Drug Metabolism and Pharmacokinetics E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Sprache: Englisch

Seitenzahl: 923

Veröffentlichungsjahr: 2025

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.

Leseprobe

Drug Metabolism and Pharmacokinetics

Frontiers, Strategies, and Applications

Edited by

Liang Shen

Vice President, Head of DMPK Department

WuXi AppTec

Copyright © 2025 by WuXi AppTec DMPK.All rights reserved.

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

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About the Editors

Liang ShenPh.D., Vice President, Head of DMPK Department, WuXi AppTecDr. Liang Shen has more than 20 years of experience in drug metabolism and pharmacokinetics (DMPK), toxicology, clinical pharmacology, and precision medicine. Dr. Shen has published or co‐authored over 50 research articles and has led or participated in the compilation or translation of four books in drug discovery or DMPK field. His extensive experience in drug discovery, preclinical candidate (PCC) profiling, and investigational new drug (IND) submissions has successfully supported multiple pipelines in the fields of oncology, immuno‐oncology, immunology, metabolic diseases, infectious diseases, central nervous system (CNS), and cardiovascular diseases to proof‐of‐concept at the early clinical stage. He received his PhD degree from the University of Georgia in the United States.

WuXi AppTec DMPKAs a global company with operations across Asia, Europe, and North America, WuXi AppTec provides a broad portfolio of R&D and manufacturing services that enable the global pharmaceutical and life sciences industry to advance discoveries and deliver groundbreaking treatments to patients. The Department of DMPK of WuXi AppTec was established in 2006 and offers in vivo and in vitro DMPK services covering stages from discovery screening to preclinical development and clinical studies. With research facilities located in the United States (New Jersey) and China (Shanghai, Suzhou, Nanjing, and Nantong), the department has supported thousands of investigational new drug (IND) and new drug applications (NDA). The services of WuXi AppTec DMPK include in vitro absorption, distribution, metabolism, excretion (ADME) studies, in vivo pharmacokinetic studies, metabolite profiling and identification studies, synthesis of radiolabeled compounds, radiolabeled ADME including human absorption, metabolism, and excretion (AME) studies, and bioanalysis. For more information, visit dmpkservice.wuxiapptec.com.

Preface

Drug metabolism and pharmacokinetics (DMPK) studies involve characterizing the absorption, distribution, metabolism, and excretion (ADME) properties of compounds. This aids in identifying drugs with enhanced safety and potency, minimizing the risk of drug‐drug interactions, and establishing a foundation for determining clinical dosage and frequency. The advancement of the pharmaceutical industry and the emergence of novel drug modalities have presented new challenges and opportunities for drug development, driving continuous innovation and progress in DMPK research.

This book is written by a team of scientists specializing in DMPK research from the DMPK Department of WuXi AppTec. The team was established in 2006 and has successfully supported thousands of investigational new drug (IND) applications globally. Drawing on a wealth of extensive practical experience and theoretical research, this book encapsulates the most recent advancements and illustrative applications. It is intended for pharmacy students, pharmaceutical industry researchers, and DMPK scientists, especially those exploring novel drug modalities.

Sixty‐eight relatively independent yet interconnected articles compose this book, 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 in the book for novel drug modalities, and therapeutics in different disease areas. Furthermore, 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.

The book is divided into three sections. Section I explores the pharmacokinetic strategies and research advancements in novel drug modalities, including proteolysis‐targeting chimeras (PROTACs), antibody‐drug conjugates (ADCs), peptide‐drug conjugates (PDCs), peptide drugs, oligonucleotide (OLIGO) drugs, and mRNA‐based vaccines and therapeutics. The mechanisms of these new drug modalities impose higher requirements on their DMPK studies. For example, ADC drugs are composed of antibodies and small molecule toxins and exhibit both large molecule and small molecule characteristics, making their in vivo process complicated and dynamic with biotransformation and drug‐to‐antibody ratio (DAR) changes. This complexity poses challenges to ADC studies such as stability, metabolite identification, and bioanalysis.

Section II focuses on the drug metabolism and pharmacokinetic studies of therapeutics in specific disease areas. With an aging population and an increasing number of patients with chronic diseases, there is a growing demand for drug development in disease areas with unique pharmacokinetic characteristics, such as ophthalmic drugs, respiratory medications, transdermal and topical drugs, and central nervous system drugs. Specific preclinical study models or methods need to be developed to address these characteristics resulting from different pathogenesis and therapeutic modes of action. For example, developing ophthalmic drugs will encounter difficulties such as multiple biological barriers, analytical complexities, and intricate experimental operations.

Section III delves into front‐edge metabolism and pharmacokinetic research strategies, methods, and applications, covering topics such as in vitro ADME, in vivo pharmacokinetics, metabolite profiling and identification, radiolabeled ADME studies, and advanced bioanalysis techniques and platforms. These approaches enable more comprehensive and accurate drug evaluation in DMPK studies.

Scientists are devoted to drug metabolism and pharmacokinetic studies, and expand the breadth and depth of their research by summarizing and optimizing the methodologies and insights from massive experience. Nevertheless, it is essential to be aware that the DMPK research will be full of opportunities and challenges with technological advancements. Continuous investment of time and resources is essential to keep pace and add to clinical breakthroughs and health sciences.

The publication of this book aims to bring together the knowledge and experience from WuXi AppTec DMPK’s forefront scientists, and contribute to new drug development in this era of industrial transformation. I sincerely thank the authors for their efforts and contributions, as well as Wiley for their review and support. I hope readers can enjoy reading while finding useful tactics in this book.

Dr. Liang Shen

Vice President, Head of DMPK DepartmentWuXi AppTec

Acknowledgments

The compilation and publication of this book have been a joint effort. Credit should be given to the authors and editors, who have delivered profound insights by drawing upon their vast DMPK expertise. Their hard work, research, and commitment in crafting this book deserve special recognition. We would like to thank all the authors and editors, listed here in alphabetical order.

Peiyun An, Weiqun Cao, Dr. Genfu Chen, Dr. Jacob Zhi Chen, Dr. Shiyan Chen, Song Chen, Yu Chen, Liwei Cheng, Dr. Qigan Cheng, Hongfang Cui, Qian Cui, Tiantian Dang, Ya Ding, Xuan Dong, Jian Fang, Quanli Feng, Flora Fu, Xinfa Fu, Li Gao, Lijia Gao, Yafei Gao, Yang Gao, Lian Guo, Qiqi Han, Huan He, Lijuan Hou, Jie Hu, Weimin Hu, Dr. Jiaming Jiang, Dr. Lifang Jiang, Dr. Furong Jiao, Dr. Jing Jin, Wei Lei, Chengyuan Li, Hongye Li, Huan Li, Huayu Li, Dr. Huihui Li, Jie Li, Lin Li, Dr. Peng Li, Qian Li, Ruixing Li, Tingting Li, Xiaotong Li, Xin Li, Yingying Li, Zhihai Li, Dr. Zhiyu Li, Danqing Lin, Haijuan Liu, Dr. Huan Liu, Huan Liu, Jian Liu, Mengjie Liu, Qing Liu, Shoutao Liu, Siyu Liu, Yanfeng Liu, Chunhong Lu, Jinlian Lu, Yikuan Lu, Dr. Dongke Ma, Dr. Liping Ma, Chen Ning, Jie Pan, Dr. Yan Pan, Linlin Pei, Hongfeng Qian, Huijuan Qian, Gengyao Qin, Dr. Li Qu, Xiang Ren, Yanfu Ren, Tingting Ruan, Dr. Liang Shen, Dr. Liqi Shi, Xinmeng Shi, Miaomiao Song, Yuanqiang Su, Hong Sun, Jianping Sun, Ziqian Sun, Cheng Tang, Liping Tang, Xue Tang, Dr. Yi Tao, Binbin Tian, Dr. Hongmei Wang, Huijuan Wang, Dr. Jie Wang, Junjie Wang, Dr. Xiangling Wang, Dr. Xiaoqi Wang, Yu Wang, Yuxi Wang, Xinxin Wen, Lili Xing, Haiwei Xiong, Tao Xiong, Dr. Mingcheng Xu, Ye Xu, Jia Xue, Dr. Huan Yan, Jinyu Yan, Dr. Yunyi Yan, Guang Yang, Rong Yang, Xianqing Yu, Dr. Jiaqi Yuan, Chao Zhang, Hefeng Zhang, Dr. Hong Zhang, Honghong Zhang, Dr. Lingling Zhang, Xuan Zhang, Yingying Zhang, Yu Zhang, Hang Zhao, Dr. Nan Zhao, Lijin Zheng, Dr. Maotian Zhou, Xinyun Zhou, Ying Zhou, Wenjun Zhu, and Zhangpei Zhu.

Section INovel Drug Modalities: Advancements and Their Pharmacokinetic Strategies

1 Proteolysis‐Targeting Chimeras (PROTACs)

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

Chengyuan Li, Yu Wang, Jing Jin

1.1.1 Introduction

In recent decades, significant advances have been achieved in the development of new therapeutic approaches. Proteolysis‐targeting chimera (PROTAC) offers a new approach to some disease treatments, which has increasingly attracted the attention of drug developers in the last five years. Additionally, PROTAC, as a new therapeutic technology, has facilitated substantial investment worldwide. In this chapter, we summarized the PROTAC’s structure and mechanism of action, its global landscape, the drug metabolism and PK (DMPK) challenges in PROTAC research, and corresponding potential solutions.

1.1.2 Structure and Mechanism of Action of PROTACs

PROTAC utilizes the body’s natural protein degradation mechanism, known as the ubiquitin–proteasome system [1]. PROTAC is a bifunctional molecule that consists of three key structural parts: a ligand that binds the target protein, a ligand that binds the ubiquitin–protein ligase (E3), and a linker that connects the two ligands (Figure 1.1).