Atkinson's Principles of Clinical Pharmacology

4th Edition - October 16, 2021
Editors: Shiew-Mei Huang, Juan J.L. Lertora, Paolo Vicini, Arthur J. Atkinson Jr.
Language: English
Hardback ISBN:
9 7 8 - 0 - 1 2 - 8 1 9 8 6 9 - 8
eBook ISBN:
9 7 8 - 0 - 1 2 - 8 1 9 8 8 4 - 1

**Selected for Doody’s Core Titles® 2024 in Pharmacology**Atkinson’s Principles of Clinical Pharmacology, Fourth Edition is the essential reference on the pharmacologic principle… Read more

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**Selected for Doody’s Core Titles® 2024 in Pharmacology**

Atkinson’s Principles of Clinical Pharmacology, Fourth Edition is the essential reference on the pharmacologic principles underlying the individualization of patient therapy and contemporary drug development. This well-regarded survey continues to focus on the basics of clinical pharmacology for the development, evaluation and clinical use of pharmaceutical products while also addressing the most recent advances in the field. Written by leading experts in academia, industry, clinical and regulatory settings, the fourth edition has been thoroughly updated to provide readers with an ideal reference on the wide range of important topics impacting clinical pharmacology.

Cover image
Title page
Table of Contents
Copyright
Contributors
Preface to the first edition
Preface to the fourth edition
Chapter 1: Introduction to clinical pharmacology
Abstract
Background
Pharmacokinetics
References
Additional sources of information
Chapter 2: Clinical pharmacokinetics
Abstract
The target concentration strategy
Concepts underlying clinical pharmacokinetics
Mathematical basis of clinical pharmacokinetics
References
Study problems
Chapter 3: Compartmental analysis of drug distribution
Abstract
Fit-for-purpose modeling of drug distribution
Physiological significance of drug distribution volumes
Physiological basis of multicompartmental models of drug distribution
Clinical consequences of different drug distribution patterns
Estimating model parameters from experimental data
Study problems
References
Chapter 4: Drug absorption and bioavailability
Abstract
Drug absorption
Bioavailability
Kinetics of drug absorption after oral administration
References
Study problems
Chapter 5: Effect of kidney disease on pharmacokinetics
Abstract
Drug dosing in patients with impaired kidney function
Effects of kidney disease on renal drug elimination mechanisms
Effects of impaired kidney function on nonrenal clearance pathways
Effects of kidney disease on drug distribution
Effects of kidney disease on drug absorption
Study problem
References
Chapter 6: Pharmacokinetics in patients requiring renal replacement therapy
Abstract
Kinetics of intermittent hemodialysis
Kinetics of CRRT and sustained renal replacement therapy
Clinical considerations
References
Chapter 7: Effect of liver disease on pharmacokinetics
Abstract
Physiologic determinants of hepatic drug clearance
Effects of liver disease on pharmacokinetics
Use of therapeutic drugs in patients with liver disease
References
Chapter 8: Noncompartmental and compartmental approaches to pharmacokinetic data analysis
Abstract
Introduction
Kinetics, pharmacokinetics, and pharmacokinetic parameters
Noncompartmental analysis
Compartmental analysis
Noncompartmental versus compartmental models
Conclusion
References
Chapter 9: Population pharmacokinetics
Abstract
Introduction
Analysis of pharmacokinetic data
Population pharmacokinetics
Model applications
Conclusions
References
Chapter 10: Pathways of drug metabolism
Abstract
Introduction
The chemistry and enzymology of drug metabolism
Oxidations and nonconjugation reactions
Non-CYP oxidations
Conjugation reactions
References
Chapter 11: Bioanalytical methods: Technological platforms and method validation
Abstract
Acknowledgments
Technological platforms of bioassays
Method validation
Case examples
Conclusion
References
Chapter 12: Clinical pharmacogenetics
Abstract
Introduction
General principles
Genetic analysis techniques and informatics
Examples of clinically relevant genetic polymorphisms
Pharmacogenetics in drug discovery, development, regulation, and utilization
Conclusions and future directions
Dedication
References
Chapter 13: Mechanisms and genetics of drug transport
Abstract
Introduction
Mechanisms of transport across biological membranes
Nomenclature, genetic classification, and function of selected membrane transporters
Role of transporters in pharmacokinetics and drug action
Pharmacogenetics and pharmacogenomics of membrane transport
Conclusions and future perspectives
Disclaimer
References
Chapter 14: Drug-drug interactions
Abstract
Introduction
PK interactions
Other interactions
Integrated investigation of DDI risk in drug development
Additional factors impacting drug interactions
Labeling and DDI management
Postmarketing surveillance and real-world data for DDI
Conclusions
Disclaimer
References
Chapter 15: Biochemical mechanisms of drug toxicity
Abstract
Introduction
Types of IDRs
Carcinogenic effects of drugs
Teratogenic effects of drugs
References
Chapter 16: Pharmacogenomic mechanisms of drug toxicity
Abstract
Acknowledgment
ADRS with a pharmacogenomic basis
Genetic mechanisms for drug-induced hypersensitivity reactions
FDA labeling of drugs for pharmacogenomic information
The role of modeling and simulation in elucidating pharmacogenomic ADR mechanisms
References
Chapter 17: Biomarkers in drug development
Abstract
Introduction
Definitions and concepts
Discovery and validation
Biomarkers in drug development
Surrogate endpoints
Surrogate endpoint examples
FDA/CDER biomarker qualification program
Contemporary approaches to biomarker development
Summary
References
Chapter 18: Imaging in drug development
Abstract
Introduction
Molecular imaging technologies
Uses for imaging in drug development
Challenges to using imaging in drug development
Conclusion
References
Chapter 19: Dose-effect and concentration-effect analysis
Abstract
Background
Drug-receptor interactions
The graded dose-effect relationship
The quantal dose-effect relationship
Pharmacodynamic models
Evaluating dose/exposure-response relationships in drug development
Case studies
Summary
References
Chapter 20: Time course of drug response
Abstract
Pharmacokinetics and delayed pharmacologic effects
Physiokinetics—The time course of effects due to physiological turnover processes
Therapeutic response, cumulative drug effects, and schedule dependence
References
Chapter 21: Disease progress models
Abstract
Clinical pharmacology and disease progress
Disease progress models
Design of trials to study disease progress
Conclusion
References
Chapter 22: Sex-specific pharmacological differences
Abstract
Introduction
Pharmacokinetics
Pharmacodynamics
Other factors affecting sex differences in PK and PD
Summary
References
Chapter 23: Drug therapy in pregnant and nursing women
Abstract
Pregnancy physiology and its effects on pharmacokinetics
Pharmacokinetic studies during pregnancy
Guidelines for the conduct of drug studies in pregnant women
Placental transfer of drugs
Teratogenesis
Drug therapy in nursing mothers
References
Chapter 24: Pediatric clinical pharmacology and therapeutics
Abstract
History of pediatric clinical pharmacology
Developmental clinical pharmacology
Ontogeny of pharmacokinetics in children
Developmental pharmacodynamics
Therapeutic considerations
Application of pediatric pharmacology to clinical study design
References
Chapter 25: Medication therapy in older adults
Abstract
Introduction
Polypharmacy in older adults
Pathophysiology of aging
Age-related changes in pharmacokinetics
Age-related changes in effector system function
Drug classes for which age confers increased risk for toxicity
Conclusion
Disclaimer
References
Chapter 26: Clinical analysis of adverse drug reactions and pharmacovigilance
Abstract
Introduction
Definitions and classification
Assessing ADRS
Managing and reporting ADRS
Pharmacovigilance: Postmarketing surveillance of adverse drug reactions
Disclaimer
References
Chapter 27: Quality assessment of drug therapy
Abstract
Introduction
Organizational influences on medication use quality
Summary
References
Chapter 28: Portfolio and project planning and management in the drug discovery, evaluation, development, and regulatory review process
Abstract
Introduction
Portfolio design, planning, and management (PDPM)
Project planning and management
Project planning and management tools
Project team management and decision-making
References
Chapter 29: Drug discovery
Abstract
Introduction
Elements of drug discovery
References
Chapter 30: Nonclinical drug development
Abstract
Introduction
Components of nonclinical drug development
Nonclinical efficacy pharmacology
Nonclinical pharmacokinetics
Nonclinical safety pharmacology
Nonclinical toxicology
Starting dose selection for FIH studies
Model based development bridging nonclinical to clinical
Nonclinical development of immuno-oncology therapeutics
References
Chapter 31: Preclinical prediction of human pharmacokinetics
Abstract
Introduction
Allometry
Physiologic pharmacokinetics
Microdosing
References
Chapter 32: Phase 1 clinical studies
Abstract
Acknowledgment
Introduction
Healthy volunteers and patients in phase 1 studies
Starting dose and dose escalation
Limitations of the use of preclinical species data to predict human exposure and toxicity
Beyond toxicity
References
Chapter 33: Pharmacokinetic and pharmacodynamic considerations in the development of biotechnology products and large molecules
Abstract
Introduction
Monoclonal antibodies
Assay of macromolecules
Interspecies scaling of macromolecules: predictions in humans
Pharmacodynamics of macromolecules
Pharmacokinetics and pharmacodynamics in biosimilar drug development
References
Chapter 34: Design of clinical development programs
Abstract
Introduction
Principles of clinical development
Legal and regulatory requirements
Evidence-based, goal-directed clinical development
Specific design issues in clinical development programs
Conduct of clinical development
Special topics
References
Chapter 35: The role of the FDA in guiding drug development
Abstract
Disclaimer
Introduction
Evolution of the FDA’s role in drug regulation
FDA’s role in guiding drug development—A science-driven agency
The role of FDA in facilitating drug development through communication
The role of FDA in developing guidance and policy to inform drug development
The role of the FDA office of clinical pharmacology
References
Chapter 36: Emerging clinical pharmacology topics in drug development and precision medicine
Abstract
Introduction
Model-informed drug development
MIDD applications
Current and future trends in MIDD
Real-world data and real-world evidence
The utility of RWD in advancing clinical pharmacology
Limitations of RWD
Future trends
Digital health technologies
The utility of DHTs to advance clinical pharmacology and medical research
The microbiome and its impact on therapy response
References
Appendix I: Abbreviated table of Laplace transforms
Appendix II: Answers to study problems—Chapters 2–5
Answers to study problems—Chapter 2
Answers to study problems—Chapter 3
Answers to study problems—Chapter 4
Answer to study problem—Chapter 5
Index

Shiew-Mei Huang

Shiew-Mei Huang, PhD, FCP, is Deputy Director at the Office of Clinical Pharmacology, Center for Drug Evaluation and Research, Food and Drug Administration. She received her BS in pharmacy from National Taiwan University, School of Pharmacy in 1975, and her PhD from the University of Illinois, Medical Center in Pharmacokinetics and Biopharmaceutics in 1981. She has more than 15 years of drug development experience (Ortho pharmaceutical and Dupont-Merck) before joining the FDA in 1996. She has more than 160 publications focusing on topics in clinical pharmacology, drug metabolism/transport interactions, and physiologically based pharmacokinetic modeling and pharmacogenomics areas. Dr. Huang is a fellow of the American Association of Pharmaceutical Scientists and a diplomate of the American Board of Clinical Pharmacology. She was President of the American Society for Clinical Pharmacology and Therapeutics (ASCPT) from 2009 to 2010. She received ASCPT Awards “Gary Neil Prize for Innovation in Drug Development” in March 2014 and “Henry Elliott Distinguished Service Award” in March 2016.

Affiliations and expertise

Deputy Director, Office of Clinical Pharmacology (OCP), Center for Drug Evaluation Research (CDER), Food and Drug Administration (FDA) Silver Spring, MD, United States

Juan J.L. Lertora

Juan J. L. Lertora, MD, PhD, is Adjunct Professor of Clinical Research at the Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, and Adjunct Professor of Medicine at the Duke University School of Medicine, Durham, NC. He is a former Director of the Clinical Pharmacology Program at the NIH Clinical Center in Bethesda, MD. As a junior faculty at the Clinical Pharmacology Center, Northwestern University School of Medicine in Chicago, he received a PMA Foundation Faculty Development Award in Clinical Pharmacology. Subsequently, he became Section Head of Clinical Pharmacology at the Tulane University School of Medicine in New Orleans. In 2010 Dr. Lertora was distinguished with the NIH Director Ruth L. Kirschstein Mentoring Award. He is also a recipient of the 2013 PhRMA Foundation Award in Excellence in Clinical Pharmacology, and the 2014 Henry W. Elliott Distinguished Service Award from the American Society for Clinical Pharmacology and Therapeutics.

Affiliations and expertise

Adjunct Professor, Division of Clinical Research, Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, United States Adjunct Professor, Department of Medicine, Duke UniversitySchool of Medicine, Durham, NC, United States

Paolo Vicini

Paolo Vicini, PhD, MBA, is Chief Development Officer at Confo Therapeutics, Ghent, Belgium. He is also Affiliate Associate Professor of Bioengineering at the University of Washington, Seattle. He was previously Vice President of Development Sciences at Kymab; Senior Director of Clinical Pharmacology, Pharmacometrics and DMPK with MedImmune Cambridge (UK); and Research Fellow in Pharmacokinetics, Dynamics, and Metabolism with Pfizer in San Diego. Before Pfizer, he was a bioengineering faculty member at the University of Washington. He is Fellow of the American Association of Pharmaceutical Scientists and a member of many other professional organizations. Dr. Vicini has direct experience in translational and clinical sciences through all phases of drug discovery and development and coauthored more than 150 scholarly publications. He holds a PhD in bioengineering from the Polytechnic of Milan and an MBA from the University of Southern California.

Affiliations and expertise

Chief Development Officer, Confo Therapeutics NV, Ghent, Belgium

Arthur J. Atkinson Jr.

Arthur J. Atkinson, Jr., M.D., M.A.C.P., is Adjunct Professor of Pharmacology at the Feinberg Medical School of Northwestern University. He has held leadership roles in clinical pharmacology for more than 50 years, working in both academia and the pharmaceutical industry, and for NIH. He founded and for 24 years directed a Clinical Pharmacology Center at Northwestern, rising to the rank of Professor of Pharmacology and Medicine. He was subsequently Corporate Vice President for Clinical Development and Medical Affairs at the Upjohn Company. Following the Upjohn-Pharmacia merger, he was recruited to be Senior Advisor in Clinical Pharmacology at the NIH Clinical Center. There, he initiated a clinical pharmacology course and served as lead editor for the previous three editions of Principles of Clinical Pharmacology, the required text for the course. Dr. Atkinson has been elected Master of the American College of Physicians and to membership in the American Association of Physicians. He received the Harry Gold Award from ASPET, the Oscar Hunter Award from ASCPT, and the Award in Excellence from the PhRMA Foundation.

Affiliations and expertise

Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States