Full Description
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
About the Editors ix
Preface xi
Acknowledgments xiii
Section I Novel Drug Modalities: Advancements and Their Pharmacokinetic Strategies 1
1 Proteolysis-Targeting Chimeras (PROTACs) 3
1.1 An Overview of PROTAC Technology and Drug Metabolism and Pharmacokinetic (DMPK) Research Strategies 3
1.2 Strategies to Improve the Oral Bioavailability of PROTACs 9
1.3 Research on PROTAC Metabolism: Strategies and Main Approaches 17
1.4 Metabolic Characteristics and Research Strategies for Metabolite Identification of PROTACs 23
1.5 Evaluation of Drug-Drug Interactions of PROTACs with Efflux Transporters 40
1.6 PROTAC Bioanalysis: Challenges and Strategies 44
2 Antibody-Drug Conjugates (ADCs) 49
2.1 General Considerations for Pharmacokinetic Studies of ADCs 49
2.2 Application of Integrated Bioanalysis in ADC DMPK Studies 53
2.3 Study Models and Bioanalysis Methods for the Payload-Related Metabolite Identification Studies of ADCs 62
2.4 Strategies and Challenges in the Determination of Drug-to-Antibody Ratio (DAR) Values for ADCs 67
2.5 In Vitro Stability of ADCs in Blood Matrices 78
2.6 Application of Radiolabeling Techniques in ADC Pharmacokinetic Studies 86
3 Peptide-Drug Conjugates (PDCs) 95
3.1 Introduction to PDCs and DMPK Research Strategies 95
3.2 Targeted Release Principle and Metabolite Identification Studies of PDCs 102
4 Peptide Drugs 115
4.1 Development, Characteristics, and Pharmacokinetic Research Strategies of Peptide Drugs 115
4.2 Metabolic Characteristics and Optimization Strategies of Peptide Drugs 123
4.3 Insights into ADME Studies of 37 Approved Therapeutic Peptides: Strategies and Radiolabeling Considerations 132
4.4 Challenges and Strategies in the Bioanalysis of Peptide Drugs 138
5 Oligonucleotide (OLIGO) Drugs 147
5.1 Oligonucleotide Drugs: An Introduction and Overview of Pharmacokinetic Strategies 147
5.2 Delivery Systems of siRNA Drugs and Their Effects on the Pharmacokinetic Profile 152
5.3 Bioanalytical Strategies for Oligonucleotide Drugs 157
5.4 Oligonucleotide Drugs: Strategies for Metabolism and Metabolite Profiling and Identification 183
5.5 ADME Characteristics of Approved siRNA and ASO Drugs 193
6 mRNA-Based Vaccines and Therapeutics 213
6.1 What Are mRNA Vaccines and Their Future 213
6.2 Strategies for Preclinical PK Evaluation of mRNA-Based Therapeutics: mRNA Vaccines, mRNA Therapeutic Drugs, and Novel Excipients 221
6.3 FDA-Approved mRNA Vaccines: Interpretation of Preclinical Pharmacokinetic (PK) Data 230
6.4 Application of Integrative Bioanalysis in mRNA Drugs DMPK Research 235
Section II Pharmacokinetic and Metabolism Studies of Therapeutics for Disease Areas 243
7 Ophthalmic Drugs 245
7.1 Ophthalmic Drugs: Preclinical Pharmacokinetic (PK) Profiles and Research Strategies 245
7.2 In Vitro Methods and Significance of Drug-Melanin Binding 253
7.3 Preclinical Pharmacokinetic Research of Ophthalmic Drugs: In Vitro and In Vivo Research Methods 259
7.4 In Vivo Bioanalysis in Ophthalmology: Challenges and Strategies 269
8 Respiratory Drugs 275
8.1 Inhaled Medications: Challenges and Strategies for Preclinical In Vivo Pharmacokinetic Studies 275
8.2 Chronic Obstructive Pulmonary Disease (COPD): Analysis of PK Profiles of Approved Inhaled Medications 285
9 Transdermal and Topical Drugs 291
9.1 Preclinical Pharmacokinetic Strategies for Topical and Transdermal Drug Products 291
9.2 Application of In Vitro Permeation Test (IVPT) for the Development of Transdermal and Topical Drugs 300
9.3 Evaluation of Transdermal Drugs in In Vivo Pharmacokinetic Studies 308
9.4 Challenges and Bioanalytical Strategies for Quantitative Detection of In Vivo Biological Samples from Skin Administration 313
10 Central Nervous System Drugs 317
10.1 Overview of Pharmacokinetic Research Strategies for Central Nervous System Drugs 317
10.2 Application of Microdialysis in Pharmacokinetic Research 329
10.3 Central Nervous System Drug Development Techniques: Exploration and Application in Large Animal Pharmacokinetics 337
Section III Research Strategies, Methods, and Applications in Pharmacokinetics and Metabolism 343
11 In Vitro ADME 345
11.1 Rapid Determination of Lipophilicity: Establishment and Application of Reversed-Phase High-Performance Liquid Chromatography (RP-HPLC) 345
11.2 Plasma Protein Binding Measurement of High Protein-Binding Drugs: Principlesand Advantages of the Flux Dialysis Method 351
11.3 How to Measure the Metabolic Clearance of Slowly Metabolized Compounds 358
11.4 Non-P450 Enzyme-Mediated Metabolism and In Vitro Assessment Method 365
11.5 In Vitro Evaluation of CYP450 Time-Dependent Inhibition (TDI): A Novel Area Under the Curve Shift (AUC Shift) Approach 377
11.6 Cytochrome P450 Reaction Phenotyping for Four Additional CYPs: Why and How 383
11.7 Overview of the Application of the Na + -Taurocholate Cotransporting Polypeptide (NTCP) in Drug Development 388
11.8 The Significance and In Vitro Methods of Lysosomal Trapping in Drug Development 397
12 In Vivo Pharmacokinetics 407
12.1 Enhancing the Bioavailability of Poorly Soluble Compounds: Strategies for Formulation Optimization in Preclinical Studies 407
12.2 Self-Emulsifying Drug Delivery System (SEDDS): Enhancing the Oral Absorption of Lipophilic Compounds 414
12.3 Application of Anesthetics in Rodent Pharmacokinetic Studies 420
12.4 Application of In Situ Single-Pass Intestinal Perfusion (SPIP) Model in the Study of Intestinal Absorption of Oral Drugs 428
12.5 Application of Liver Biopsy in Preclinical Pharmacokinetic Studies 436
13 Metabolite Profiling and Identification 441
13.1 High-Throughput Identification of Drug Metabolic Soft Spots for Lead Optimization 441
13.2 Application of Metabolite Biosynthesis Technology in the Precise Identification of Drug Metabolite Structures 449
13.3 Detection of Reactive Metabolites and Its Application in Drug Research and Development 456
13.4 UGT Enzymes: Metabolite Identification and Toxicity Assessment Strategies 466
13.5 Insights into the R&D Strategies of Deuterated Drugs from the Drug Metabolism Perspective 472
14 Radiolabeled In Vivo ADME Studies 479
14.1 Placental Transfer and Milk Excretion Studies Based on Radioactive Tracer Technique 479
14.2 Visualization of Tissue Distribution: Quantitative Whole-Body Autoradiography (qwba) 486
14.3 Preclinical and Clinical Research Strategy for Human Radiolabeled Mass Balance Studies 490
14.4 Key Considerations for Conducting Radiolabeled Human Mass Balance Studies 496
15 Bioanalysis 503
15.1 Application of High-Throughput Mass Spectrometry in In Vitro ADME 503
15.2 Application and Detection Techniques of Biomarkers in Drug Development 510
15.3 Analysis and Detection Strategies of Liposome Drugs in Biological Samples 516
15.4 DMPK Research Strategies of Chiral Drugs Based on UPCC-MS/MS and UPLC-MS/MS Dual Analytical Platforms 523
15.5 Integrated Qualitative and Quantitative Bioanalysis of Intact Protein with High-Resolution Mass Spectrometry 530
15.6 Nanobodies: Kinetics and Bioanalytical Strategies 540
Index 549
