Drug Metabolism and Pharmacokinetics

Name: Drug Metabolism and Pharmacokinetics | Frontiers, Strategies, and Applications
Brand: Wiley
Price: 246.99 EUR
Availability: OnlineOnly

Frontiers, Strategies, and Applications

Liang Shen AppTec DMPK WuXi(Herausgeber*in)

Wiley (Verlag)

1. Auflage

Erschienen am 28. Mai 2025

579 Seiten

E-Book

PDF mit Adobe-DRM

Systemvoraussetzungen

978-1-394-30014-3 (ISBN)

246,99 €inkl. 7% MwSt.

Systemvoraussetzungen

für PDF mit Adobe-DRM

E-Book Einzellizenz

Als Download verfügbar

Beschreibung

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.

Weitere Details

Weitere Ausgaben

Personen

Inhalt

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
References
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
References
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
References
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
References
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
References
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
References
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
References
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
References
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
References
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
References
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
References
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
References
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
References
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
References
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
4.4.3 Challenges and Strategies in LC-MS/MS Analysis of Peptide Drugs
4.4.3.1 Low Response
4.4.3.2 Nonspecific Binding
4.4.3.3 Endogenous Interference
4.4.3.4 Poor Stability
4.4.4 Case Studies of Peptide Analysis Using LC-MS/MS
4.4.5 Summary
References
Chapter 5 Oligonucleotide (OLIGO) Drugs
5.1 Oligonucleotide Drugs: An Introduction and Overview of Pharmacokinetic Strategies
5.1.1 Introduction
5.1.1.1 Introduction to Oligonucleotide Drugs
5.1.2 Advantages of Oligonucleotide Drug Development
5.1.2.1 Short Development Time
5.1.2.2 Lower Production Cost than Biologics
5.1.2.3 High Success Rate in Research and Development
5.1.3 Challenges in the Pharmacokinetic (PK) Evaluation of Oligonucleotide Drugs
5.1.4 Summary
References
5.2 Delivery Systems of siRNA Drugs and Their Effects on the Pharmacokinetic Profile
5.2.1 Introduction
5.2.2 Delivery Systems for Approved siRNA Drugs
5.2.2.1 Lipid Nanoparticle (LNP) Delivery System
5.2.2.2 N-Acetylgalactosamine(GalNAc) Delivery System
5.2.3 Influence of Delivery Systems on siRNA Drugs' PK Profile
5.2.4 Prospects for the Development of Oligonucleotide Drug Delivery Systems
References
5.3 Bioanalytical Strategies for Oligonucleotide Drugs
5.3.1 Introduction
5.3.1.1 Diverse Chemical Modifications and Delivery Systems
5.3.1.2 Involvement of Multiple Bioanalytical Methods
5.3.1.3 Involvement of Multiple Types of Sample Analysis
5.3.1.4 Immunogenicity
5.3.2 Application of Liquid Chromatography-Mass Spectrometry (LC-MS) in Quantitative Analysis of Oligonucleotides
5.3.2.1 LC-MS/MS for Oligonucleotide Quantification
5.3.2.2 Advantages of LC-MS/MS Technology
5.3.2.3 Challenges of LC-MS/MS Technology
5.3.2.4 Development of Sample Pretreatment Methods
5.3.2.5 LC-MS/MS Method Development
5.3.2.6 Application of HRMS
5.3.2.7 Process for Establishing LC-MS/MS Bioanalytical Methods for Oligonucleotides
5.3.3 Application of Liquid Chromatography Fluorescence (LC-FL) Detection Methods for Quantitative Bioanalysis of Oligonucleotides
5.3.3.1 Principle of the Hybridization-BasedLC-FLAssay Method
5.3.3.2 Advantages of the LC-FLMethod
5.3.3.3 Challenges of Hybridization-BasedLC-FluorescenceDetection Methods
5.3.3.4 Case Study of the Quantitative Analysis of GalNAc-siRNA Conjugates Using an LC-FL Method
5.3.4 Application of LBA Detection Methods for Quantitative Bioanalysis of Oligonucleotides
5.3.4.1 Principle of Ligand Binding Assays (LBAs)
5.3.4.2 Advantages of Ligand Binding Assays (LBAs)
5.3.4.3 Challenges of Ligand Binding Assays (LBAs)
5.3.4.4 Case Study of the Quantitative Analysis of GalNAc-siRNA-Conjugated Oligonucleotides Using LBA Methods
5.3.5 Application of RT-qPCR Detection Methods for Quantitative Bioanalysis of Oligonucleotides
5.3.5.1 Principles of Oligonucleotide Quantitative Analysis Using RT-qPCR
5.3.5.2 Advantages of RT-qPCRfor Oligonucleotide Quantitative Analysis
5.3.5.3 Challenges and Solutions in Using RT-qPCRfor Oligonucleotide Quantification
5.3.5.4 Case Study of the Quantitative Analysis of GalNAc-siRNA Using SL-RT-qPCR
5.3.6 Summary
References
5.4 Oligonucleotide Drugs: Strategies for Metabolism and Metabolite Profiling and Identification
5.4.1 Introduction
5.4.2 Metabolism Studies, Metabolite Profiling, and Identification of Oligonucleotide Drugs
5.4.2.1 Metabolic Enzymes and Metabolic Pathways
5.4.2.2 Strategies and Methods for the Metabolism Study of Oligonucleotides
5.4.2.3 Strategies for In Vitro and In Vivo Metabolism Studies of Oligonucleotides
5.4.2.4 Analytical Methods for Oligonucleotide Metabolite Identification Studies
5.4.3 Challenges and Solutions of Oligonucleotide Analysis
5.4.3.1 Sample Pretreatment
5.4.3.2 LC-MS/MS Sample Analysis
5.4.4 LC-MS/MS Data Analysis and Metabolite Identification
5.4.5 Summary
References
5.5 ADME Characteristics of Approved siRNA and ASO Drugs
5.5.1 Introduction
5.5.2 Overview of siRNA Drugs (Part A)
5.5.2.1 Absorption of Approved siRNA Drugs
5.5.2.2 Distribution of EMA/FDA-ApprovedsiRNA Drugs
5.5.2.3 Metabolism of Approved siRNAs
5.5.2.4 Excretion of Approved siRNAs
5.5.2.5 DDI of Approved siRNAs
5.5.3 Overview of ASO Drugs (Part B)
5.5.3.1 Introduction to ASO Drugs
5.5.3.2 ADME Characteristics of FDA-ApprovedASOs
5.5.3.3 Current Knowledge Gaps and Future Prospects
References
Chapter 6 mRNA-Based Vaccines and Therapeutics
6.1 What Are mRNA Vaccines and Their Future
6.1.1 Introduction
6.1.2 The Overview of Vaccine Development Throughout the COVID-19 Pandemic
6.1.2.1 Pathogenesis of COVID-19
6.1.2.2 Mechanism of Action of Vaccines
6.1.2.3 Analysis of the Advantages and Disadvantages of Different Types of Vaccines
6.1.2.4 Approved and Emergency Authorized COVID-19 Vaccines
6.1.3 Application Prospects for mRNA Vaccines
6.1.3.1 mRNA Vaccines Against Infectious Diseases
6.1.3.2 mRNA Vaccines Against Cancer
6.1.4 Insight into the DMPK Studies for mRNA Vaccine Development
6.1.5 Summary
References
6.2 Strategies for Preclinical PK Evaluation of mRNA-Based Therapeutics: mRNA Vaccines, mRNA Therapeutic Drugs, and Novel Excipients
6.2.1 Introduction
6.2.2 Development History and Mechanism of Action of mRNA Drugs
6.2.3 Types and Properties of mRNA-Based Therapeutics: mRNA Vaccines and mRNA Therapeutic Drugs
6.2.4 Insights into PK Studies of mRNA-Based Therapeutics
6.2.5 PK Studies and Case Analysis of mRNA-Based Therapeutics
6.2.6 Strategies for Preclinical PK Assessment of mRNA Vaccines, mRNA Therapeutic Drugs, and Novel Excipients
References
6.3 FDA-Approved mRNA Vaccines: Interpretation of Preclinical Pharmacokinetic (PK) Data
6.3.1 Introduction
6.3.2 Interpretation of Preclinical PK Data for BNT162b2 (COMIRNATY)
6.3.2.1 Biodistribution Study of BNT162b2 mRNA
6.3.2.2 In Vivo Pharmacokinetic (PK) Study of ALC-0315 and ALC-0159 in Rats
6.3.2.3 In Vivo Distribution Study of BNT162b2 LNP
6.3.2.4 In Vitro and In Vivo Metabolic Studies of ALC-0315 and ALC-0159
6.3.3 Interpretation of Preclinical PK Data for mRNA Vaccine: mRNA-1273
6.3.3.1 Biodistribution of mRNA-1273mRNA
6.3.3.2 PK, Distribution, Metabolism, and Excretion of Lipids
References
6.4 Application of Integrative Bioanalysis in mRNA Drugs DMPK Research
6.4.1 Introduction
6.4.2 Contents and Platforms of mRNA Integration Bioanalysis
6.4.2.1 mRNA Bioanalytical Platform
6.4.2.2 Novel Lipid Bioanalysis
6.4.2.3 Bioanalysis of Expressed Proteins
6.4.2.4 Immunogenicity Analysis
6.4.2.5 Analysis of mRNA Drug Biomarkers
6.4.3 Conclusion
References
Section II Pharmacokinetic and Metabolism Studies of Therapeutics for Disease Areas
Chapter 7 Ophthalmic Drugs
7.1 Ophthalmic Drugs: Preclinical Pharmacokinetic (PK) Profiles and Research Strategies
7.1.1 Introduction
7.1.2 Physiological Structure of the Eye
7.1.3 Routes for Ocular Drug Delivery
7.1.4 Barriers to Ocular Drug Delivery
7.1.5 Strategies for Ophthalmic Preclinical Pharmacokinetics Studies
7.1.5.1 Selection of Animal Species in Ophthalmic Preclinical Pharmacokinetics Studies
7.1.5.2 Pharmacokinetics Models in Ophthalmic Preclinical Pharmacokinetics Studies
7.1.5.3 Strategies for Preclinical Pharmacokinetics Studies
7.1.6 Case Study
7.1.7 Summary
References
7.2 In Vitro Methods and Significance of Drug-Melanin Binding
7.2.1 Introduction
7.2.2 Definition and Function of Melanin
7.2.3 Effects of Drug Binding to Melanin
7.2.3.1 Pharmacological Effects of Drug Binding to Melanin
7.2.3.2 Potential Adverse Effects of Drug-Melanin Binding
7.2.4 Research Methods for Drug Binding to Melanin In Vitro
7.2.4.1 Equilibrium Dialysis Method
7.2.4.2 Centrifugation Method
7.2.5 Integrated Application of In Vitro Melanin-Drug Binding Models in Drug Research and Development
7.2.6 Summary
References
7.3 Preclinical Pharmacokinetic Research of Ophthalmic Drugs: In Vitro and In Vivo Research Methods
7.3.1 Introduction
7.3.2 In Vitro Assays
7.3.2.1 In Vitro Ophthalmic Permeability Study
7.3.3 In Vivo Assays
7.3.3.1 Ocular Administration Routes and Their Advantages and Disadvantages
7.3.3.2 Ocular Tissue Collection and Sample Processing
7.3.3.3 Ophthalmic Sample Processing
7.3.3.4 Ophthalmic Examination
7.3.3.5 Preclinical Ophthalmic Formulations
7.3.4 Others
References
7.4 In Vivo Bioanalysis in Ophthalmology: Challenges and Strategies
7.4.1 Introduction
7.4.2 Challenges and Strategies of Ophthalmic Bioanalysis After Ocular Drug Administration
7.4.2.1 Low Exposure of Ocular Drugs in Plasma
7.4.2.2 Nonspecific Binding Issues of Ocular Drugs
7.4.2.3 Difficulty in Acquiring an Authentic Blank Matrix
7.4.3 Challenges and Strategies for Tear Sample Bioanalysis of Ocular Drugs
7.4.3.1 Capillary Tube Method
7.4.3.2 Filter Paper Strip Method
7.4.4 Challenges and Strategies in Drug-Melanin Binding
7.4.5 Summary
References
Chapter 8 Respiratory Drugs
8.1 Inhaled Medications: Challenges and Strategies for Preclinical In Vivo Pharmacokinetic Studies
8.1.1 Introduction
8.1.2 Challenges in the Development of Inhaled Drugs
8.1.2.1 Increasing Lung Deposition Rates
8.1.2.2 Prolonging Lung Retention
8.1.3 Choice of Inhalation Device
8.1.4 Inhaled Delivery Techniques and Study Design for Preclinical In Vivo PK Studies
8.1.4.1 Selection of Inhalation Devices for Preclinical PK Studies
8.1.4.2 Preclinical Study Design for Inhaled Delivery
8.1.4.3 Sampling Design
8.1.4.4 Data Analysis
8.1.5 Preclinical Inhaled Delivery Platform
8.1.6 Summary
References
8.2 Chronic Obstructive Pulmonary Disease (COPD): Analysis of PK Profiles of Approved Inhaled Medications
8.2.1 Introduction
8.2.2 Overview of Medications for Stable Chronic Obstructive Pulmonary Disease (COPD)
8.2.3 What Is Tiotropium (LAMA) and Its Structural Characteristics?
8.2.4.1 Absorption of Tiotropium
8.2.4.2 Distribution of Tiotropium
8.2.4.3 Metabolism of Tiotropium
8.2.4.4 Clearance (Excretion) of Tiotropium
8.2.4.5 Drug Interactions (DDIs) of Tiotropium
8.2.4 PK Profile of Tiotropium
8.2.4.1 Absorption of Tiotropium
8.2.4.2 Distribution of Tiotropium
8.2.4.3 Metabolism of Tiotropium
8.2.4.4 Clearance (Excretion) of Tiotropium
8.2.4.5 Drug Interactions (DDIs) of Tiotropium
8.2.5 Drug Combination: Tiotropium (LAMA)/Olodaterol Hydrochloride (LABA)
8.2.6 Summary
References
Chapter 9 Transdermal and Topical Drugs
9.1 Preclinical Pharmacokinetic Strategies for Topical and Transdermal Drug Products
9.1.1 Introduction
9.1.2 Drug Permeation and Research Method of Topical and Transdermal Drugs
9.1.3 DMPK Research Strategies in the Development of Topical and Transdermal Drug Products
9.1.3.1 General Considerations
9.1.3.2 Special Considerations for Topical Dermatological Products
9.1.3.3 Special Considerations for Transdermal Products
9.1.4 Summary
References
9.2 Application of In Vitro Permeation Test (IVPT) for the Development of Transdermal and Topical Drugs
9.2.1 Introduction
9.2.2 Applications of In Vitro Permeation Test (IVPT)
9.2.3 Relevant Guidance Requirements
9.2.4 How to Choose and Build Suitable Skin Models
9.2.5 Commonly Used Apparatus and Parameter Configuration
9.2.6 IVPT Validation Study
9.2.7 Summary
References
9.3 Evaluation of Transdermal Drugs in In Vivo Pharmacokinetic Studies
9.3.1 Introduction
9.3.2 Species Selection and Evaluation
9.3.3 Comparison of Administration Methods Across Different Skin Models
9.3.4 Collection and Processing of Skin Samples
References
9.4 Challenges and Bioanalytical Strategies for Quantitative Detection of In Vivo Biological Samples from Skin Administration
9.4.1 Introduction
9.4.2 Strategies for Quantitative Detection of Biological Samples
9.4.2.1 Plasma Sample Analysis
9.4.2.2 Skin Tissue Sample Analysis
9.4.3 Summary
References
Chapter 10 Central Nervous System Drugs
10.1 Overview of Pharmacokinetic Research Strategies for Central Nervous System Drugs
10.1.1 Introduction
10.1.2 Brain Barrier
10.1.3 The Way Substances Enter the Blood-Brain Barrier
10.1.3.1 How to Improve Permeability of Small Molecules to the Blood-BrainBarrier
10.1.4 Brain Permeability Evaluation Assays
10.1.4.1 In Vitro Permeability and Transporter Evaluation Assays
10.1.4.2 In Vivo Brain Penetration Evaluation Models
10.1.5 Common Misconceptions in Central Nervous System Drugs Evaluations and Development
10.1.6 Summary
References
10.2 Application of Microdialysis in Pharmacokinetic Research
10.2.1 Introduction
10.2.1.1 Background
10.2.1.2 Introduction of Microdialysis Technology
10.2.1.3 Microdialysis System Device
10.2.1.4 Microdialysis Application
10.2.2 Microdialysis Case Sharing
10.2.2.1 Brain Microdialysis
10.2.2.2 Skin Microdialysis
10.2.2.3 Renal Microdialysis
10.2.3 Summary
References
10.3 Central Nervous System Drug Development Techniques: Exploration and Application in Large Animal Pharmacokinetics
10.3.1 Introduction
10.3.2 Application of Cisterna Magna Cannulation (CMC) Animal Models in IV Administration
10.3.3 Administration Methods That Bypass the Blood-Brain Barrier: Lateral Ventricle and Intrathecal Injection
10.3.3.1 Intra-cerebroventricularInjection (ICV)
10.3.3.2 Intrathecal Injection (IT)
References
Section III Research Strategies, Methods, and Applications in Pharmacokinetics and Metabolism
Chapter 11 In Vitro ADME
11.1 Rapid Determination of Lipophilicity: Establishment and Application of Reversed-Phase High-Performance Liquid Chromatography (RP-HPLC)
11.1.1 Introduction
11.1.2 Characterizing Lipophilicity Based on Log P Values
11.1.3 Methods for Determining Log P
11.1.4 Establishing RP-HPLC Methods for Lipophilicity Determination
11.1.4.1 Reversed-PhaseHigh-PerformanceLiquid Chromatography Lipophilicity
11.1.4.2 Reversed-PhaseHigh-PerformanceLiquid Chromatography Lipophilicity
11.1.5 Summary
References
11.2 Plasma Protein Binding Measurement of High Protein-Binding Drugs: Principles and Advantages of the Flux Dialysis Method
11.2.1 Introduction
11.2.2 How to Measure Plasma Protein Binding?
11.2.3 Principles and Methods of Flux Dialysis
11.2.4 Kinetic Modeling of the Flux Dialysis Methods
11.2.5 Assay Validation Results
11.2.6 Advantages of the Flux Dialysis Method
11.2.7 Derivation Process of Several Formulas
References
11.3 How to Measure the Metabolic Clearance of Slowly Metabolized Compounds
11.3.1 Introduction
11.3.2 In Vitro Metabolic Stability Study Models
11.3.3 The Plated Hepatocyte Method
11.3.3.1 Validation of the Plated Hepatocyte Method
11.3.4 Suspension Hepatocyte Relay Method
11.3.4.1 Assay Principle and Protocol
11.3.4.2 Results
11.3.5 Practical Application of Metabolic Stability Models
11.3.6 Summary
References
11.4 Non-P450 Enzyme-Mediated Metabolism and In Vitro Assessment Method
11.4.1 Introduction
11.4.2 The Importance of Non-P450 Enzymes
11.4.3 Aldehyde Oxidase (AO) and Xanthine Oxidase (XO)
11.4.4 Aldo-Keto Reductase (AKR)
11.4.5 Flavin Monooxygenase (FMO)
11.4.6 Monoamine Oxidase (MAO)
11.4.7 The Decision Tree of Non-P450 Oxidase-Mediated Drug Metabolism
11.4.8 Conclusion
References
11.5 In Vitro Evaluation of CYP450 Time-Dependent Inhibition (TDI): A Novel Area Under the Curve Shift (AUC Shift) Approach
11.5.1 Introduction
11.5.2 Limitations of the Traditional Approach for Evaluating Time-Dependent CYP Inhibition
11.5.3 Establishment of the AUC Shift Approach for Evaluating CYP450 TDI
11.5.4 Applications of the AUC Shift Approach for Evaluating TDI Potentials
11.5.5 Summary
Reference
11.6 Cytochrome P450 Reaction Phenotyping for Four Additional CYPs: Why and How
11.6.1 Introduction
11.6.2 Why Do We Need to Establish Additional Human CYP Reaction Phenotyping Assays?
11.6.2.1 The requirements of CYP enzyme research scope in FDA Guidance
11.6.2.2 Additional enzymes play a major role in the metabolism of a drug
11.6.3 When Should We Conduct the Additional Human CYP Reaction Phenotyping Assays?
11.6.4 How Do We Establish These Additional Cytochrome P450 Reaction Phenotyping Assays?
11.6.5 Results of the Additional Human CYP Reaction Phenotyping Assays
11.6.6 Application of the Additional Human CYP Reaction Phenotyping Assays
11.6.7 Summary
References
11.7 Overview of the Application of the Na+-Taurocholate Cotransporting Polypeptide (NTCP) in Drug Development
11.7.1 Introduction
11.7.2 Structure of Na+-Taurocholate Cotransporting Polypeptide
11.7.3 Function of Na+-Taurocholate Cotransporting Polypeptide and Its Application in Drug Development
11.7.3.1 NTCP and Hepatitis Viruses
11.7.3.2 NTCP and Bile Acid (Salt) Circulation
11.7.4 In Vitro Na+-Taurocholate Cotransporting Polypeptide Model and Its Main Applications
11.7.5 Summary
References
11.8 The Significance and In Vitro Methods of Lysosomal Trapping in Drug Development
11.8.1 Introduction
11.8.2 Overview of Lysosomes
11.8.2.1 Structure of Lysosomes
11.8.2.2 Function of Lysosomes
11.8.3 Mechanism of Lysosomal Trapping and Its Effect on Absorption, Distribution, Metabolism, and Excretion (ADME)
11.8.3.1 Mechanism of Lysosomal Trapping
11.8.3.2 Effect of Lysosomal Trapping in Absorption, Distribution, Metabolism, and Excretion (ADME)
11.8.4 Application of Lysosomal Trapping
11.8.4.1 Lysosomal Membrane Permeabilization-Induced Cell Death
11.8.5 In Vitro Methods for Lysosomal Trapping
11.8.5.1 Direct Method (LC-MS/MS Analysis)
11.8.5.2 Indirect Method (Accumulation of Lyso Tracker Probes)
11.8.6 Establishment of Lysosomal Trapping Assay
11.8.6.1 Transwell System
11.8.6.2 Plated-CellSystem
11.8.6.3 Comparison of the Transwell System and the Plated-CellSystem
11.8.7 Summary
References
Chapter 12 In Vivo Pharmacokinetics
12.1 Enhancing the Bioavailability of Poorly Soluble Compounds: Strategies for Formulation Optimization in Preclinical Studies
12.1.1 Introduction
12.1.2 Poorly Soluble Compounds and Why Are They Prevalent?
12.1.3 How to Improve In Vivo Absorption of Poorly Soluble Compounds?
12.1.4 Selecting Appropriate Solvents
12.1.5 Particle Size Reduction to Increase Dissolution Rate
12.1.6 Summary
References
12.2 Self-Emulsifying Drug Delivery System (SEDDS): Enhancing the Oral Absorption of Lipophilic Compounds
12.2.1 Introduction
12.2.2 Components and Advantages of the Self-Emulsifying Drug Delivery System
12.2.2.1 Components of the Self-EmulsifyingDrug Delivery System
12.2.2.2 Advantages of the Self-EmulsifyingDrug Delivery System
12.2.3 Application of Self-Emulsifying Drug Delivery System
12.2.4 Formulation Design and Pharmacokinetic (PK) Study Process of Self-Emulsifying Drug Delivery System
12.2.4.1 Developmental Process
12.2.4.2 Formulation Design
12.2.4.3 Methodology for the In Vitro Evaluation of Self-Emulsifying Drug Delivery
12.2.4.4 Factors Influencing Animal Experiments and Strategies
12.2.5 Summary
References
12.3 Application of Anesthetics in Rodent Pharmacokinetic Study
12.3.1 Introduction
12.3.2 Introduction to Anesthesia
12.3.2.1 Background of Anesthesia
12.3.2.2 Introduction to Rodent Anesthesia Program
12.3.3 Drug-Drug Interaction (DDI) During Anesthesia
12.3.4 Summary
References
12.4 Application of In Situ Single-Pass Intestinal Perfusion (SPIP) Model in the Study of Intestinal Absorption of Oral Drugs
12.4.1 Introduction
12.4.2 Influencing Factors and Common Research Methods of Intestinal Absorption of Drugs
12.4.3 SPIP Model Establishment and Validation Data
12.4.3.1 SPIP Overview and Model Establishment Method
12.4.3.2 Introduction of SPIP Parameters
12.4.3.3 Validation Data
12.4.4 Applications of SPIP
12.4.4.1 Biowaiver and Permeability Classification Identification
12.4.4.2 Study on Absorption and Mechanism of Different Intestinal Segments
12.4.5 Summary
References
12.5 Application of Liver Biopsy in Preclinical Pharmacokinetic Studies
12.5.1 Introduction
12.5.2 Introduction of Liver Biopsy
12.5.3 Risks and Experiences of Liver Biopsy Techniques
12.5.4 Cases and Advantages
12.5.5 Summary
References
Chapter 13 Metabolite Profiling and Identification
13.1 High-Throughput Identification of Drug Metabolic Soft Spots for Lead Optimization
13.1.1 Introduction
13.1.2 The Importance of Conducting Metabolic Soft Spot Identification Studies
13.1.3 Strategies for Drug Design Based on Metabolism
13.1.3.1 Blocking Metabolic Sites
13.1.3.2 Backbone Modification
13.1.3.3 "Open ring" and "Snap ring" Strategies
13.1.3.4 Prodrug Modification
13.1.4 How to Conduct Metabolic Soft Spot Identification Research with High Throughput
13.1.5 Conclusion
References
13.2 Application of Metabolite Biosynthesis Technology in the Precise Identification of Drug Metabolite Structures
13.2.1 Introduction
13.2.2 Strategy for Precise Identification of Drug Metabolite Structures
13.2.3 Introduction of Metabolite Biosynthesis Technology
13.2.3.1 In Vivo Animal Transformation
13.2.3.2 Cellular or Subcellular Components Transformation
13.2.3.3 Recombinase Transformation
13.2.3.4 Microbial Transformation
13.2.4 Biosynthesis and Structure Identification Process
13.2.5 Case of Metabolite Biosynthesis and Structure Identification
13.2.6 Summary
References
13.3 Detection of Reactive Metabolites and Its Application in Drug Research and Development
13.3.1 Introduction
13.3.2 Drug Safety Concerns Arising from Reactive Metabolites
13.3.3 Common Pharmacovigilance Structure
13.3.4 Detection Methods and Technology Platforms for Reactive Metabolites
13.3.5 Application of Reactive Metabolite Studies in Drug Development
13.3.6 Summary
References
13.4 UGT Enzymes: Metabolite Identification and Toxicity Assessment Strategies
13.4.1 Introduction
13.4.2 Mechanism of Toxicity by Acyl Glucuronide Metabolites
13.4.3 Identification of Acyl Glucuronide Metabolites
13.4.4 Assessment of the Possible Risks of Acyl Glucuronide Metabolites
13.4.5 Strategies for Assessing Safety Risks Due to Glucuronide Metabolites
13.4.6 Summary
References
13.5 Insights into the R&D Strategies of Deuterated Drugs from the Drug Metabolism Perspective
13.5.1 Introduction
13.5.2 What Deuterated Drugs Are
13.5.3 R&D Status of Deuterated Drugs
13.5.4 Benefits of Deuteration
13.5.5 Uncertainty of Deuteration Strategy
13.5.6 Summary
References
Chapter 14 Radiolabeled In Vivo ADME Studies
14.1 Placental Transfer and Milk Excretion Studies Based on Radioactive Tracer Technique
14.1.1 Introduction
14.1.2 Overview of Medication Used in Pregnant and Lactating Women
14.1.3 The Transport Mechanism of Drugs in the Placenta and Mammary Gland
14.1.4 Application of Radioactive Tracer Technique to Study Placental Transfer and Milk Excretion
14.1.4.1 Placental Transfer Study
14.1.4.2 Milk Excretion Studies
14.1.5 Summary
References
14.2 Visualization of Tissue Distribution: Quantitative Whole-Body Autoradiography (QWBA)
14.2.1 Introduction
14.2.2 Advantages of QWBA Over Traditional Tissue Distribution
14.2.3 When to Conduct a QWBA Study
14.2.4 How to Design a QWBA Study?
14.2.5 Application Cases for QWBA
14.2.6 QWBA Is the Gold Standard of Tissue Distribution Study
References
14.3 Preclinical and Clinical Research Strategy for Human Radiolabeled Mass Balance Studies
14.3.1 Introduction
14.3.2 Test Articles Requiring Human Radiolabeled Mass Balance Study
14.3.3 Considerations for Designing Mass Balance Studies
14.3.3.1 Administered radioactivity dose and investigational drug dose
14.3.3.2 Route of administration and formulation of the investigational drug
14.3.3.3 Sample collection and handling
14.3.3.4 Reporting requirements
14.3.4 Considerations for Unconventional Mass Balance Studies
14.3.5 Research Strategy at Clinical Stages
14.3.6 Research Strategy at the Preclinical Stage
References
14.4 Key Considerations for Conducting Radiolabeled Human Mass Balance Studies
14.4.1 Introduction
14.4.2 What Is the Implementation of Mass Balance Studies for Marketed New Drugs?
14.4.3 How to Select the Study Methods for Human Mass Balance?
14.4.3.1 Conventional radioactive tracer technique -liquid scintillation counter (LSC)
14.4.3.2 Micro-radioactivetracer technique -acceleratormass spectrometry (AMS)
14.4.3.3 Liquid chromatography-tandemmass spectrometry (LC-MS
14.4.3.4 Fluorine-19nuclear magnetic resonance (19F-NMR)
14.4.4 When to Carry Out Radiolabeled Human Mass Balance Studies?
14.4.5 How to Select Nuclide and Administered Radioactivity?
14.4.6 Considerations on Administration Frequency, Dosage, and Dose Route
14.4.7 How to Select Volunteers?
14.4.8 What About Insufficient Recovery?
14.4.9 What Are the Other Considerations of Guidelines?
References
Chapter 15 Bioanalysis
15.1 Application of High-Throughput Mass Spectrometry in In Vitro ADME
15.1.1 Introduction
15.1.2 Mass Spectrometry-Based High-Throughput Screening Analysis Technology
15.1.2.1 Cassette Technology
15.1.2.2 Multiplex LC Technology
15.1.2.3 Online Solid-PhaseExtraction (Online SPE) Technology
15.1.2.4 Acoustic Ejection Mass Spectrometry
15.1.3 Practice of HTS MS in DMPK
15.1.3.1 Case Study I: Online SPE-BasedRapid MS Analysis of 5-Aminolevulinic Acid (5-ALA
15.1.3.2 Case Study II: Library Compounds QC Based on AEMS
15.1.4 Summary
References
15.2 Application and Detection Techniques of Biomarkers in Drug Development
15.2.1 Introduction
15.2.2 Application of Biomarkers in Drug Development
15.2.3 Biomarker Detection Technologies and Testing Methods
15.2.3.1 Biomarker Detection Technologies
15.2.3.2 Biomarker Detection Methods
15.2.4 Summary
References
15.3 Analysis and Detection Strategies of Liposome Drugs in Biological Samples
15.3.1 Introduction
15.3.2 Establishment of Determination Methods for Liposomal Drugs in Biological Samples
15.3.3 Summary
References
15.4 DMPK Research Strategies of Chiral Drugs Based on UPCC-MS/MS and UPLC-MS/MS Dual Analytical Platforms
15.4.1 Introduction
15.4.1.1 Different Enantiomers, Different Functions
15.4.2 Regulations for Chiral Drugs
15.4.3 Chiral Drugs Pharmacokinetic Research Strategy
15.4.4 Challenge for Chiral Drug Analysis in Biological Samples
15.4.4.1 Enantiomers' Properties
15.4.4.2 Chromatographic Separation Difficulties
15.4.4.3 Other Bioanalytical Challenges
15.4.5 Chiral Drug Bioanalysis Approach
15.4.6 Chiral Drug Bioanalysis Platforms
15.4.7 Summary
References
15.5 Integrated Qualitative and Quantitative Bioanalysis of Intact Protein with High-Resolution Mass Spectrometry
15.5.1 Introduction
15.5.2 Basic Techniques and Methods
15.5.2.1 Immunoaffinity Capture
15.5.2.2 Front-EndSeparation Technique
15.5.2.3 Ionization Technique
15.5.2.4 High-ResolutionMass Spectrometry
15.5.3 Case Sharing
15.5.3.1 Study on Pharmacokinetics of Monoclonal Antibody by Intact Protein Profiling
15.5.3.2 Intact Protein Profiling for Bioanalysis of Antibody-Conjugated Drugs
15.5.4 Conclusion
References
15.6 Nanobodies: Kinetics and Bioanalytical Strategies
15.6.1 Introduction
15.6.2 Structure and Function of Nanobodies
15.6.3 Kinetic Properties and Optimization Strategies of Nanobodies
15.6.4 Industry R&D Progress of Nanobodies
15.6.4.1 Bioanalytical Strategies for Nanobodies
15.6.5 Summary
References
Index
EULA

Systemvoraussetzungen

Als PDF speichern Als Link merken