepts and current topics including ADME and transporter studies in drug discovery and development, active and toxic metabolites, modeling and simulation, and developing biologics and individual medicines. Part B describes the ADME systems and methods; these include ADME screening technologies, permeability and transporter studies, distribution across specialized barriers such as blood–brain barrier (BBB) or placenta, cytochrome P450 (CYP) inhibition, induction, phenotyping, animal models for studying metabolism and transporters, and bile collection. Part C of the book discusses analytical tools including liquid chromatography-mass spectrometry (LC-MS) technologies for quantitation, metabolite identification and profiling, accelerator mass spectrometry (AMS) and radioprofiling, nuclear magnetic resonance (NMR), supercritical fluid chromatography (SFC) and other separation techniques, mass spectrometric imaging, and quantitative whole-body autoradiography (QWBA) tissue distribution techniques. Part D presents new and evolving technologies such as stem cells, genetically modified animal models, and siRNA techniques in ADME studies. Other techniques included in this section are target imaging technologies, radiosynthesis, formulation, and testing of cardiovascular toxicity potential.

We would like to thank our colleagues who are the experts and leading practitioners of the techniques described in the book for their contributions. We hope that this book is useful and serves as a quick reference to all drug hunters and to all those who are new to the discipline of ADME.

DONGLU ZHANG

SEKHAR SURAPANENI

CONTRIBUTORS

Suresh K. Balani, DMPK/NCDS, Millennium: The Takeda Oncology Company, Cambridge, MA, USA

Praveen V. Balimane, Bristol-Myers Squibb, Princeton, NJ, USA

Vanessa N. Barth, Translational Sciences, Eli Lilly and Company, Indianapolis, IN, USA

Leslie Bell, Novartis Institutes for BioMedical Research, Cambridge, MA, USA

Rajinder Bhardwaj, DMPK, Chemical Sciences and Pharmacokinetics, Lundbeck Research USA, Paramus, NJ, USA

Catherine L. Booth-Genthe, Respiratory Therapeutic Area Unit, GlaxoSmithKline, King of Prussia, PA, USA

Hong Cai, Bristol-Myers Squibb, Pennington, NJ, USA

Gamini Chandrasena, DMPK, Chemical Sciences and Pharmacokinetics, Lundbeck Research USA, Paramus, NJ, USA

Jiwen Chen, Bristol-Myers Squibb, Pennington, NJ, USA

Saeho Chong, College of Pharmacy, Seoul National University, Seoul, Korea

Lisa J. Christopher, Bristol-Myers Squibb, Princeton, NJ, USA

Jun Dai, Bristol-Myers Squibb, Princeton, NJ, USA

Li Di, Pfizer Global Research and Development, Groton, CT, USA

Ashok Dongre, Bristol-Myers Squibb, Pennington, NJ, USA

Dieter M. Drexler, Bristol-Myers Squibb, Wallingford, CT, USA

Richard W. Edom, Janssen Pharmaceutical Companies of Johnson & Johnson, Raritan, NJ, USA

Charles S. Elmore, Radiochemistry, AstraZeneca, Mölndal, Sweden

Adrian J. Fretland, Nonclinical Safety, Early ADME Department, Roche, Nutley, NJ, USA

Timothy J. Garrett, Clinical and Translational Science Institute, University of Florida, Gainesville, FL, USA

Lingling Guan, Ricerca Biosciences, Concord, OH, USA

Anshul Gupta, Drug Metabolism and Pharmacokinetics, AstraZeneca, Waltham, MA, USA

Yong-Hae Han, Bristol-Myers Squibb, Princeton, NJ, USA

Imad Hanna, Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, East Hanover, NJ, USA

David C. Hay, MRC Centre for Regenerative Medicine, Edinburgh, UK

Haizheng Hong, College of Oceanography and Environmental Sciences, Xiamen University, Fujian, China

Cornelis E.C.A. Hop, Department of Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, CA, USA

Matthew Hoffmann, Celgene Corporation, Summit, NJ, USA

Stella Huang, Bristol-Myers Squibb, Wallingford, CT, USA

W. Griffith Humphreys, Bristol-Myers Squibb, Princeton, NJ, USA

Wenying Jian, Johnson & Johnson Pharmaceutical Research & Development, Raritan, NJ, USA

Xi-Ling Jiang, Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, USA

Kim A. Johnson, Bristol-Myers Squibb, Wallingford, CT, USA

Janan Jona, Small Molecule Process and Product Development/Preformulation, Amgen Inc., Thousand Oaks, CA, USA

Elizabeth M. Joshi, Department of Drug Disposition, Lilly Research Laboratories, Indianapolis, IN, USA

Nataraj Kalyanaraman, Pharmacokinetics and Drug Metabolism, Amgen Inc., Thousand Oaks, CA, USA

Jiesheng Kang, Sanofi-Aventis U.S. Inc., Bridgewater, NJ, USA

Edward H. Kerns, Therapeutics for Rare and Neglected Diseases, NIH Center for Translational Therapeutics, Rockville, MD, USA

Yuan-Hon Kiang, Small Molecular Process and Product Development/Preformulation, Amgen Inc., Thousand Oaks, CA, USA

Wing Wah Lam, Janssen Pharmaceutical Companies of Johnson & Johnson, Raritan, NJ, USA

Chun Li, Metabolism and Pharmacokinetics, Genomics Institute of the Novartis Research Foundation, San Diego, CA, USA

Mingxiang Liao, DMPK/NCDS, Millennium: The Takeda Oncology Company, Cambridge, MA, USA

Heng-Keang Lim, Janssen Pharmaceutical Companies of Johnson & Johnson, Raritan, NJ, USA

Zhongping (John) Lin, Frontage Laboratories, Inc. Malvern, PA, USA

Chang-Xiao Liu, State Key Laboratory of Drug Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin, China

Tom Lloyd, Worldwide Clinical Trials Drug Development Solutions Bioanalytical Sciences, Austin, TX, USA

Anthony Y.H. Lu, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, USA

Qiang Ma, Receptor Biology Laboratory, Toxicology and Molecular Biology Branch, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Morgantown, WV, USA

Daniel P. Magparangalan, Covidien, St. Louis, MO, USA

Brad D. Maxwell, Bristol-Myers Squibb, Princeton, NJ, USA

Kaushik Mitra, Merck & Co. Inc., Rahway, NJ, USA

Voon Ong, San Diego, CA, USA

Ryan M. Pelis, Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada

Natalia Penner, Department of Drug Metabolism and Pharmacokinetics, Biogen Idec, Cambridge, MA, USA

Chandra Prakash, Department of Drug Metabolism and Pharmacokinetics, Biogen Idec, Cambridge, MA, USA

Darren L. Reid, Small Molecular Process and Product Development/Preformulation, Amgen Inc., Thousand Oaks, CA, USA

Kevin L. Salyers, Pharmacokinetics and Drug Metabolism, Amgen Inc., Thousand Oaks, CA, USA

Mark Seymour, Xceleron, Heslington, York, UK

Adam Shilling, Incyte Corp, Wilmington, DE, USA

Lisa A. Shipley, Drug Metabolism and Pharmacokinetics, Merck & Co., Inc., West Point, PA, USA

Yue-Zhong Shu, Bristol-Myers Squibb, Princeton, NJ, USA

Jose Silva, Janssen Pharmaceutical Companies of Johnson & Johnson, Raritan, NJ, USA

Matthew D. Silva, Amgen Inc., Thousand Oaks, CA, USA

Sekhar Surapaneni, Drug Metabolism and Pharmacokinetics, Celgene Corporation, Summit, NJ, USA

Adrienne A. Tymiak, Bristol-Myers Squibb, Princeton, NJ, USA

Jianling Wang, Novartis Institutes for BioMedical Research, Cambridge, MA, USA

Lifei Wang, Bristol-Myers Squibb, Princeton, NJ, USA

Xiaomin Wang, Celgene Corporation, Summit, NJ, USA

David B. Wang-Iverson, Bristol-Myers Squibb, Princeton, NJ, USA

Naidong Weng, Janssen Pharmaceutical Companies of Johnson & Johnson Raritan, NJ, USA

Caroline Woodward, Department of Drug Metabolism and Pharmacokinetics, Biogen Idec, Cambridge, MA, USA

Cindy Q. Xia, Biotransformation/DMPK, Drug Safety and Disposition, Millennium: The Takeda Oncology Company, Cambridge, MA, USA

Yang Xu, Pharmacokinetics and Drug Metabolism, Amgen Inc., Thousand Oaks, CA, USA

Ming Yao, Bristol-Myers Squibb, Princeton, NJ, USA

Richard A. Yost, Department of Chemistry, University of Florida, Gainesville, FL, USA

Ai-Ming Yu, Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, USA

Haoyu Zeng, Safety Assessment, Merck Research Laboratories, West Point, PA, USA

Donglu Zhang, Bristol-Myers Squibb, Princeton, NJ, USA

Yingru Zhang, Bristol-Myers Squibb, Princeton, NJ, USA

Zhoupeng Zhang, Merck & Co. Inc., Rahway, NJ, USA

Mingshe Zhu, Bristol-Myers Squibb, Princeton, NJ, USA

Peijuan Zhu, Respiratory Therapeutic Area Unit, GlaxoSmithKline, King of Prussia, PA, USA

PART A: ADME: OVERVIEW AND CURRENT TOPICS

1

REGULATORY DRUG DISPOSITION AND NDA PACKAGE INCLUDING MIST

Sekhar Surapaneni

1.1 INTRODUCTION

Drug metabolism and pharmacokinetics (DMPK) plays an important and integral part in drug discovery and development. In drug discovery, during lead optimization and drug candidate identification, metabolism studies are conducted to screen a large number of compounds with potential liabilities. The emphasis is on generating data efficiently and in a timely fashion related to a compound’s absorption, distribution, metabolism, and excretion (ADME) characteristics. Advances in analytical technologies, drug metabolism, and transporter biology has enabled drug metabolism scientists develop in vitro and in vivo tools to screen a large number of compounds efficiently and incorporate ADME information in lead optimization and identification. This early characterization for metabolic and pharmacokinetic (PK) properties is an essential element of lead optimization and candidate selection [1, 2]. Metabolism studies in the early drug discovery stages often involve evaluating a series of compounds to help identify and select a candidate for further development. The main purposes of these studies are to see if the compound has adequate metabolic stability, has low potential for any drug–drug interactions due to cytochrome P450 (CYP) induction or inhibition, and is not metabolized by polymorphic enzymes (such as CYP2D6) or exclusively by a single enzyme. In addition, the metabolites are characterized to assess if any reactive metabolites of safety concern are generated. Recent survey suggests that the DMPK role in early optimization has resulted in reduced attrition due to PK-related issues from 40% (1990s) to <10% (2000s) [3]. Once the compound is selected for clinical development, detailed PK/ADME studies are conducted to characterize the bioavailability, metabolic properties, distribution, and excretion and elimination of the drug. These studies provide information to assess safety and provide data for registration. The focus of this chapter is to describe the various DMPK studies performed at various stages of drug development and how they are captured when filing a new drug application (NDA). Figure shows the various DMPK studies conducted at different stages of drug development. The schematic is intended as an illustration, but the precise timing of the studies depends not only on the drug and its properties but also on the intended therapeutic benefit and target population. There are a number of regulatory guidance documents issued by regulatory authorities (U.S. Food and Drug Administration [FDA], European Medicines Agency [EMEA], etc.), and these guidelines are expected to be adhered to during the conduct of and metabolism studies. In addition, DMPK provides bioanalytical support for safety (toxicology and first-in-human) and efficacy (proof of concept or pivotal clinical) studies. The method development, validation, and sample analysis are expected to be conducted according to the guidelines issued by regulatory agencies worldwide, and any sample analysis conducted under good laboratory practice (GLP) guidelines is expected to meet the standards set forth under these guidelines. The metabolism data generated at various stages of development need to be integrated and summarized for regulatory filing and approval. The agreement to assemble all the quality, safety, and efficacy information in a common format (Common Technical Document or CTD) and the technical requirements for the registration of pharmaceuticals has been harmonized by the International Committee on Harmonization (ICH) process. This has revolutionized the regulatory review process and harmonized electronic submissions. Table shows the table of contents for the drug metabolism contributions in a CTD for an NDA. The objectives of this chapter are to discuss DMPK studies conducted during development and to reference the regulatory guidance documents that apply to various studies. The purposes are to integrate the information across studies and species and to present information related to safety and efficacy in an unambiguous and transparent manner to help regulators evaluate the content and main features of the drug.