Basics and Clinical Applications of Drug Disposition in Special Populations E-Book
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- Sprache: Englisch
An up-to-date exploration of techniques for effectively treating patients from special populations
In Basics and Clinical Applications of Drug Disposition in Special Populations, a team of distinguished researchers delivers a timely and authoritative discussion of how to predict drug disposition in special populations, including people with obesity, pediatric patients, geriatric patients, and patients with renal and hepatic impairment. The authors use pharmacokinetic models to account for variabilities between populations and to better predict drug disposition.
The book offers a collection of 15 chapters written by recognized experts in their respective fields. They cover topics ranging from the optimization of drug dosing regimens in specialized populations to model-based approaches in drug treatment among pediatrics.
Readers will also find:
- A thorough introduction to considerations and regulatory affairs for clinical research in special populations
- Comprehensive explorations of drug disposition in geriatrics, patients with hepatic insufficiency, and patients with renal insufficiency
- Practical discussions of model-based pharmacokinetic approaches
- Complete treatments of artificial intelligence in drug development
Perfect for practicing pharmacologists, pharmacists, and clinical chemists, Basics and Clinical Applications of Drug Disposition in Special Populations will also benefit medical professionals who provide medical and pharmaceutical care to special populations.
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Veröffentlichungsjahr: 2025
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Table of Contents
Cover
Table of Contents
Title Page
Copyright Page
Dedication Page
About the Editors
List of Contributors
Foreword
Preface
1 Pharmacokinetic Principles and Concepts: An Overview
1.1 Introduction
1.2 Pharmacokinetic Parameters
1.3 Pharmacokinetic Models
1.4 Applications
1.5 Conclusion
References
2 Model‐Based Pharmacokinetic Approaches
2.1 Introduction
2.2 Basics of Pharmacokinetics
2.3 Pharmacokinetic (PK) Models
2.4 Model Development and Validation
2.5 Applications of Model‐Based Approaches
2.6 Modeling in Special Populations
2.7 Software and Tools for PK Modeling
2.8 Regulatory Perspectives of PK Modeling
2.9 Future Directions of PK Modeling
2.10 Conclusion
Abbreviations
References
3 Physiologically Based Pharmacokinetic Modeling
3.1 Introduction
3.2 Significance of PBPK Modeling
3.3 Principles for the Development of PBPK for Special Populations
3.4 Data Integration for Special Populations
3.5 Applications of PBPK Modeling
3.6 Regulatory Applications/Pre–Post Market Utilization
3.7 Case Studies
3.8 Lessons Learned
3.9 Conclusion
References
4 Therapeutic Drug Monitoring in Special Populations
4.1 Introduction
4.2 Pediatrics
4.3 TDM Practices in Pediatrics
4.4 Conclusion
4.5 Pregnancy
4.6 The Elderly
4.7 Conclusion
4.8 Hepatic and Renal Impairments
4.9 Conclusion
4.10 Overall Conclusion and Future Direction
Acknowledgment
References
5 Optimization of Drug Dosing Regimen
5.1 Introduction
5.2 Dosing Regimen Optimization Approaches and Strategies
5.3 Dosing Regimen in Special Populations
5.4 Conclusion
References
6 Artificial Intelligence in Drug Development
6.1 Introduction
6.2 Application of AI in Drug Design
6.3 AI Use in Drug Formulation
6.4 Drug Release Characterization Using AI
6.5 AI‐Based Dose/Dosing Regimen
6.6 Dissolution Rate Predictions with AI
6.7 Clinical End‐Point Evaluation with AI
6.8 AI in Prediction of Fate of Drugs Administered Via Mucosal, Transdermal, and Parenteral Routes
6.9 AI‐Integrated Mechanistic Modeling Platform for Drug Delivery and Monitoring
6.10 AI‐Based Tools for Metabolism and Clearance Prediction
6.11 Limitations of Existing Tools
6.12 Conclusions
6.13 Conflict of Interest
Acknowledgments
References
7 Drug Disposition in Neonates and Infants
7.1 Introduction
7.2 Drug Absorption in Neonates and Infants
7.3 Drug Distribution in Neonates and Infants
7.4 Hepatic Metabolism of Drugs in Neonates and Infants
7.5 Drug Excretion in Neonates and Infants
7.6 Pharmacodynamics in Neonates and Infants
7.7 Age‐Related Dosing Regimen in Neonates and Infants
7.8 Conclusion
References
8 Drug Disposition in Adolescents
8.1 Introduction
8.2 Physiological Considerations in Adolescents
8.3 Medication Adherence Challenges in Adolescents
8.4 Psychological Development on Drug Disposition
8.5 Risk‐Taking behaviors and Their Implications on Medication Use
8.6 Drug Use Among Adolescents
8.7 Pharmacokinetic Variability in Adolescents Drug Examples
8.8 Legal and Ethical Considerations
8.9 Conclusion
References
9 Drug Disposition in Pregnancy
9.1 Introduction
9.2 Physiological Changes in Pregnancy
9.3 Placental Drug Disposition
9.4 Drug Classification in Pregnancy
9.5 Pharmacokinetic (PK) Modeling
9.6 Physiologically Based Pharmacokinetic (PBPK) Modeling
9.7 Limitations in PK and PBPK Models
9.8 PBPK Model Variables
9.9 Determining Treatment During Pregnancy
9.10 Fetal Blood Flow and Drug Processing
9.11 Teratogens
9.12 Conclusion
Abbreviations
References
10 Drug Disposition in Obesity
10.1 Introduction
10.2 Index of Obesity
10.3 Pathogenesis of Obesity/Overweight
10.4 Drug Disposition in Obesity
10.5 Drug Dose Calculations in Obese Patients
10.6 Disposition of Drugs in Obesity
10.7 Conclusion
References
11 Drug Disposition in Critical Care Patients
11.1 Introduction
11.2 Pharmacokinetic Considerations in Critical Care Patients
11.3 Dosing Algorithms for Commonly Administered Drugs in Critical Care Patients
11.4 Conclusion
References
12 Drug Disposition in Renal Insufficiency
12.1 Renal Physiology
12.2 Glomerular Filtration Rate
12.3 Acute Kidney Injury
12.4 Chronic Kidney Disease
12.5 Medication Dosing Modifications
12.6 Epidemiology and Outcomes of Patients with CKD
References
13 Drug Disposition in Hepatic Insufficiency
13.1 Introduction
13.2 The Spectrum of Liver Diseases
13.3 Liver Function and Drug Metabolism
13.4 Dosing Algorithms in Clinical Practice
13.5 Drug Disposition and Factors That Influence Drug Disposition
13.6 Major Classes of Drugs and Hepatic Insufficiency
13.7 Cases Demonstrating Application of Dosing Algorithms
13.8 Limitations of Current Dosing Strategies
13.9 Conclusion and Future Perspectives
References
14 Drug Disposition in Geriatrics
14.1 Introduction
14.2 Absorption
14.3 Distribution
14.4 Metabolism
14.5 Excretion
14.6 Hepatic
14.7 Renal
14.8 Cardiac
14.9 Sex Differences
14.10 Psychoactive Drugs
14.11 Anesthesiology Drugs
14.12 Drug Interactions
14.13 Drug Side Effects
14.14 Conclusion
Abbreviations
References
15 Considerations and Regulatory Affairs for Clinical Research in Special Populations
15.1 Introduction
15.2 Regulatory Frameworks for Clinical Research in Special Populations
15.3 Key Considerations for Clinical Trials in Special Population Groups
15.4 Pregnant Population Groups
15.5 Geriatric Populations
15.6 Critical Care
15.7 Summary Points
15.8 Conclusion
References
Index
End User License Agreement
List of Tables
Chapter 2
Table 2.1 Overview of model‐based approaches [2,4–7].
Table 2.2 Differences between traditional and model‐based pharmacokinetic a...
Table 2.3 Comparison of IV bolus, IV infusion, and oral administration (the...
Table 2.4 Model parameters and their unit [40].
Table 2.5 Clinical utility of model‐based approaches in PK studies. Adapted...
Table 2.6 Software used for PK modeling. Adapted from [69].
Chapter 3
Table 3.1 Physicochemical properties of compounds selected for case study (...
Chapter 4
Table 4.1 Application of precision dosing pediatrics
Table 4.2 Examples of drugs for which TDM could be beneficial during pregna...
Chapter 5
Table 5.1 Dosing adjustment for antimicrobials in continuous renal replacem...
Table 5.2 Advantages and disadvantages of antimicrobial stewardship strateg...
Chapter 7
Table 7.1 Factors that affect drug absorption in neonates and infants.
Table 7.2 Factors affecting drug distribution in neonates and infants.
Table 7.3 Ontogeny of phase II drug metabolizing enzymes.
Chapter 9
Table 9.1 Former FDA Pregnancy Categories (1979) [Adapted from the United S...
Table 9.2 Notable Drug Metabolizing CYPs.
Table 9.3 Selected, common pharmacological agents with teratogenic effects.
Chapter 10
Table 10.1 Classification of BMI.
Table 10.2 Impact of obesity on hepatic drug metabolism.
Table 10.3 Impact of obesity on renal drug excretion.
Table 10.4 Dose size descriptors that can be used in dose calculation.
Table 10.5 Examples of drugs and the body size descriptors that are used in...
Chapter 11
Table 11.1 Dosing algorithms of narcotic analgesics in adult ICU patients....
Table 11.2 Dosing algorithms for selected sedatives employed in ICUs.
Table 11.3 Dosing regimen for selected neuromuscular blockers.
Chapter 12
Table 12.1 Equations to assess GFR.
Table 12.2 The Rifle classification.
Table 12.3 AKIN classification.
Table 12.4 CKD stages.
Table 12.5 UACR risk stratification.
Table 12.6 Equations used to calculate GFR.
Table 12.7 ACE inhibitor drug dosage management in patients with CKD.
Table 12.8 Beta‐blocker drug dosage management in patients with CKD.
Table 12.9 Diuretic drug dosage management in patients with CKD.
Table 12.10 Hypoglycemic drug dosage management in patients with CKD.
Table 12.11 Antimicrobial drug dosage management in patients with CKD.
Table 12.12 Statin drug dosage management in patients with CKD.
Chapter 14
Table 14.1 Changes in absorption, distribution, metabolism, and elimination...
Table 14.2 Physiological changes in geriatric patients.
Table 14.3 Change in the pharmacodynamic effect of common drugs in geriatri...
Table 14.4 Formulas to estimate the change in renal function with age.
Table 14.5 Pre‐, intra‐, and postoperative anesthesia drug considerations....
List of Illustrations
Chapter 1
Figure 1.1 Overview of the basic pharmacokinetic processes.
Chapter 2
Figure 2.1 Types of models.
Figure 2.2 Catenary model.
Figure 2.3 Mamillary model.
Figure 2.4 Cyclic model.
Figure 2.5 One‐compartment closed model.
Figure 2.6 One‐compartment open model.
Figure 2.7 Representation of one‐compartment open model showing absorption (...
Chapter 3
Figure 3.1 “Learn, confirm and apply” development cycle used to build and op...
Figure 3.2 Application of PBPK modeling in a pediatric population [5] / with...
Figure 3.3 PBPK modeling strategy employed to predict exposure in neonates a...
Chapter 4
Figure 4.1 The clinical condition and disease state of patients have signifi...
Chapter 5
Figure 5.1 Overview of dose selection during clinical trials.
Figure 5.2 Relationship between drug characteristics, PK parameters and crit...
Figure 5.3 Dynamic interaction between infection, preferred antimicrobial ag...
Figure 5.4 Tools available to optimize antimicrobials in ICU patients.
Figure 5.5 Factors to be considered during antimicrobial dose adjustment dur...
Figure 5.6 Application of MIDD in paediatric dose selection.
Chapter 8
Figure 8.1 An overview of drug profile in adolescents and challenges.
Chapter 9
Figure 9.1 Physiological changes in pregnancy
Figure 9.2 Placenta
Figure 9.3 Teratogenicity by organ system.
Chapter 10
Figure 10.1 Pathophysiological changes in obesity that can affect drug dispo...
Chapter 13
Figure 13.1 A summary of drug disposition in hepatic insufficiency.
Chapter 14
Figure 14.1 Decline in liver volume by age.
Figure 14.2 Decline in the number of functional nephrons by age.
Figure 14.3 Flow chart for prescribing medications in geriatric patients.
Guide
Cover Page
Table of Contents
Title Page
Copyright Page
Dedication
About the Editors
List of Contributors
Foreword
Preface
Begin Reading
Index
WILEY END USER LICENSE AGREEMENT
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Basics and Clinical Applications of Drug Disposition in Special Populations
Edited by
Seth Kwabena Amponsah
University of Ghana Medical SchoolAccra, Ghana
Yashwant V. Pathak
USF Health Taneja College of PharmacyTampa, Florida, USA
Copyright © 2025 by John Wiley & Sons, Inc. All rights reserved, including rights for text and data mining and training of artificial technologies or similar technologies.
Published by JohnWiley & Sons, Inc., Hoboken, New Jersey.Published simultaneously in Canada.
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Library of Congress Cataloging‐in‐Publication Data Applied for:
Hardback ISBN: 9781394251285
Cover Design: WileyCover Image: Courtesy of Seth Kwabena Amponsah and Yashwant V. Pathak
Dedication
I dedicate this book to my academic mentors, Professor Kwasi Agyei Bugyei and Professor George Obeng Adjei. I also dedicate this book to a very good friend, Dr. Enoch Narh Kudjordjie.
—Seth Kwabena Amponsah
This book is dedicated to the elders and people of ancient traditions and cultures who believe in working for humanity.
—Yashwant V. Pathak
About the Editors
Seth Kwabena Amponsah is an associate professor and former head of Department of Medical Pharmacology, University of Ghana Medical School. He has an MPhil and PhD in pharmacology. He has had postdoctoral fellowships under BANGA‐Africa Project and BSU III (DANIDA—Denmark). He has over 13 years’ experience in teaching and research. He teaches students in the medical school, school of pharmacy, school of nursing and midwifery, and school of biomedical and allied health sciences. His research focus includes clinical pharmacology (infectious disease and antimicrobial stewardship): prudent use of antimicrobials, antimicrobial level monitoring, and efficacy of antimicrobials in patients. He also has experience in population pharmacokinetic modeling, non‐compartment pharmacokinetic estimation, and pharmacokinetic evaluation of new drug formulations. He has supervised several undergraduate and postgraduate students. He has published over 60 research articles, 3 books, 20 book chapters and several conference abstracts. He is an academic editor for PLOS One and an associate editor for Pan African Medical Journal.
Yashwant V. Pathak has over 16 years of versatile administrative experience in an Institution of Higher education as dean (and over 30 years as faculty and as a researcher in higher education after his PhD). Presently holds the position for associate dean for faculty affairs and tenured professor of pharmaceutical sciences. He is an internationally recognized scholar, researcher, and educator in the areas of health care education, nanotechnology, drug delivery systems, and nutraceuticals. He has received many international and national awards including four Fulbright Fellowships, Endeavour Executive Fellowship by Australian Government, four outstanding faculty awards, and he was selected as fellow of American Association for Advancement of Science (AAAS) in 2021. He has published over 350 research publications, reviews, and chapters in various books. He has edited over 60 books in various fields including nanotechnology, nutraceuticals, conflict management, and cultural studies. He is also actively involved many nonprofit organizations, to mention a few, Hindu Swayamsevak Sangh, USA, Sewa International USA, International accreditation council for Dharma Schools and Colleges, International commission for Human rights and religious freedom, and Uberoi Foundation for religious studies, among others.
List of Contributors
Fried A. AbilbaDepartment of Paediatric and ChildHealth PharmacyTamale Teaching HospitalTamaleGhana
James A. AkingbasoteRegulatory ToxicologistLondon, OntarioCanada
Raphael N. AlolgaState Key Laboratory of NaturalMedicines, Department ofPharmacognosyChina Pharmaceutical UniversityNanjingChinaandClinical Metabolomics CenterDepartment of PharmacognosyChina Pharmaceutical UniversityNanjingChina
Emmanuel B. AmoafoDepartment of PharmaceuticalSciencesNorth Dakota State UniversityFargo, NDUSA
Seth K. AmponsahDepartment of Medical PharmacologyUniversity of Ghana Medical SchoolAccraGhana
Aparna AnandanTranslational Research LaboratoryDepartment of BiotechnologyBharathiar UniversityCoimbatore, Tamil NaduIndia
Unais AnnenkottilTranslational Research LaboratoryDepartment of BiotechnologyBharathiar UniversityCoimbatoreTamil Nadu, India
Vishnu P. AthilingamTranslational Research LaboratoryDepartment of BiotechnologyBharathiar UniversityCoimbatore, Tamil NaduIndia
Michael M. AttahDivision of Clinical PharmacologyIndiana University School ofMedicineIndianapolis, INUSAandDepartment of Pharmacy PracticeCollege of PharmacyPurdue UniversityWest Lafayette, INUSA
Jacob A. AyembillaDepartment of Science LaboratoryTechnologyAccra Technical UniversityAccraGhana
Stefanos BelavilasUniversity of South Florida MorsaniCollege of MedicineTampa, FLUSA
Gabriella BlancoUniversity of South Florida MorsaniCollege of MedicineTampa, FLUSA
Alexandra BurtonNationwide Children's HospitalColumbus, OHUSA
Nishanth ChalasaniUniversity of South Florida MorsaniCollege of MedicineTampa, FLUSA
Samuel CockeyUniversity of South Florida MorsaniCollege of MedicineTampa, FLUSA
Justin ColeUniversity of South Florida MorsaniCollege of MedicineTampa, FLUSA
Dominique CookUniversity of South Florida MorsaniCollege of MedicineTampa, FLUSA
Aparoop DasDepartment of PharmaceuticalSciencesDibrugarh UniversityDibrugarh, AssamIndia
Dibyajyoti DasDepartment of PharmaceuticalSciencesDibrugarh UniversityDibrugarh, AssamIndiaandPratiksha Institute of PharmaceuticalScienceGuwahati, AssamIndia
Mansa Fredua‐AgyemanDepartment of Pharmaceutics andMicrobiology, School of PharmacyUniversity of GhanaAccraGhana
Anuradha K. GajjarDepartment of PharmaceuticalChemistryL. M. College of PharmacyAhmedabad, GujaratIndia
Urvashee GogoiDepartment of PharmaceuticalSciencesDibrugarh UniversityDibrugarh, AssamIndia
David GyamfiDepartment of PharmaceuticalSciencesNorth Dakota State UniversityFargo, NDUSA
Arindam HalderSun Pharmaceutical Industries Ltd.Vadodara, GujaratIndia
Rana HannaUniversity of South Florida MorsaniCollege of MedicineTampa, FLUSA
Kartik HariharanSun Pharmaceutical Industries Ltd.Vadodara, GujaratIndia
Elora HilmasNationwide Children's HospitalColumbus, OHUSA
Md Ariful IslamDepartment of PharmaceuticalSciencesDibrugarh UniversityDibrugarh, AssamIndia
Partha P. KalitaFaculty of ScienceAssam down town UniversityGuwahati, AssamIndia
Ali KarimiUniversity of South Florida MorsaniCollege of MedicineTampa, FLUSA
Ajay J. KhopadeSun Pharmaceutical Industries Ltd.Vadodara, GujaratIndia
Seema KohliPharmacy DepartmentK N Polytechnic CollegeJabalpur, MPIndia
Awo A. KwapongDepartment of Pharmaceuticsand Microbiology, School ofPharmacyUniversity of GhanaAccraGhana
Stephanie LeighDepartment of Pharmacy andPharmacology, Faculty of HealthSciencesUniversity of the WitwatersrandJohannesburgSouth Africa
Millena LevinUniversity of South Florida MorsaniCollege of MedicineTampa, FLUSA
Deborah LiawUniversity of South Florida MorsaniCollege of MedicineTampa, FLUSA
Mahesh P. MoreNovel Formulation LaboratorySekkei Bio Pvt Ltd.Bangalore, KAIndia
Chinenye E. MuolokwuDepartment of PharmaceuticalSciences, School of PharmacyCollege of Health and HumanSciencesNorth Dakota State UniversityFargo, NDUSA
Sarah NestlerUniversity of South Florida MorsaniCollege of MedicineTampa, FLUSA
Viswanadha V. PadmaTranslational ResearchLaboratory, Department ofBiotechnologyBharathiar UniversityCoimbatore, Tamil NaduIndia
Amitkumar K. PatelSaffron Health LLCEast Brunswick, NJUSA
Jayvadan K. PatelVie Saine Pharma LLCSheridan, WYUSA
Kashyap M. PatelDepartment of PharmaceuticsL. M. College of PharmacyAhmedabad, GujaratIndia
Manish P. PatelDepartment of PharmaceuticsL. M. College of PharmacyAhmedabad, GujaratIndia
Vivek PatelApex professional UniversityPasighat, Arunachal PradeshIndiaandSun Pharmaceutical Industries Ltd.Vadodara, GujaratIndia
Kalyani PathakDepartment of PharmaceuticalSciencesDibrugarh UniversityDibrugarh, AssamIndia
Manash P. PathakFaculty of Pharmaceutical SciencesAssam Down Town UniversityGuwahati, AssamIndia
Yahwant V. PathakUSF Health Taneja College ofPharmacyUniversity of South FloridaTampa, FLUSA
Goonaseelan C. PillaiDivision of Clinical PharmacologyUniversity of Cape TownRondeboschSouth AfricaandCP+ Associates GmbHBaselSwitzerland
Amruta PotdarUniversity of South Florida MorsaniCollege of MedicineTampa, FLUSA
Pallab PramanikDepartment of PharmaceuticalSciencesDibrugarh UniversityDibrugarh, AssamIndia
Charles PreussDepartment of MolecularPharmacology & PhysiologyUniversity of South Florida MorsaniCollege of MedicineTampa, FLUSA
Jon J. SahariahDepartment of PharmaceuticalSciencesDibrugarh UniversityDibrugarh, AssamIndia
Riya SaikiaDepartment of PharmaceuticalSciencesDibrugarh UniversityDibrugarh, AssamIndia
Surovi SaikiaTranslational Research LaboratoryDepartment of BiotechnologyBharathiar UniversityCoimbatore, Tamil NaduIndia
Dhruv ShahSun Pharmaceutical Industries Ltd.Vadodara, GujaratIndia
Ellen SiUniversity of South Florida MorsaniCollege of MedicineTampa, FLUSA
Ankita A. SinghPharmacy DepartmentK N Polytechnic CollegeJabalpur, MPIndia
Sandra K. SzlapinskiRegulatory ToxicologistLondon, OntarioCanada
Rahul S. TadeH R Patel Institute of PharmaceuticalEducation and ResearchDhule, MSIndia
Benjamin TagoeDepartment of PharmaceuticalSciences, School of PharmacyCollege of Health and HumanSciencesNorth Dakota State UniversityFargo, NDUSA
Teresa TravnicekUniversity of South Florida MorsaniCollege of MedicineTampa, FLUSA
Jacob TreanorUniversity of South Florida MorsaniCollege of MedicineTampa, FLUSA
Maxine TurnerDepartment of Pharmacy andPharmacology, Faculty of HealthSciencesUniversity of the WitwatersrandJohannesburgSouth Africa
Shakil Z. VhoraDepartment of PharmaceuticsL. M. College of PharmacyAhmedabad, GujaratIndia
Kyle WestonRegulatory ToxicologistToronto, OntarioCanada
Yelena WuNationwide Children's HospitalColumbus, OHUSA
Foreword
The fundamentals of pharmacokinetics are essential in understanding the fate of administered drugs in patients. Pharmacokinetic knowledge is also relevant in drug‐dose adjustment in patients undergoing treatment or management in medical practice. Pharmacokinetic considerations are even more important in determining optimal drug dosing in special patient populations, such as pediatrics, critically ill patients, and geriatrics. These populations often exhibit variations in drug disposition of administered drugs compared to healthy adults, from whom pharmacokinetic data of drugs are usually derived. As such, understanding these differences is essential in providing effective and safe pharmacotherapy in these vulnerable populations.
In pediatric patients for instance, age, weight, and maturation of organs influence drug disposition. Additionally, renal function can impact on drug clearance in this cohort of the population.
Geriatrics also experience age‐related changes in disposition of drugs. Decrease in renal and liver functions and a decline in total body water can alter drug distribution, metabolism, and excretion. In geriatrics, these changes can lead to increased drug exposure and susceptibility to adverse drug reactions.
Likewise, hemodynamic, metabolic, and biochemical derangements in critically ill patients can affect drug disposition. Critical illness can alter drug protein binding, volume of distribution, hepatic metabolism, and renal clearance. Indeed, understanding the unique pharmacokinetic profiles of these populations is essential for healthcare providers to make informed decisions regarding drug dosing and monitoring.
Unfortunately, few books are readily available on the market that focus on drug disposition in special populations. This edited book has 15 chapters that discusses relevant topics such as model‐based pharmacokinetic approaches; physiologically based pharmacokinetic modeling; optimization of drug‐dosing regimen; drug disposition in neonates, infants, adolescents, geriatrics, and critically ill patients. Regulatory affairs for clinical research in special populations are also extensively discussed.
Distinguished scientists and researchers have made contributions to this book; with each chapter well written and easy to understand.
I believe that this book will be a great resource for clinicians, biomedical scientists, and students of the medical fraternity. I am, therefore, very happy to write the foreword for this book, Basics and Clinical Applications of Drug Disposition in Special Populations, edited by Seth K. Amponsah and Yaswant V. Pathak.
I congratulate the editors and contributing authors and look forward to seeing this book on the market.
Professor Kwasi Agyei Bugyei
Pharmacokineticist and Former Head, Department of Pharmacology, University of Ghana Medical School
Preface
Over the years, there has been growing interest in the field of pharmacokinetics/pharmacodynamics and its applications. Currently, pharmacokinetic and pharmacodynamic models aid better understanding of drug disposition and effect. Indeed, models can range in complexity from models with a single compartment to models containing multiple compartments. Each type of model from the simplest, one‐compartment model to more complex models has its own applications and can be used to gain valuable information from preclinical and clinical data.
It is well documented that clinical response to drugs vary widely between individuals and that most of this variability is at the pharmacokinetic level. In general, variability arises because of interindividual differences in rates of drug absorption, distribution, and elimination (metabolism and excretion). The pharmacokinetics of a drug can vary from person to person, and it is affected by age, gender, diet, environment, body weight, pathophysiology, genetics, and drug–drug or drug–food interactions. Indeed, the disposition (pharmacokinetics) of a drug can vary in special populations such as paediatrics, geriatrics, obese individuals, and patients with renal and hepatic impairment. To better explain the time course of drugs, pharmacokinetic models that take into account these possible variabilities have been used to predict drug disposition.
After carefully studying literature, we found that there are few books available on the market that compile the various aspects of the pharmacokinetics of drugs in special populations; hence, this book will be a great resource for clinicians, scientists, and researchers. This book covers topics such as optimization of drug‐dosing regimen, model‐based approaches in drug treatment, therapeutic drug monitoring, and pharmacotherapeutic considerations in special populations (neonates, infants, adolescents, geriatrics, among others). The book also contains 15 chapters with rich content, presenting fundamental facts, as well as practical and clinically related data. Renowned scientists/researchers in the field of pharmacokinetics, pharmacodynamics, mathematical, and computational science have contributed to this book. The current book will be a good resource for pharmacometricians, health care professionals (pediatricians, geriatricians, and endocrinologists), and academic institutions.
The editors appreciate the effort of each contributor who shared knowledge through writing chapters in this book. The editors are also grateful to John Wiley & Sons Inc. for facilitating all processes involved in getting this book published.
Seth Kwabena Amponsah and Yashwant V. Pathak
1Pharmacokinetic Principles and Concepts: An Overview
Seth K. Amponsah1 and Yahwant V. Pathak2
1 Department of Medical Pharmacology, University of Ghana Medical School, Accra, Ghana
2 USF Health Taneja College of Pharmacy, University of South Florida, Tampa, FL, USA
1.1 Introduction
Pharmacokinetics, a subset of pharmacology, describes the disposition of drugs in the body. The word “pharmacokinetics” is derived from two root words: “kinetics,” which relates to the study of how things change with time, and “pharmaco,” which pertains to pharmaceutical agents or drugs [1]. Pharmacokinetics, which describes the absorption, distribution, metabolism, and excretion of drugs (Figure 1.1), is not just theoretical but a practical tool in ensuring the efficacy and safety of drugs in a patient. Pharmacokinetics is an important arm of the drug development process, helping to achieve the correct dosage, frequency, and delivery method [2].
Indeed, pharmacokinetics provides insights into how the body handles drugs, paving the way for the development of personalized medicine. Pharmacokinetics also assesses the temporal effects of toxic agents in the body [3]. A good understanding of pharmacokinetic principles is essential for healthcare professionals and researchers in the pharmaceutical industry who are at the forefront of developing personalized medicine. Furthermore, comprehension of the basic principles of pharmacokinetics is essential in optimizing drug therapy and ensuring patients receive the best care.
Figure 1.1 Overview of the basic pharmacokinetic processes.
1.2 Pharmacokinetic Parameters
There are four main pharmacokinetic parameters: absorption, distribution, metabolism, and excretion. Although distinct, these parameters are interrelated and usually occur after a drug is administered to the body [4]. Importantly, some drugs access circulation without going through the process of absorption: drugs given intravenously [5].
1.2.1 Absorption
The rate and extent to which a drug is absorbed are dependent on the route of administration (oral, subcutaneous, intrathecal, intravenous, etc.), the formulation, the physicochemical properties, and the physiological factors that affect the absorption site [6]. After an oral (p.o.) administration of a drug, it is absorbed across the intestinal lumen into the portal vein and then to the liver. Subsequently, it will often undergo first‐pass metabolism before entering systemic circulation, reducing drug bioavailability [4]. Bioavailability, therefore, can be defined as the proportion of an administered drug that reaches systemic circulation in its active form. It comprises both the rate and the extent of drug absorption, and they are both influenced by several factors, such as the physicochemical properties of the drug, formulation, and the physiological conditions of the gastrointestinal tract (GIT). Following oral administration, drugs must undergo dissolution in GIT fluids before traversing the walls of the gut for absorption. Dissolution is heavily dependent on the solubility of the drug, as well as gastric pH and GIT motility.
When a drug is administered intravenously, there is no absorption because the drug goes directly from the administration site into circulation—almost near 100% bioavailability. Other routes may reduce the bioavailability of drugs because of incomplete absorption [6]. Generally, lipid‐soluble drugs at physiological pH are effectively absorbed via passive diffusion. Additionally, drug absorption can occur through different mechanisms, such as active and facilitated diffusion (carrier‐mediated membrane transport) and other nonspecific transporter systems, such as the P‐glycoprotein transporter [7]. In addition, the presence of food in the stomach can either enhance or hinder the absorption of certain drugs, which is also dependent on the characteristics of the drugs. For example, high‐fat meals may enhance the absorption of lipophilic drugs [8].
Various strategies are employed to enhance drug bioavailability, some of which include formulation modifications (such as nanoparticles and liposomes) and techniques such as micronization. These methods enhance dissolution and absorption rates [5]. Indeed, an in‐depth understanding of drug absorption principles is essential in drug development and in ensuring maximal therapeutic outcomes. As such, researchers and health professionals need to consider the aforementioned factors that affect drug absorption [2].
1.2.2 Distribution
After a drug is absorbed into the systemic circulation, it undergoes equilibration between the vascular compartment and several body compartments, including interstitial and intracellular spaces. It is worth noting that the molecular structure of a drug determines its degree of distribution in different tissues: adipocytes, muscle, and brain. Notably, the brain and testes possess barriers that confer unique characteristics, rendering drugs less susceptible to distribution within these organs [9]. Following entry into the bloodstream, drugs can bind to plasma proteins, such as albumin, or remain unbound. The fraction of the bound drug acts as a reservoir, facilitating the gradual release of the drug. At the same time, the unbound portion remains pharmacologically active and is available for distribution to several tissues [10]. The degree of protein binding significantly influences drug distribution, duration of action, and elimination [11].
Many factors influence how drugs are distributed in the body. Some of these factors include the degree of blood flow to tissues, the permeability of tissues, and the physicochemical properties of the drug. For example, organs with high blood flow, such as the brain, kidney, and liver, receive drugs much quicker than tissues with low blood flow, such as fat and muscle tissues [12]. The ability of a drug to cross cell membranes is often determined by its solubility profile and molecular size. Lipophilic drugs can cross membranes more easily and accumulate in fatty tissues, while hydrophilic drugs are more likely to remain in the extracellular fluid [13].
Often, the extent to which drugs are distributed can be represented as the volume of distribution (Vd). Vd can be defined as the theoretical volume in which the total amount of drug must be homogenously distributed to produce the observable blood concentration. A drug with a large Vd signifies that it is extensively distributed into tissues, while a small Vd suggests limited distribution, chiefly within the vascular compartment [14]. For instance, digoxin shows a large Vd due to its extensive tissue binding, especially in skeletal and cardiac muscles [15].
Understanding drug distribution is essential, as this will help optimize therapeutic effects and minimize adverse events. Variability in drug distribution can be a result of age, body composition, and pathological conditions.
1.2.3 Metabolism
After drugs are absorbed into the systemic circulation, a number of them have to undergo metabolism in the liver. Drugs that undergo metabolism are usually lipophilic. The process of metabolism converts lipophilic drugs into more water‐soluble metabolites to aid their excretion. In the liver, drugs undergo chemical modifications through enzymatic reactions [16]. Metabolism does not only facilitate the excretion of drugs but also plays a key role in regulating the pharmacological activity of drugs. Metabolism can potentially convert inactive prodrugs into active compounds [17]. Also, parent drugs that are active can be metabolized into less active or inactive forms.
Drug metabolism occurs through different chemical reactions, which are classified as phase I (functionalization) and phase II (conjugation) [18]. In phase I reactions, lipophilic drugs are biotransformed through processes such as oxidation, reduction, and hydrolysis. These reactions are capable of converting inactive prodrugs into active forms. With oxidation reactions, metabolites often retain some of their pharmacological activity. For instance, diazepam undergoes phase I reaction to become desmethyldiazepam, which is then further metabolized into oxazepam. The two metabolites exhibit pharmacological effects similar to those of diazepam. The cytochrome P450 enzyme (CYP) system, also known as microsomal mixed function oxidase, is the notable catalyst for most phase I reactions [19, 20].
During phase II metabolism, drugs are conjugated with polar endogenous substrates like glucuronic acid, sulfate, and glutathione. Conjugation reactions usually make the drug pharmacologically inactive and water soluble. Phase II reactions occur mainly in the liver but can also occur in the kidneys, lungs, and intestines [21]. Due to genetic differences (single nucleotide polymorphism), the activity of CYP enzymes can vary significantly among individuals. These variations could influence how drugs are metabolized, potentially impacting drug effectiveness and safety. For instance, polymorphisms in CYP2D6 can lead to different phenotypes of enzymes, and this can affect the metabolism of a drug like codeine, which is converted into its active form, morphine [22].
In addition to genetic factors, metabolism can be affected by age, liver disease, diet, and concomitant drug use. For example, neonates and geriatrics frequently exhibit reduced enzyme activity, and this has to be adequately catered for with dosage adjustments [23].
Furthermore, liver diseases such as cirrhosis have been shown to reduce drug metabolism, possibly leading to the accumulation of the drug and ultimately an increased risk of adverse effects. Also, specific diets may induce or inhibit CYP enzymes, thereby influencing the metabolism of some drugs. For example, grapefruit juice inhibits CYP3A4 and can significantly raise the plasma concentration of drugs metabolized by this enzyme [24].
1.2.4 Excretion
Excretion is the process of physically removing a drug from the body, either as the parent compound or a metabolite. Two of the most important channels for drug excretion are urine and bile. While polar compounds are effectively excreted without metabolism in the liver, lipophilic compounds usually require metabolism [25]. Drugs move to the kidneys through circulation and are filtered from the blood in the glomerulus. Also, drugs can undergo active tubular secretion in the proximal tubules, usually involving transporters that pump drugs into the renal tubules. Parent drugs and metabolites may be reabsorbed into circulation from the kidneys. Tubular reabsorption can be affected by the ionization state of the drug and the pH of urine [26]. For instance, weak acidic drugs are more likely to be reabsorbed in acidic urine, while weak basic drugs are reabsorbed in alkaline urine [27]. Indeed, if a drug is lipophilic, it is most likely to be reabsorbed.
Aside from renal excretion, drugs can be secreted into bile (biliary excretion); usually large molecular weight drugs and conjugate drug metabolites. In biliary excretion, drugs are eliminated in feces or undergo enterohepatic circulation. Enterohepatic circulation can prolong the duration of action and/or half‐life of drugs [28].
1.3 Pharmacokinetic Models
Pharmacokinetic models involve fitting mathematical equations to experimental observations of drug concentration in plasma. They are useful in predicting drug concentration‐time profiles. Common examples include compartmental, non‐compartmental, and physiologically based pharmacokinetic (PBPK) models. Compartmental models limit the human body to one or more compartments, each proposed to distribute drugs equally [29]. The one‐compartment model portrays the body as a single homogenous compartment and assumes that the drug quickly reaches equilibrium. This model is best suited for drugs that enter the body rapidly and uniformly, such as intravenous drugs. Conversely, the two‐compartment model divides the body into core compartments associated with the blood and well‐perfused organs and a peripheral compartment associated with less perfused tissues. For drugs that exhibit a dispersion phase followed by an elimination phase, this model is best suited [30].
Pharmacokinetic data can be assessed through non‐compartmental analysis (NCA), which deviates from the compartmental organization presuppositions. The NCA, which was founded on statistical moment theory, can calculate the Vd, clearance (CL), and area under the curve (AUC) directly from the concentration–time data. This method is appropriate when choosing a model‐independent analysis or when the complexity of compartmental models is deemed unnecessary [31].
Using physiologically based pharmacokinetic (PBPK) models becomes essential when a more comprehensive and mechanical approach, integrating physiological, biochemical, and anatomical data about the human body, is required. Based on actual organ and tissue volume, rate of blood flow, and specific characteristics of drugs, this model partitions the body into distinct compartments [32].
1.4 Applications
Applying pharmacokinetic principles in clinical settings is relevant for optimizing drug therapy. Pharmacokinetic principles find great use in individualized dosing, which involves adjusting drug doses based on specific patient factors such as age, weight, renal and hepatic function, and genetic makeup. Furthermore, therapeutic drug monitoring (TDM) is often used for drugs that have narrow therapeutic indices. This is to ensure accurate dosing and also to prevent subtherapeutic or toxic effects. For instance, the dosing of phenytoin, an antiepileptic drug, is tailored through TDM to maintain plasma drug concentrations within the therapeutic range [33]. Another notable application of pharmacokinetic principles in the clinical setting is the management of drug–drug interactions. A robust understanding of the pharmacokinetics of drugs enables healthcare workers to anticipate and effectively address potential interactions. For example, CYP enzyme inhibitors, such as ketoconazole, can increase the plasma concentrations of drugs metabolized by these enzymes, eventually increasing the risk of toxicity. On the other hand, enzyme inducers, such as rifampin, can decrease drug concentrations and subsequently decrease drug efficacy [34].
1.5 Conclusion
Pharmacokinetics processes serve as a keystone in clinical pharmacology and advance the safe and effective use of drugs. The application of these critical principles helps healthcare workers customize drug dosing according to patient‐specific requirements, manage drug interactions, and optimize therapeutic outcomes. Aside from enhancing patient care, pharmacokinetic models play a crucial role in the drug development continuum, from preclinical studies to market authorization. Pharmacokinetic research holds great potential for further enhancing drug therapy and fostering its precision.
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