Drug Metabolism and Pharmacokinetics : Frontiers, Strategies, and Applications.

Format:

Book

Author/Creator:

Shen, Liang.

Language:

English

Physical Description:

1 online resource (579 pages)

Edition:

1st ed.

Place of Publication:

Newark : John Wiley & Sons, Incorporated, 2025.

Summary:

Practical, state-of-the-art pharmacokinetic research methods, ideas, advancements, applications, and strategies Drawing on a wealth of extensive practical experience and theoretical research, Drug Metabolism and Pharmacokinetics encapsulates the most recent advancements and illustrative applications in the field. Sixty-eight relatively independent yet interconnected articles are included, each offering a unique perspective and providing in-depth interpretation. Readers can either read systematically or select specific topics of interest from the table of contents. Basic concepts, frontier advancements, DMPK research strategies, and technical methods are covered for novel drug modalities and therapeutics in different disease areas. The book encompasses a wide range of application and validation cases for DMPK research, including studies in in vitro ADME, in vivo pharmacokinetics, metabolite profiling and identification, radiolabeled ADME, and bioanalysis. Case studies showing the application of topics covered are included throughout, along with valuable insights into problem-solving and critical thinking. Written by a team of scientists specializing in DMPK research from the DMPK Department of WuXi AppTec, Drug Metabolism and Pharmacokinetics discusses sample topics including: ADME properties, metabolite identification, and bioanalytical strategies for oligonucleotide drugs Strategies and challenges in the determination of drug-to-antibody ratio (DAR) values of antibody-drug conjugates (ADCs) Breaking barriers in CNS drug development with intrathecal and intracerebroventricular administration Application and detection techniques of biomarkers in drug development Flux dialysis method for assessing plasma protein binding of high protein-binding drugs Drug Metabolism and Pharmacokinetics is an essential forward-thinking reference on the subject for pharmacy students, pharmaceutical industry researchers, and DMPK scientists, especially those exploring novel drug modalities.

Contents:

Cover

Title Page

Copyright Page

Contents

About the Editors

Preface

Acknowledgments

Section I Novel Drug Modalities: : Advancements and Their Pharmacokinetic Strategies

Chapter 1 Proteolysis-Targeting Chimeras (PROTACs)

1.1 An Overview of PROTAC Technology and Drug Metabolism and Pharmacokinetic (DMPK) Research Strategies

1.1.1 Introduction

1.1.2 Structure and Mechanism of Action of PROTACs

1.1.3 PROTAC Landscape Analysis

1.1.3.1 PROTAC Research and Development Progress: International Pharmaceutical Companies

1.1.3.2 PROTAC Research and Development Progress: Chinese Pharmaceutical Companies

1.1.4 Why Is DMPK Research Critical to PROTAC Drug Development?

1.1.5 The Strategy of the DMPK Study for PROTAC Drugs

1.1.6 Summary

References

1.2 Strategies to Improve the Oral Bioavailability of PROTACs

1.2.1 Introduction

1.2.2 PROTAC Molecules Hardly Meet Lipinski's Rule of Five

1.2.3 Strategies to Improve PROTAC's Bioavailability

1.2.3.1 Improve the PROTAC's Solubility

1.2.3.2 Improve the PROTAC's Permeability

1.2.3.3 Improve the PROTAC's Metabolic Stability

1.2.3.4 Choose Smaller E3 Ligand

1.2.3.5 Introduce Intramolecular Hydrogen Bonds

1.2.3.6 Select Appropriate Solutions

1.2.3.7 Use Prodrug Strategy

1.2.3.8 Use Molecular Glues

1.2.4 Summary

1.3 Research on PROTAC Metabolism: Strategies and Main Approaches

1.3.1 Introduction

1.3.2 Understanding the Key Metabolic Enzymes of PROTACs

1.3.3 Selecting an Appropriate In Vitro Metabolic Model

1.3.4 Facilitating Structural Optimization Through Studies on Metabolic Soft Spots

1.3.5 Summary

1.4 Metabolic Characteristics and Research Strategies for Metabolite Identification of PROTACs

1.4.1 Introduction.

1.4.2 Importance of Metabolite Identification Studies in the Development Process of PROTAC Drugs

1.4.3 Structural Characteristics of PROTAC Drugs

1.4.3.1 POI Ligand

1.4.3.2 E3 Ligand

1.4.3.3 Linker

1.4.4 Metabolic Characteristics of PROTAC Drugs

1.4.4.1 The Influence of PROTAC's E3 Ligand on PROTAC Metabolism

1.4.4.2 The Influence of PROTAC's POI Ligand on PROTAC Metabolism

1.4.4.3 The Influence of Linker on PROTAC Metabolism

1.4.4.4 Relationship Between the Metabolic Characteristics of Various PROTAC Components and the Whole Molecule

1.4.4.5 Summary of Metabolic Characteristics of PROTACs

1.4.5 Challenges and Strategies for PROTAC Metabolite Identification Studies

1.4.5.1 Selection of Metabolic Models

1.4.5.2 Method Development

1.4.5.3 Structural Characterization of Metabolites

1.4.5.4 Semi-quantificationof Metabolites

1.4.6 Summary

1.5 Evaluation of Drug-Drug Interactions of PROTACs with Efflux Transporters

1.5.1 Introduction

1.5.2 What Is a BCRP Transporter?

1.5.3 How to Evaluate the Inhibition of BCRP by PROTACs

1.5.4 Case Study and Analysis on the Inhibition of BCRP by PROTACs

1.5.5 Customized Assay on PROTACs

1.5.6 Results

1.5.7 Summary

1.6 PROTAC Bioanalysis: Challenges and Strategies

1.6.1 Introduction

1.6.2 Key Points of PROTAC Bioanalysis

1.6.2.1 Optimal MS Parameters

1.6.2.2 Peak Shape Optimization - Peak Splitting

1.6.2.3 Elimination of Nonspecific Binding

1.6.2.4 Controllable Matrix Stability

1.6.3 PROTAC Bioanalysis Process

Chapter 2 Antibody-Drug Conjugates (ADCs)

2.1 General Considerations for Pharmacokinetic Studies of ADCs

2.1.1 Introduction

2.1.2 ADC Drug PK Evaluation

2.1.3 ADC Drug PK Study Strategies.

2.1.4 Relationship Between ADC Payload Release and ADC Toxicity as well as DDI

2.2 Application of Integrated Bioanalysis in ADC DMPK Studies

2.2.1 Introduction

2.2.2 Overall Strategy for ADC Bioanalysis

2.2.2.1 ADC DAR Characterization in Animal Plasma/Serum

2.2.2.2 Quantitative Analysis of ADC-RelatedComponents

2.2.2.3 Anti-therapeuticAntibody (ATA) Investigation of ADCs

2.2.3 ADC DAR Characterization

2.2.3.1 What Is DAR?

2.2.3.2 How to Determine ADC DAR?

2.2.4 Quantitative Bioanalysis of ADC Drug Components in Serum/Plasma or Other Biological Matrices

2.2.4.1 Ligand Binding Assays (LBAs

2.2.4.2 Liquid Chromatography-Mass Spectrometry (LC-MS)

2.2.5 Summary

2.3 Study Models and Bioanalysis Methods for the Payload-Related Metabolite Identification Studies of ADCs

2.3.1 Introduction

2.3.2 Study Models

2.3.3 Analytical Procedures

2.3.4 Case Analysis

2.3.5 Conclusion

2.4 Strategies and Challenges in the Determination of Drug-to-Antibody Ratio (DAR) Values for ADCs

2.4.1 Introduction

2.4.2 Common Conjugation Strategies for ADCs

2.4.3 Structural Characteristics of Cysteine-Conjugated ADCs

2.4.4 Application of High-Resolution Mass Spectrometry (HRMS) in the Detection of DAR Values of ADC Drugs in Biological Samples

2.4.5 Case Study: Analysis of DAR Values for DS-8201

2.4.6 Difficulties and Countermeasures of DAR Value Detection by LC-HRMS

2.4.7 Summary

2.5 In Vitro Stability of ADCs in Blood Matrices

2.5.1 Introduction

2.5.2 In Vitro Stability of ADCs in Plasma

2.5.3 In Vitro Stability of ADCs in Serum

2.5.4 In Vitro Stability of ADCs in Whole Blood

2.5.5 Analyte Selection for ADC In Vitro Stability Study

2.5.6 Summary of In Vitro Stability Studies of Marketed ADCs

2.5.7 Summary

References.

2.6 Application of Radiolabeling Techniques in ADC Pharmacokinetic Studies

2.6.1 Introduction

2.6.2 Radiolabeling Strategies for ADC Drugs

2.6.3 Screening ADCs with Optimal DAR Value at the Drug Discovery and Development Stages

2.6.4 Using the Radiolabeling Technique to Profile the In Vivo PK Characteristics of ADCs at the Application Stage

2.6.5 Summary

Chapter 3 Peptide-Drug Conjugates (PDCs)

3.1 Introduction to PDCs and DMPK Research Strategies

3.1.1 Introduction

3.1.2 Types of PDC Payloads

3.1.3 Advantages of PDCs

3.1.4 PDCs in the Clinical Stage and on the Market

3.1.5 Pharmacokinetic Characteristics of PDCs

3.1.5.1 Absorption

3.1.5.2 Distribution

3.1.5.3 Metabolism

3.1.5.4 Excretion

3.1.6 Challenges in the Development of PDCs

3.1.7 DMPK Strategy for PDCs

3.1.8 Desired Capabilities for PDCs

3.1.8.1 Plasma Protein Binding of PDCs

3.1.8.2 Bioanalysis of PDCs

3.1.8.3 Bioanalysis of Immunogenicity

3.1.8.4 MetID of PDCs

3.1.9 Summary

3.2 Targeted Release Principle and Metabolite Identification Studies of PDCs

3.2.1 Introduction

3.2.2 Metabolic Characteristics of Marketed PDCs

3.2.3 Design Principle of Current Mainstream PDCs and PDCs Under Development

3.2.3.1 Targeted Delivery: Target Receptor Versus Targeted Peptide (Table 3.5)

3.2.3.2 Targeted Release: Payload Release Mechanism

3.2.3.3 Examples of PDCs in the Clinical Stage

3.2.3.4 Other Research Hotspots of PDCs

3.2.4 Study Strategy and Case Sharing for Metabolite Profiling and Identification of PDCs

3.2.4.1 In Vitro and In Vivo Metabolism Research System of PDCs

3.2.4.2 Experimental Method for MetID of PDCs

3.2.4.3 Difficulties and Solutions in Metabolite Analysis

3.2.4.4 Case Study of PDC Metabolite Identification

3.2.5 Summary and Prospect

Chapter 4 Peptide Drugs

4.1 Development, Characteristics, and Pharmacokinetic Research Strategies of Peptide Drugs

4.1.1 Introduction

4.1.2 Characteristics and Advantages of Peptide Drugs

4.1.3 Drug Metabolism and Pharmacokinetics Properties of Peptides

4.1.3.1 Absorption

4.1.3.2 Distribution

4.1.3.3 Metabolism

4.1.3.4 Excretion

4.1.4 DMPK Research Strategy for Peptide Drugs

4.1.5 Summary

4.2 Metabolic Characteristics and Optimization Strategies of Peptide Drugs

4.2.1 Introduction

4.2.2 Metabolic Enzymes and Sites of Peptide Drugs

4.2.2.1 Gastrointestinal Metabolism

4.2.2.2 Hepatic Metabolism

4.2.2.3 Renal Metabolism

4.2.2.4 Blood Metabolism

4.2.2.5 Metabolism in Other Tissues

4.2.2.6 Receptor-MediatedMetabolism

4.2.3 Stability Test of Peptides and Investigation of Metabolic Sites

4.2.4 Methods to Improve the Metabolic Stability of Peptides

4.2.4.1 Substitution of l-AminoAcids for d-AminoAcids or Unnatural Amino Acids

4.2.4.2 N-orC-TerminalModification

4.2.4.3 Cyclization or Bicyclization

4.2.4.4 PEGylation

4.2.4.5 Addition of Ligand Improves Binding to Albumin or IgG

4.2.5 Summary

4.3 Insights into ADME Studies of 37 Approved Therapeutic Peptides: Strategies and Radiolabeling Considerations

4.3.1 Introduction

4.3.2 Current Landscape of Radiolabeled ADME Studies for Therapeutic Peptides

4.3.3 Industry Recommendations for Conducting In Vivo ADME Studies of Therapeutic Peptides

4.3.4 Utilization of Radioisotopes in In Vivo ADME Studies of Therapeutic Peptides and Considerations for Labeling Sites

4.3.5 Case Analysis of Radioactive Tracer Technique in the In Vivo ADME Study of Therapeutic Peptides

4.3.6 Summary

4.4 Challenges and Strategies in the Bioanalysis of Peptide Drugs

4.4.1 Introduction.

4.4.2 Advantages of LC-MS/MS in the Bioanalysis of Peptide Drugs.

Notes:

Description based on publisher supplied metadata and other sources.

ISBN:

1-394-30015-8

1-394-30014-X

OCLC:

1521495105