Predictive ADMET E-Book

Jianling Wang

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

Seitenzahl: 1169

Veröffentlichungsjahr: 2014

Beschreibung

This book helps readers integrate in silico, in vitro, and in vivo ADMET (absorption, distribution, metabolism, elimination and toxicity) and PK (pharmacokinetics) data with routine testing applications so that pharmaceutical scientists can diagnose ADMET problems and present appropriate recommendations to move drug discovery programs forward.

The book introduces the current clinical practice for drug discovery and development along with the impact on early risk assessment; consolidates the tools and models to intelligently integrate existing in silico, in vitro and in vivo ADMET data; and demonstrates successful cases and lessons learned from real drug discovery and development. In short, it is a book aimed to provide a practical road map for drug discovery and development scientists to generate efficacious and safe drugs for unmet medical needs.

Leseprobe

PREDICTIVE ADMET

Integrative Approaches in Drug Discovery and Development

Edited by

Edited by

Jianling Wang

Metabolism and PharmacokineticsNovartis Institutes for Biomedical ResearchCambridge, MA, USA

Laszlo Urban

Preclinical Safety ProfilingNovartis Institutes for Biomedical ResearchCambridge, MA, USA

Copyright © 2014 by John Wiley & Sons, Inc. All rights reserved.

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

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Library of Congress Cataloging-in-Publication Data:

Predictive ADMET : integrative approaches in drug discovery and development / edited by Jianling Wang, Laszlo Urban. p. ; cm. Includes bibliographical references and index. ISBN 978-1-118-29992-0 (cloth) I. Wang, Jianling, 1958- editor of compilation. II. Urban, Laszlo, 1951- editor of compilation. [DNLM: 1. Drug Discovery-methods. 2. Pharmacokinetics. QV 745] RM301.25 615.1′.dc23 2013038054

CONTENTS

PREFACE

CONTRIBUTORS

I

:

INTRODUCTION TO THE CURRENT SCIENTIFIC, CLINICAL, AND SOCIAL ENVIRONMENT OF DRUG DISCOVERY AND DEVELOPMENT

1: CURRENT SOCIAL, CLINICAL, AND SCIENTIFIC ENVIRONMENT OF PHARMACEUTICAL R&D

1.1 THE CHANGING LANDSCAPE OF EPIDEMIOLOGY AND MEDICAL CARE

1.2 COST OF DRUG DEVELOPMENT

1.3 THE NEW PARADIGM OF ADME/PK ASSESSMENT

1.4 INCREASED SAFETY EXPECTATIONS

1.5 TRANSLATIONAL VALUE OF

IN VITRO

PROFILING DATA

1.6 SUMMARY

REFERENCES

2: POLYPHARMACOLOGY AND ADVERSE BIOACTIVITY PROFILES PREDICT POTENTIAL TOXICITY AND DRUG-RELATED ADRS

2.1 INTRODUCTION

2.2

IN VITRO

ADMET PROFILING

2.3 COMPUTATIONAL METHODS PREDICTING ADMET PROPERTIES

2.4 OUTLOOK

2.5 ACKNOWLEDGMENTS

REFERENCES

II

:

INTELLIGENT INTEGRATION AND EXTRAPOLATION OF ADMET DATA

3: ADMET DIAGNOSIS MODELS

3.1 INTRODUCTION

3.2 SOLUBILITY DIAGNOSIS

3.3 DIAGNOSING PERMEABILITY

3.4 GENERAL STRATEGY TO APPLY ADME DIAGNOSIS MODELS

3.5 CONCLUDING REMARKS

REFERENCES

4: PATH (PROBE ADME AND TEST HYPOTHESES): A USEFUL APPROACH ENABLING HYPOTHESIS-DRIVEN ADME OPTIMIZATION

4.1 INTRODUCTION

4.2 ASSUMPTIONS AND LIMITATIONS

4.3 CLEARANCE IVIVC

4.4 ORAL BIOAVAILABILITY (%F) IVIVC

4.5 PAYOFFS FOR INTELLIGENT DATA INTEGRATION IN EARLY DRUG DISCOVERY

REFERENCES

5: PK-MATRIX—A PERMEABILITY: INTRINSIC CLEARANCE SYSTEM FOR PREDICTION, CLASSIFICATION, AND PROFILING OF PHARMACOKINETICS AND DRUG–DRUG INTERACTIONS

5.1 INTRODUCTION

5.2 SETTING UP THE PK-MATRIX

5.3 PK-MATRIX DISTRIBUTION/CLASSIFICATION OF DRUGS

5.4 DISTRIBUTION OF DDIS ACCORDING TO

P

e

CLASSES

5.5

IN VITRO

VERSUS

IN VIVO

PREDICTION AND CLASSIFICATION

5.6 CASE STUDIES

5.7 DISCUSSION

5.8 SUMMARY

REFERENCES

6: MAXIMIZING THE POWER OF A LOCAL MODEL FOR ADMET-PROPERTY PREDICTION

6.1 INTRODUCTION

6.2 SAR METHODOLOGY

6.3 CASES IN DRUG DISCOVERY

6.4 POTENTIAL CAVEATS FOR QSAR ANALYSES

REFERENCES

7: CHEMOINFORMATIC AND CHEMOGENOMIC APPROACH TO ADMET

7.1 INTRODUCTION

7.2 QSAR TO ADMET

7.3 STRUCTURE-BASED APPROACHES TO ADMET

7.4 CHEMOGENOMICS TO ADMET

7.5 COMBINATION OF VARIOUS APPROACHES EXEMPLIFIED FOR P-GP

ACKNOWLEDGMENTS

REFERENCES

8: MULTIPARAMETER OPTIMIZATION OF ADMET FOR DRUG DESIGN

8.1 INTRODUCTION

8.2 ESTABLISHING THE RULES

8.3 APPROACHES TO MPO

8.4 CASE STUDY: COMPOUND PRIORITIZATION FOR A BALANCE OF PROPERTIES

8.5 CONCLUSION

REFERENCES

9: PBPK: INTEGRATING

IN VITRO

AND

IN SILICO

DATA IN PHYSIOLOGICALLY BASED MODELS

9.1 WHAT IS PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELING?

9.2 PBPK HISTORY AND CURRENT STATUS

9.3 PBPK APPLICATION AT DIFFERENT STAGES OF PHARMACEUTICAL RESEARCH AND DEVELOPMENT

9.4 ADVANTAGES, LIMITATIONS, AND FUTURE PERSPECTIVES OF PBPK MODELING

REFERENCES

10: EMERGING FULL MECHANISTIC PHYSIOLOGICALLY BASED MODELING

10.1 INTRODUCTION

10.2 PARADIGM SHIFT

10.3 PAST PARADIGM OF BIOPHARMACEUTICAL MODELING

10.4 FUTURE PARADIGM OF BIOPHARMACEUTICAL MODELING

10.5 IMPACT OF FULL-MECHANISTIC MODELING ON DRUG DISCOVERY AND DEVELOPMENT

10.6 EPISTEMOLOGY AND GOOD SIMULATION PRACTICE

10.7 OUTLOOK

REFERENCES

11: PHARMACOKINETIC/ PHARMACODYNAMIC MODELING IN DRUG DISCOVERY: A TRANSLATIONAL TOOL TO OPTIMIZE DISCOVERY COMPOUNDS TOWARD THE IDEAL TARGET-SPECIFIC PROFILE

11.1 INTRODUCTION

11.2 THE DISTINCTION BETWEEN DRUG AND SYSTEM-SPECIFIC PARAMETERS

11.3 EXTRAPOLATION OF

IN VITRO

BIOASSAYS

11.4 CONCENTRATION-RESPONSE RELATIONSHIPS AND THE IMPACT OF TIME

11.5 THE UTILITY OF TRANSLATION BIOMARKERS

11.6 PK/PD STUDY DESIGN: UNDERSTANDING PK DRIVERS FOR PD/EFFICACY RESPONSE

11.7 CAPTURING PHARMACODYNAMIC UNCERTAINTY

11.8 PERSPECTIVES

REFERENCES

III

:

ASSESSMENT AND MITIGATION OF CRITICAL CLINICALLY RELEVANT ADMET RISKS IN DRUG DISCOVERY AND DEVELOPMENT

12:

IN VITRO–IN SILICO

TOOLS TO PREDICT PHARMACOKINETICS OF POORLY SOLUBLE DRUG COMPOUNDS

12.1 INTRODUCTION AND GENERAL CONSIDERATIONS

12.2

IN VITRO–IN SILICO–IN VIVO

APPROACH

REFERENCES

13: EVALUATION OF THE COLLECTIVE IMPACT OF PASSIVE PERMEABILITY AND ACTIVE TRANSPORT ON

IN VIVO

BLOOD-BRAIN BARRIER AND GASTROINTESTINAL DRUG ABSORPTION

13.1 INTRODUCTION TO DRUG ABSORPTION

13.2 GASTROINTESTINAL DRUG ABSORPTION

13.3 BLOOD-BRAIN BARRIER DRUG ABSORPTION

13.4 CASE STUDY

13.5 CONCLUSION

REFERENCES

14: INTEGRATED ASSESSMENT OF DRUG CLEARANCE AND CROSS-SPECIES SCALABILITY

14.1 PHARMACOKINETIC CONSIDERATIONS OF CLEARANCE

14.2 PHYSIOLOGICAL CONSIDERATIONS OF CLEARANCE

14.3 CLEARANCE PATHWAYS FOR MARKETED DRUGS

14.4 OVERVIEW OF THE INTEGRATION OF CLEARANCE ASSESSMENT INTO DRUG DISCOVERY

14.5

IN SILICO

METHODS FOR CLEARANCE IN DRUG DISCOVERY

14.6

IN VITRO

CLEARANCE ASSAYS

14.7

IN VITRO

METABOLIC CLEARANCE ASSAYS

14.8 HOW TO USE

IN VITRO

METABOLIC CLEARANCE ASSAYS

14.9

IN VITRO

ASSAYS FOR PREDICTION OF TRANSPORTER-MEDIATED CLEARANCE

14.10 UNDERLYING PRINCIPLES IN THE USE OF ANIMALS FOR CROSS-SPECIES SCALABILITY

14.11 SINGLE-SPECIES SCALING OF CLEARANCE

14.12 PERSPECTIVE ON SINGLE-VERSUS MULTIPLE-SPECIES ALLOMETRIC SCALING

14.13 PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODELING

14.14 EXAMPLES OF THE USE OF PBPK MODELING TO PREDICT PHARMACOKINETIC PROFILE OF FLUCONAZOLE AND SILDENAFIL

14.15 OVERALL PERSPECTIVE ON CROSS-SPECIES SCALING OF CLEARANCE FOR DRUG DISCOVERY

REFERENCES

15: PRACTICAL ANTICIPATION OF HUMAN EFFICACIOUS DOSES AND PHARMACOKINETICS USING PRECLINICAL

IN VITRO

AND

IN VIVO

DATA

15.1 INTRODUCTION

15.2 METHODS FOR ANTICIPATING HUMAN PHARMACOKINETICS

15.3 CASE STUDIES

15.4 DISCUSSIONS, MODELS LIMITATIONS, AND ASSUMPTIONS

15.5 CONCLUSIONS

REFERENCES

16: MANAGEMENT AND MITIGATION OF HUMAN DRUG–DRUG INTERACTION RISKS IN THE DRUG DISCOVERY AND DEVELOPMENT PHASES

16.1 INTRODUCTION

16.2 CYTOCHROME P450-MEDIATED DRUG–DRUG INTERACTIONS

16.3 TRANSPORTER-MEDIATED DRUG–DRUG INTERACTIONS

16.4 CONCLUSIONS

REFERENCES

17: INTEGRATED ASSESSMENT AND CLINICAL TRANSLATION OF

IN VITRO

OFF-TARGET SAFETY PHARMACOLOGY RISKS

17.1 INTRODUCTION

17.2 ON- VERSUS OFF-TARGET PHARMACOLOGY/TOXICITY

17.3 EXPOSURE-CENTRIC APPROACH: CONSIDERING PLASMA PROTEIN BINDING AND FREE TISSUE EXPOSURE

17.4 QUANTITATIVE

IN VITRO/IN VIVO

EXTRAPOLATION

REFERENCES

18: INTEGRATED RISK ASSESSMENT OF CARDIOVASCULAR SAFETY IN DRUG DISCOVERY

18.1 INTRODUCTION

18.2 OVERVIEW OF PRECLINICAL MODELS

18.3 INDIRECT MODULATION OF CARDIAC ION CHANNELS AND IMPLICATIONS FOR CARDIAC SAFETY

18.4 PRECLINICAL STRATEGIES TO IDENTIFY CARDIAC ION CHANNEL–RELATED LIABILITIES

18.5 TRANSLATIONAL VALUE OF PRECLINICAL ASSESSMENT AND INTEGRATED RISK ASSESSMENT

18.6 THERAPEUTIC INDEX

18.7 CARDIAC SAFETY EVALUATION OF BIOLOPHARMACEUTICALS

18.8 CONCLUSIONS

REFERENCES

19: DRUG-INDUCED HEPATOTOXICITY: ADVANCES IN PRECLINICAL PREDICTIVE STRATEGIES AND TOOLS

19.1 INTRODUCTION: THE ISSUE OF IDIOSYNCRATIC DRUG-INDUCED LIVER INJURY (IDILI)

19.2 OVERVIEW OF PRECLINICAL SURROGATE MODELS AVAILABLE TO PREDICT DILI:

IN VIVO

,

IN VITRO

, AND

IN SILICO

TOOLS

19.3 KEY CHALLENGES TO PREDICT IDIOSYNCRATIC DRUG-INDUCED LIVER INJURY IN THE DRUG DISCOVERY AND DEVELOPMENT PHASES

19.4 RECOMMENDED STRATEGY FOR INTEGRATED IDILI RISK ASSESSMENT AND MITIGATION PROCESSES

19.5 CONCLUSIONS AND FORWARD-LOOKING CONSIDERATIONS

REFERENCES

20: CARCINOGENICITY AND TERATOGENICITY ASSESSMENT

20.1 INTRODUCTION

20.2 CARCINOGENICITY

20.3 NONGENOTOXIC CARCINOGENESIS

20.4 EMBRYO-FETAL TOXICITY TESTING

REFERENCES

21: NEPHROTOXICITY: DEVELOPMENT OF BIOMARKERS FOR PRECLINICAL AND CLINICAL APPLICATION

21.1 INTRODUCTION

21.2 DIAGNOSIS OF NEPHROTOXICITY

21.3 PRESENT AND FUTURE OF RENAL SAFETY MANAGEMENT IN DRUG DEVELOPMENT

REFERENCES

IV

:

SUCCESS STORIES AND LESSONS LEARNED

22: EARLY INTERVENTION WITH FORMULATION STRATEGIES FOR MULTIDIMENSIONAL PROBLEMS TO OPTIMIZE FOR SUCCESS

22.1 INTRODUCTION

22.2 COMBINING FORMULATION STRATEGIES TO OVERCOME POOR SOLUBILITY AND INHIBIT CRYSTALLIZATION

22.3 FORMULATION STRATEGIES TO AVOID EFFLUX LIABILITY

22.4 IDENTIFYING SOLUBILIZATION AS A KEY STRATEGY TO IMPROVE ORAL EXPOSURE

22.5 MANAGING UNFAVORABLE PHYSCIOCHEMICAL PROPERTIES, POSSIBLE FOOD EFFECTS, AND LIKELY DRUG INTERACTIONS IN PARALLEL THROUGH FORMULATION-BASED APPROACHES