Seth Kwabena Amponsah, PhD, is an Associate Professor at the Department of Medical Pharmacology at the University of Ghana Medical School. He has published over 70 research articles, 20 book chapters, 4 books, and several conference abstracts. Yashwant V. Pathak, PhD, is Associate Dean for Faculty Affairs and Tenured Professor of Pharmaceutical Sciences at the University of South Florida. He has published over 410 research articles, reviews, book chapters, and books.

• About the Editors xxiList of Contributors xxiiiForeword xxixPreface xxxi1 Pharmacokinetic Principles and Concepts: An Overview 1Seth K. Amponsah and Yahwant V. Pathak1.1 Introduction 11.2 Pharmacokinetic Parameters 21.2.1 Absorption 21.2.2 Distribution 31.2.3 Metabolism 41.2.4 Excretion 51.3 Pharmacokinetic Models 51.4 Applications 61.5 Conclusion 7References 72 Model-Based Pharmacokinetic Approaches 11Manish P. Patel, Kashyap M. Patel, Shakil Z. Vhora, Anuradha K. Gajjar, Jayvadan K. Patel, and Amitkumar K. Patel2.1 Introduction 112.1.1 Importance of PK 122.1.2 Overview of Model-Based Approaches 132.2 Basics of Pharmacokinetics 142.2.1 Key Pharmacokinetic Parameters 142.2.1.1 Absorption 142.2.1.2 Key Parameter 142.2.1.3 Distribution 142.2.1.4 Key Parameter 152.2.1.5 Metabolism 152.2.1.6 Key Parameter 152.2.1.7 Excretion 152.2.1.8 Key Parameter 152.2.2 Differences Between Traditional and Model-Based Pharmacokinetic Approaches 162.3 Pharmacokinetic (PK) Models 172.3.1 Introduction 172.3.2 Compartment Modeling 182.3.2.1 One-Compartment Model 212.3.2.2 Multi-Compartment Model 212.3.2.3 Two-Compartment Model 242.3.3 Population PK Model 252.3.4 Physiologically Based PK (PBPK) Model 262.4 Model Development and Validation 272.4.1 Data Requirements for Model Development 272.4.2 Data Requirements for Model Validation 292.4.3 Steps in Model Building (E.g., Model Selection and Parameter Estimation) 292.5 Applications of Model-Based Approaches 312.5.1 Dose Optimization 312.5.2 Predicting Drug Interactions 322.5.3 Drug Tailoring in Special Populations (E.g., Pediatrics, Geriatrics, and Renal Impairment) 332.5.4 Translational PK from Preclinical to Clinical Settings 342.6 Modeling in Special Populations 362.6.1 Challenges and Considerations 362.6.1.1 Challenges in PK Modeling 362.6.1.2 Considerations in PK Modeling 362.7 Software and Tools for PK Modeling 372.7.1 Gastroplus™ 382.7.2 Berkeley Madonna 382.7.3 MATLAB 382.7.4 PK-Sim® 392.7.5 Simcyp® 392.7.6 Auxiliary PBPK Modeling Software 392.7.6.1 Julia 392.7.6.2 Nonmem 392.7.6.3 Phoenix WinNonlin 402.7.6.4 GraphPad Prism 402.7.6.5 Minitab 402.7.6.6 PlotDigitizer 402.7.6.7 GNU MCSim 402.7.6.8 WebPlotDigitizer 402.8 Regulatory Perspectives of PK Modeling 402.9 Future Directions of PK Modeling 432.10 Conclusion 43Abbreviations 44References 453 Physiologically Based Pharmacokinetic Modeling 53Mahesh P. More and Rahul S. Tade3.1 Introduction 533.2 Significance of PBPK Modeling 563.3 Principles for the Development of PBPK for Special Populations 573.4 Data Integration for Special Populations 573.4.1 Demographic Data 583.4.2 Physiological Consideration 583.4.3 Ontogeny 583.4.4 Age and Maturation Changes 593.4.5 Steady State Volume of Distribution (Vdss) 593.5 Applications of PBPK Modeling 603.5.1 Dose Optimization/Regimen/Selection 603.5.2 Dose Individualization/Precision Dosing 613.5.3 Biopharmaceutics 623.6 Regulatory Applications/Pre–Post Market Utilization 623.7 Case Studies 643.7.1 Simulation Application 643.7.2 Successful Applications 673.8 Lessons Learned 683.9 Conclusion 68References 704 Therapeutic Drug Monitoring in Special Populations 75James A. Akingbasote, Sandra K. Szlapinski, Elora Hilmas, Kyle Weston, Yelena Wu, and Alexandra Burton4.1 Introduction 754.2 Pediatrics 764.2.1 Importance of TDM in Pediatrics 764.2.2 Pharmacokinetic Differences in Pediatric Patients 774.2.3 Drug Absorption in the Pediatric Population 774.2.4 Drug Distribution in the Pediatric Population 784.2.5 Drug Metabolism and Elimination in the Pediatric Population 794.3 TDM Practices in Pediatrics 794.3.1 Vancomycin 804.3.2 Aminoglycosides 814.3.3 Ganciclovir/Valganciclovir 824.3.4 Antiepileptic Drugs (AEDs) 834.3.5 Enoxaparin 844.4 Conclusion 854.5 Pregnancy 854.5.1 Physiological Adaptations in Pregnancy 854.5.2 Current State of Clinical Practice of TDM in Pregnancy 874.5.3 TDM in Pregnancy 894.5.3.1 Antiepileptics 894.5.3.2 Antidepressants 904.5.3.3 Antiretroviral Drugs 914.5.3.4 Immunomodulatory Drugs 934.5.4 Challenges in the Implementation of TDM in the Pregnant Population 944.6 The Elderly 954.6.1 Physiological Changes in the Elderly 954.6.2 Effect of Aging on Drug Pharmacokinetics 954.6.3 Application of TDM in the Elderly 974.6.3.1 Cardiac Glycosides 984.6.3.2 Serotonin–Norepinephrine Reuptake Inhibitor (SNRI) 984.6.3.3 Anticoagulants 994.6.3.4 Benzodiazepines 994.7 Conclusion 1014.8 Hepatic and Renal Impairments 1014.8.1 Hepatic Impairment 1024.8.2 TDM in Patients with Hepatic Impairment 1044.8.2.1 Meropenem 1054.8.2.2 Metoprolol 1054.8.2.3 Midazolam 1064.8.3 Renal Impairment 1074.8.4 Prerenal Disease 1094.8.5 Intrinsic Renal Vascular Disease 1094.8.6 Intrinsic Glomerular Disease (Nephritic or Nephrotic) 1094.8.7 TDM in Renal Impairment 1094.8.7.1 Vancomycin 1114.8.7.2 Metformin 1114.9 Conclusion 1124.10 Overall Conclusion and Future Direction 112Acknowledgment 113References 1145 Optimization of Drug Dosing Regimen 133Vivek Patel, Kartik Hariharan, Dhruv Shah, Arindam Halder, Ajay J. Khopade, Amitkumar K. Patel, and Jayvadan K. Patel5.1 Introduction 1335.2 Dosing Regimen Optimization Approaches and Strategies 1345.2.1 Models Used for Dosing Regimen Selection 1345.2.1.1 Pharmacometric Models 1345.2.1.2 PK Models 1355.2.1.3 Empirical Dose–Response Models 1365.2.1.4 Multiple Comparison Procedures Models (MCP-Mod) 1365.2.1.5 Model Averaging 1375.2.2 Role of Patient Characteristics in Dose Selection 1375.2.2.1 Phenotype-Guided Dosing 1375.2.2.2 Genotype-Guided Drug Dosing 1385.2.3 Therapeutic Drug Monitoring (TDM) 1385.3 Dosing Regimen in Special Populations 1395.3.1 Dosing Regimen in Cancer Patients 1395.3.1.1 Metronomic Chemotherapy 1405.3.2 Dosing Regimen for Patients on Antimicrobial Therapy 1425.3.2.1 Antimicrobial Stewardship Strategy 1455.3.2.2 Mathematical Models for Optimizing Antimicrobial Therapy 1465.3.2.3 Antimicrobial Dosing Strategies During CRRT 1475.3.2.4 Methods for Enhancing Dosing of Antimicrobials via Nebulization 1495.3.3 Dosing Regimen in Pediatric Patients 1495.3.3.1 Physiological Differences Between Pediatric and Adult Patients 1495.3.3.2 Application of MIDD in Pediatric Dose Selection 1495.3.3.3 Scaling from Adults to Pediatric Patients 1505.3.3.4 Scaling from Animals to Pediatric Patients 1505.3.3.5 Integrating Mechanistic Models in Neonates and Infants 1505.3.3.6 Dose Optimization in Neonates and Infants 1515.4 Conclusion 151References 1526 Artificial Intelligence in Drug Development 161Surovi Saikia, Aparna Anandan, Unais Annenkottil, Vishnu P. Athilingam, Partha P. Kalita, and Viswanadha V. Padma6.1 Introduction 1616.2 Application of AI in Drug Design 1626.2.1 Target Identification and Validation 1626.2.2 Drug Candidate Design and Optimization 1626.2.3 Virtual Screening and Molecular Docking 1636.2.4 Synthesis Planning 1636.2.5 Predicting Drug Toxicity and Pharmacokinetics 1636.2.6 Personalized Medicine 1636.3 AI Use in Drug Formulation 1636.4 Drug Release Characterization Using AI 1646.5 AI-Based Dose/Dosing Regimen 1656.6 Dissolution Rate Predictions with AI 1666.7 Clinical End-Point Evaluation with AI 1666.8 AI in Prediction of Fate of Drugs Administered Via Mucosal, Transdermal, and Parenteral Routes 1676.9 AI-Integrated Mechanistic Modeling Platform for Drug Delivery and Monitoring 1696.10 AI-Based Tools for Metabolism and Clearance Prediction 1696.11 Limitations of Existing Tools 1716.12 Conclusions 1716.13 Conflict of Interest 171Acknowledgments 171References 1727 Drug Disposition in Neonates and Infants 179David Gyamfi, Emmanuel B. Amoafo, Awo A. Kwapong, Mansa Fredua-Agyeman, and Seth K. Amponsah7.1 Introduction 1797.2 Drug Absorption in Neonates and Infants 1807.3 Drug Distribution in Neonates and Infants 1827.4 Hepatic Metabolism of Drugs in Neonates and Infants 1857.4.1 Phase I Metabolism 1857.4.2 Phase II Metabolism 1877.5 Drug Excretion in Neonates and Infants 1887.6 Pharmacodynamics in Neonates and Infants 1907.7 Age-Related Dosing Regimen in Neonates and Infants 1907.8 Conclusion 192References 1938 Drug Disposition in Adolescents 203Aparoop Das, Kalyani Pathak, Riya Saikia, Manash P. Pathak, Urvashee Gogoi, Jon J. Sahariah, Dibyajyoti Das, Md Ariful Islam, and Pallab Pramanik8.1 Introduction 2038.2 Physiological Considerations in Adolescents 2068.2.1 Organ Development: Liver and Kidney Maturation 2068.2.2 Variations in Body Composition 2088.2.3 Hormonal Changes 2088.2.3.1 Males 2088.2.3.2 Females 2098.2.4 Other Physiological Changes 2108.3 Medication Adherence Challenges in Adolescents 2118.4 Psychological Development on Drug Disposition 2128.5 Risk-Taking behaviors and Their Implications on Medication Use 2138.6 Drug Use Among Adolescents 2158.6.1 Acetaminophen Use in Adolescents 2158.6.2 Antidepressant Use in Adolescents 2158.6.3 Drugs for ADHD 2168.7 Pharmacokinetic Variability in Adolescents Drug Examples 2178.7.1 Acetaminophen 2178.7.2 Theophylline 2178.7.3 Antidepressants 2188.7.4 Drugs for ADHD 2188.8 Legal and Ethical Considerations 2198.8.1 Consent and Confidentiality in Adolescent Healthcare 2198.8.2 Involving Adolescents in Treatment Decisions 2208.8.3 Regulatory Aspects of Adolescents Drug Prescribing 2218.9 Conclusion 221References 2229 Drug Disposition in Pregnancy 229Jacob Treanor, Stefanos Belavilas, Dominique Cook, Justin Cole, Amruta Potdar, and Charles Preuss9.1 Introduction 2299.2 Physiological Changes in Pregnancy 2309.2.1 Changes in Absorption 2319.2.2 Changes in Distribution and Free Medication 2319.2.3 Changes in Cytochrome Metabolism 2339.2.4 Changes in Renal Excretion 2339.2.5 General Considerations in Drug Dosing with Pregnancy 2349.3 Placental Drug Disposition 2349.3.1 Placental Barrier Anatomy and Physiology 2359.3.2 Placental Transport Mechanisms 2379.3.3 Methods of Study for Placental Drug Transfer 2389.4 Drug Classification in Pregnancy 2399.5 Pharmacokinetic (PK) Modeling 2419.6 Physiologically Based Pharmacokinetic (PBPK) Modeling 2429.7 Limitations in PK and PBPK Models 2449.8 PBPK Model Variables 2449.9 Determining Treatment During Pregnancy 2459.10 Fetal Blood Flow and Drug Processing 2459.10.1 Hepatic and Renal Processing 2469.10.2 Embryonic Staging 2489.11 Teratogens 2499.11.1 Thalidomide 2509.11.2 Alcohol 2519.11.3 Smoking and E-cigarettes 2519.11.4 Caffeine 2529.11.5 Antibiotics 2539.11.6 Retinoids 2549.12 Conclusion 257Abbreviations 257References 25810 Drug Disposition in Obesity 265Seema Kohli and Ankita A. Singh10.1 Introduction 26510.2 Index of Obesity 26510.3 Pathogenesis of Obesity/Overweight 26610.4 Drug Disposition in Obesity 26710.4.1 Absorption 26710.4.2 Distribution 26810.4.3 Metabolism 26810.4.4 Renal Excretion 27010.5 Drug Dose Calculations in Obese Patients 27010.5.1 Volume of Distribution (Vd) 27010.5.2 Drug Clearance 27110.5.3 Body Size Description 27110.5.4 Drug Dose Calculation 27210.6 Disposition of Drugs in Obesity 27310.6.1 Volatile Agents 27310.6.2 Thiopental 27410.6.3 Propofol 27410.6.4 Midazolam 27410.6.5 Acetaminophen 27410.6.6 Opioids 27510.6.7 Unfractionated Heparin 27510.6.8 Cephazolin 27510.6.9 Enoxaparin 27510.7 Conclusion 276References 27611 Drug Disposition in Critical Care Patients 281Chinenye E. Muolokwu, Benjamin Tagoe, Michael M. Attah, and Seth K. Amponsah11.1 Introduction 28111.2 Pharmacokinetic Considerations in Critical Care Patients 28211.2.1 Drug Absorption Considerations in Critical Care Patients 28211.2.2 Drug Distribution Considerations in Critical Care Patients 28311.2.3 Drug Metabolism Considerations in Critical Care Patients 28411.2.4 Drug Excretion Considerations in Critical Care Patients 28511.3 Dosing Algorithms for Commonly Administered Drugs in Critical Care Patients 28611.3.1 Antibacterial and Antifungal Agents 28611.3.1.1 Aminoglycosides 28711.3.1.2 β-Lactam Antibiotics 28811.3.1.3 Fluoroquinolones 28811.3.1.4 Oxazolidinones 28911.3.1.5 Antifungal Agents 28911.3.2 Inotropes 29111.3.3 Antiviral Drugs 29211.3.4 Narcotic Analgesics 29211.3.4.1 Morphine and Pethidine 29211.3.4.2 Fentanyl and Derivatives 29311.3.5 Sedatives and Hypnotics 29311.3.5.1 Midazolam 29411.3.5.2 Lorazepam 29511.3.6 Neuromuscular Blockers 29511.4 Conclusion 297References 29712 Drug Disposition in Renal Insufficiency 305Sarah Nestler, Deborah Liaw, Gabriella Blanco, Rana Hanna, Ellen Si, and Charles Preuss12.1 Renal Physiology 30512.1.1 General Anatomical Structure 30512.1.2 General Function of the Nephron 30612.1.3 Water Regulation 30612.1.4 Glomerular Filtration Rate (GFR) 30712.1.5 Acid–Base Regulation 30712.2 Glomerular Filtration Rate 30712.3 Acute Kidney Injury 30812.3.1 Diagnostic Criteria and Classification 30812.3.2 Causes of AKI 31012.3.3 Prerenal 31012.3.4 Intrinsic 31012.3.5 Postrenal 31112.4 Chronic Kidney Disease 31112.4.1 Diagnostic Criteria and Classification 31112.4.2 Causes of Chronic Kidney Disease 31212.5 Medication Dosing Modifications 31312.5.1 Medication Dosing in Patients with CKD 31312.5.2 Medications to Treat CKD-Induced HTN and Medications to Avoid in CKD 31412.5.2.1 Antihypertensives 31412.5.2.2 Hypoglycemics 31612.5.2.3 Antimicrobials 31712.5.2.4 Statins 32112.5.2.5 NSAIDs 32212.5.2.6 Analgesics 32212.6 Epidemiology and Outcomes of Patients with CKD 323References 32413 Drug Disposition in Hepatic Insufficiency 327Fried A. Abilba, Jacob A. Ayembilla, and Raphael N. Alolga13.1 Introduction 32713.2 The Spectrum of Liver Diseases 32813.3 Liver Function and Drug Metabolism 33013.3.1 Impact of Hepatic Insufficiency on Drug Metabolism 33113.3.2 Pharmacokinetic Changes in Hepatic Insufficiency 33213.3.3 Effect of Liver Diseases on Pharmacokinetics of Drugs 33313.4 Dosing Algorithms in Clinical Practice 33413.4.1 Drug Selection 33513.4.2 Dosing Adjustments 33613.4.3 Pharmacokinetic Considerations 33613.5 Drug Disposition and Factors That Influence Drug Disposition 33613.6 Major Classes of Drugs and Hepatic Insufficiency 33713.6.1 Anticoagulants 33713.6.2 Antibiotics 33813.6.3 Analgesics 33813.6.4 Anticonvulsants 33813.6.5 Antidepressants 33913.6.6 Antiretrovirals 33913.7 Cases Demonstrating Application of Dosing Algorithms 33913.7.1 Case 1: Warfarin for Anticoagulation 33913.7.1.1 The Use of Warfarin in a Patient with Hereditary Bleeding Disorder 33913.7.1.2 Dosing Algorithm of Warfarin 34013.7.2 Case 2: Acetaminophen for Pain Management 34013.7.2.1 Dosing Algorithm for Paracetamol and Other Cytochrome p 450Enzyme-inducing Drugs in Hepatic Insufficiency Using Child-Pugh Score 34113.7.3 Case 3: Valproic Acid for Seizure Control 34113.7.4 Case 4: Metronidazole for Infection 34213.7.5 Case 5: Efavirenz for HIV Treatment 34213.8 Limitations of Current Dosing Strategies 34213.9 Conclusion and Future Perspectives 34313.9.1 Emerging Technologies and Precision Medicine 34313.9.2 Potential Impact of Pharmacogenomics 34413.9.3 Areas of Research Interest 344References 34514 Drug Disposition in Geriatrics 349Ali Karimi, Samuel Cockey, Millena Levin, Teresa Travnicek, Nishanth Chalasani, and Charles Preuss14.1 Introduction 34914.2 Absorption 35114.3 Distribution 35214.4 Metabolism 35414.5 Excretion 35614.6 Hepatic 36014.7 Renal 36114.8 Cardiac 36314.9 Sex Differences 36314.10 Psychoactive Drugs 36514.11 Anesthesiology Drugs 36614.12 Drug Interactions 36714.13 Drug Side Effects 36814.14 Conclusion 371Abbreviations 372References 37315 Considerations and Regulatory Affairs for Clinical Research in Special Populations 377Stephanie Leigh, Maxine Turner, and Goonaseelan C. Pillai15.1 Introduction 37715.2 Regulatory Frameworks for Clinical Research in Special Populations 37815.2.1 The Historical Evolution of Regulatory Frameworks for Special Population Research 37815.2.2 Current Global Regulatory Frameworks for Special Population Research 38015.2.3 Current Regional Regulations Concerning Clinical Research Involving Special Populations 38215.2.3.1 The United States: Food and Drug Regulatory Authority (us Fda) 38215.2.3.2 Europe: European Medicines Agency (EMA) 38315.2.3.3 The United Kingdom: The Medicines and Healthcare Products Regulatory Agency (MHRA) 38315.2.3.4 Australia: The Therapeutic Goods Administration (TGA) 38415.2.3.5 Brazil: National Health Surveillance Agency (ANVISA) 38515.2.3.6 India: Central Drugs Standard Control Organization (CDSCO) 38715.2.3.7 China: National Medical Products Administration (NMPA) 38815.2.3.8 South Africa: The South African Health Products Regulatory Authority (SAHPRA) 38915.2.4 Holistic Analysis of Regional Regulations Concerning Clinical Research Involving Special Populations 39115.3 Key Considerations for Clinical Trials in Special Population Groups 39215.3.1 Pediatric Population Groups 39215.3.1.1 Regulatory Guidelines Governing Pediatric Clinical Research 39215.3.2 Regional Legislations Governing Clinical Research in Pediatric Populations 39315.3.2.1 The United States: Food and Drug Regulatory Authority (us Fda) 39315.3.2.2 Europe: European Medicines Agency (EMA) 39515.3.2.3 The United Kingdom: The Medicines and Healthcare Products Regulatory Agency (MHRA) 39615.3.2.4 India: Central Drugs Standard Control Organization (CDSCO) 39615.3.2.5 Other Global Jurisdictions 39715.3.3 Holistic Analysis of Regional Regulations Concerning Clinical Research Involving Pediatric Populations 39815.3.4 Ethical Considerations for Clinical Research in Pediatric Populations 39815.3.4.1 Assent and Informed Consent 39915.3.4.2 Participant Recruitment 40215.4 Pregnant Population Groups 40315.4.1 Historical Exclusion of Pregnant Persons in Clinical Research 40315.4.2 Regulatory Guidelines Governing Clinical Research in Pregnant Persons 40415.4.3 Regional Legislations Governing Clinical Research in Pregnant Persons 40615.4.3.1 The United States: Food and Drug Regulatory Authority (us Fda) 40615.4.3.2 Europe: European Medicines Agency (EMA) 40615.4.3.3 Australia: The Therapeutic Goods Administration (TGA) 40715.4.3.4 Brazil: National Health Surveillance Agency (ANVISA) 40715.4.3.5 India: Central Drugs Standard Control Organization (CDSCO) 40815.4.3.6 China: National Medical Products Administration (NMPA) 40915.4.4 Challenges and Barriers to Clinical Research in Pregnant Persons 40915.5 Geriatric Populations 41015.5.1 Key Regulatory Guidelines Governing Geriatric Clinical Research 41115.5.2 Regional Legislations Governing Clinical Research in Geriatric Populations 41215.5.2.1 The United States: Food and Drug Regulatory Authority (us Fda) 41215.5.2.2 Europe: European Medicines Agency (EMA) 41415.5.2.3 The United Kingdom: The Medicines and Healthcare Products Regulatory Agency (MHRA) 41515.5.2.4 India: Central Drugs Standard Control Organization (CDSCO) 41615.5.2.5 Other Global Jurisdictions 41715.5.3 Challenges and Barriers to Clinical Research in Geriatric Populations 41715.6 Critical Care 41715.6.1 Key Regulatory Guidelines Governing Critical Care Clinical Research 41815.6.2 Regional Legislations Governing Clinical Research in Critical Care Populations 41815.6.2.1 The United States: Food and Drug Regulatory Authority (us Fda) 41815.6.2.2 Europe: European Medicines Agency (EMA) 42015.6.2.3 The United Kingdom: The Medicines and Healthcare Products Regulatory Agency (MHRA) 42015.6.2.4 India: Central Drugs Standard Control Organization (CDSCO) 42115.6.2.5 Other Global Jurisdictions 42115.6.3 Challenges and Barriers to Clinical Research in Critical Care Populations 42215.7 Summary Points 42215.7.1 Regulatory Guidelines 42215.7.2 Ethical Considerations 42315.7.3 Participant Recruitment 42315.8 Conclusion 423References 424Index 435

Seth Kwabena Amponsah, PhD, is an Associate Professor at the Department of Medical Pharmacology at the University of Ghana Medical School. He has published over 70 research articles, 20 book chapters, 4 books, and several conference abstracts. Yashwant V. Pathak, PhD, is Associate Dean for Faculty Affairs and Tenured Professor of Pharmaceutical Sciences at the University of South Florida. He has published over 410 research articles, reviews, book chapters, and books.

• About the Editors xxiList of Contributors xxiiiForeword xxixPreface xxxi1 Pharmacokinetic Principles and Concepts: An Overview 1Seth K. Amponsah and Yahwant V. Pathak1.1 Introduction 11.2 Pharmacokinetic Parameters 21.2.1 Absorption 21.2.2 Distribution 31.2.3 Metabolism 41.2.4 Excretion 51.3 Pharmacokinetic Models 51.4 Applications 61.5 Conclusion 7References 72 Model-Based Pharmacokinetic Approaches 11Manish P. Patel, Kashyap M. Patel, Shakil Z. Vhora, Anuradha K. Gajjar, Jayvadan K. Patel, and Amitkumar K. Patel2.1 Introduction 112.1.1 Importance of PK 122.1.2 Overview of Model-Based Approaches 132.2 Basics of Pharmacokinetics 142.2.1 Key Pharmacokinetic Parameters 142.2.1.1 Absorption 142.2.1.2 Key Parameter 142.2.1.3 Distribution 142.2.1.4 Key Parameter 152.2.1.5 Metabolism 152.2.1.6 Key Parameter 152.2.1.7 Excretion 152.2.1.8 Key Parameter 152.2.2 Differences Between Traditional and Model-Based Pharmacokinetic Approaches 162.3 Pharmacokinetic (PK) Models 172.3.1 Introduction 172.3.2 Compartment Modeling 182.3.2.1 One-Compartment Model 212.3.2.2 Multi-Compartment Model 212.3.2.3 Two-Compartment Model 242.3.3 Population PK Model 252.3.4 Physiologically Based PK (PBPK) Model 262.4 Model Development and Validation 272.4.1 Data Requirements for Model Development 272.4.2 Data Requirements for Model Validation 292.4.3 Steps in Model Building (E.g., Model Selection and Parameter Estimation) 292.5 Applications of Model-Based Approaches 312.5.1 Dose Optimization 312.5.2 Predicting Drug Interactions 322.5.3 Drug Tailoring in Special Populations (E.g., Pediatrics, Geriatrics, and Renal Impairment) 332.5.4 Translational PK from Preclinical to Clinical Settings 342.6 Modeling in Special Populations 362.6.1 Challenges and Considerations 362.6.1.1 Challenges in PK Modeling 362.6.1.2 Considerations in PK Modeling 362.7 Software and Tools for PK Modeling 372.7.1 Gastroplus™ 382.7.2 Berkeley Madonna 382.7.3 MATLAB 382.7.4 PK-Sim® 392.7.5 Simcyp® 392.7.6 Auxiliary PBPK Modeling Software 392.7.6.1 Julia 392.7.6.2 Nonmem 392.7.6.3 Phoenix WinNonlin 402.7.6.4 GraphPad Prism 402.7.6.5 Minitab 402.7.6.6 PlotDigitizer 402.7.6.7 GNU MCSim 402.7.6.8 WebPlotDigitizer 402.8 Regulatory Perspectives of PK Modeling 402.9 Future Directions of PK Modeling 432.10 Conclusion 43Abbreviations 44References 453 Physiologically Based Pharmacokinetic Modeling 53Mahesh P. More and Rahul S. Tade3.1 Introduction 533.2 Significance of PBPK Modeling 563.3 Principles for the Development of PBPK for Special Populations 573.4 Data Integration for Special Populations 573.4.1 Demographic Data 583.4.2 Physiological Consideration 583.4.3 Ontogeny 583.4.4 Age and Maturation Changes 593.4.5 Steady State Volume of Distribution (Vdss) 593.5 Applications of PBPK Modeling 603.5.1 Dose Optimization/Regimen/Selection 603.5.2 Dose Individualization/Precision Dosing 613.5.3 Biopharmaceutics 623.6 Regulatory Applications/Pre–Post Market Utilization 623.7 Case Studies 643.7.1 Simulation Application 643.7.2 Successful Applications 673.8 Lessons Learned 683.9 Conclusion 68References 704 Therapeutic Drug Monitoring in Special Populations 75James A. Akingbasote, Sandra K. Szlapinski, Elora Hilmas, Kyle Weston, Yelena Wu, and Alexandra Burton4.1 Introduction 754.2 Pediatrics 764.2.1 Importance of TDM in Pediatrics 764.2.2 Pharmacokinetic Differences in Pediatric Patients 774.2.3 Drug Absorption in the Pediatric Population 774.2.4 Drug Distribution in the Pediatric Population 784.2.5 Drug Metabolism and Elimination in the Pediatric Population 794.3 TDM Practices in Pediatrics 794.3.1 Vancomycin 804.3.2 Aminoglycosides 814.3.3 Ganciclovir/Valganciclovir 824.3.4 Antiepileptic Drugs (AEDs) 834.3.5 Enoxaparin 844.4 Conclusion 854.5 Pregnancy 854.5.1 Physiological Adaptations in Pregnancy 854.5.2 Current State of Clinical Practice of TDM in Pregnancy 874.5.3 TDM in Pregnancy 894.5.3.1 Antiepileptics 894.5.3.2 Antidepressants 904.5.3.3 Antiretroviral Drugs 914.5.3.4 Immunomodulatory Drugs 934.5.4 Challenges in the Implementation of TDM in the Pregnant Population 944.6 The Elderly 954.6.1 Physiological Changes in the Elderly 954.6.2 Effect of Aging on Drug Pharmacokinetics 954.6.3 Application of TDM in the Elderly 974.6.3.1 Cardiac Glycosides 984.6.3.2 Serotonin–Norepinephrine Reuptake Inhibitor (SNRI) 984.6.3.3 Anticoagulants 994.6.3.4 Benzodiazepines 994.7 Conclusion 1014.8 Hepatic and Renal Impairments 1014.8.1 Hepatic Impairment 1024.8.2 TDM in Patients with Hepatic Impairment 1044.8.2.1 Meropenem 1054.8.2.2 Metoprolol 1054.8.2.3 Midazolam 1064.8.3 Renal Impairment 1074.8.4 Prerenal Disease 1094.8.5 Intrinsic Renal Vascular Disease 1094.8.6 Intrinsic Glomerular Disease (Nephritic or Nephrotic) 1094.8.7 TDM in Renal Impairment 1094.8.7.1 Vancomycin 1114.8.7.2 Metformin 1114.9 Conclusion 1124.10 Overall Conclusion and Future Direction 112Acknowledgment 113References 1145 Optimization of Drug Dosing Regimen 133Vivek Patel, Kartik Hariharan, Dhruv Shah, Arindam Halder, Ajay J. Khopade, Amitkumar K. Patel, and Jayvadan K. Patel5.1 Introduction 1335.2 Dosing Regimen Optimization Approaches and Strategies 1345.2.1 Models Used for Dosing Regimen Selection 1345.2.1.1 Pharmacometric Models 1345.2.1.2 PK Models 1355.2.1.3 Empirical Dose–Response Models 1365.2.1.4 Multiple Comparison Procedures Models (MCP-Mod) 1365.2.1.5 Model Averaging 1375.2.2 Role of Patient Characteristics in Dose Selection 1375.2.2.1 Phenotype-Guided Dosing 1375.2.2.2 Genotype-Guided Drug Dosing 1385.2.3 Therapeutic Drug Monitoring (TDM) 1385.3 Dosing Regimen in Special Populations 1395.3.1 Dosing Regimen in Cancer Patients 1395.3.1.1 Metronomic Chemotherapy 1405.3.2 Dosing Regimen for Patients on Antimicrobial Therapy 1425.3.2.1 Antimicrobial Stewardship Strategy 1455.3.2.2 Mathematical Models for Optimizing Antimicrobial Therapy 1465.3.2.3 Antimicrobial Dosing Strategies During CRRT 1475.3.2.4 Methods for Enhancing Dosing of Antimicrobials via Nebulization 1495.3.3 Dosing Regimen in Pediatric Patients 1495.3.3.1 Physiological Differences Between Pediatric and Adult Patients 1495.3.3.2 Application of MIDD in Pediatric Dose Selection 1495.3.3.3 Scaling from Adults to Pediatric Patients 1505.3.3.4 Scaling from Animals to Pediatric Patients 1505.3.3.5 Integrating Mechanistic Models in Neonates and Infants 1505.3.3.6 Dose Optimization in Neonates and Infants 1515.4 Conclusion 151References 1526 Artificial Intelligence in Drug Development 161Surovi Saikia, Aparna Anandan, Unais Annenkottil, Vishnu P. Athilingam, Partha P. Kalita, and Viswanadha V. Padma6.1 Introduction 1616.2 Application of AI in Drug Design 1626.2.1 Target Identification and Validation 1626.2.2 Drug Candidate Design and Optimization 1626.2.3 Virtual Screening and Molecular Docking 1636.2.4 Synthesis Planning 1636.2.5 Predicting Drug Toxicity and Pharmacokinetics 1636.2.6 Personalized Medicine 1636.3 AI Use in Drug Formulation 1636.4 Drug Release Characterization Using AI 1646.5 AI-Based Dose/Dosing Regimen 1656.6 Dissolution Rate Predictions with AI 1666.7 Clinical End-Point Evaluation with AI 1666.8 AI in Prediction of Fate of Drugs Administered Via Mucosal, Transdermal, and Parenteral Routes 1676.9 AI-Integrated Mechanistic Modeling Platform for Drug Delivery and Monitoring 1696.10 AI-Based Tools for Metabolism and Clearance Prediction 1696.11 Limitations of Existing Tools 1716.12 Conclusions 1716.13 Conflict of Interest 171Acknowledgments 171References 1727 Drug Disposition in Neonates and Infants 179David Gyamfi, Emmanuel B. Amoafo, Awo A. Kwapong, Mansa Fredua-Agyeman, and Seth K. Amponsah7.1 Introduction 1797.2 Drug Absorption in Neonates and Infants 1807.3 Drug Distribution in Neonates and Infants 1827.4 Hepatic Metabolism of Drugs in Neonates and Infants 1857.4.1 Phase I Metabolism 1857.4.2 Phase II Metabolism 1877.5 Drug Excretion in Neonates and Infants 1887.6 Pharmacodynamics in Neonates and Infants 1907.7 Age-Related Dosing Regimen in Neonates and Infants 1907.8 Conclusion 192References 1938 Drug Disposition in Adolescents 203Aparoop Das, Kalyani Pathak, Riya Saikia, Manash P. Pathak, Urvashee Gogoi, Jon J. Sahariah, Dibyajyoti Das, Md Ariful Islam, and Pallab Pramanik8.1 Introduction 2038.2 Physiological Considerations in Adolescents 2068.2.1 Organ Development: Liver and Kidney Maturation 2068.2.2 Variations in Body Composition 2088.2.3 Hormonal Changes 2088.2.3.1 Males 2088.2.3.2 Females 2098.2.4 Other Physiological Changes 2108.3 Medication Adherence Challenges in Adolescents 2118.4 Psychological Development on Drug Disposition 2128.5 Risk-Taking behaviors and Their Implications on Medication Use 2138.6 Drug Use Among Adolescents 2158.6.1 Acetaminophen Use in Adolescents 2158.6.2 Antidepressant Use in Adolescents 2158.6.3 Drugs for ADHD 2168.7 Pharmacokinetic Variability in Adolescents Drug Examples 2178.7.1 Acetaminophen 2178.7.2 Theophylline 2178.7.3 Antidepressants 2188.7.4 Drugs for ADHD 2188.8 Legal and Ethical Considerations 2198.8.1 Consent and Confidentiality in Adolescent Healthcare 2198.8.2 Involving Adolescents in Treatment Decisions 2208.8.3 Regulatory Aspects of Adolescents Drug Prescribing 2218.9 Conclusion 221References 2229 Drug Disposition in Pregnancy 229Jacob Treanor, Stefanos Belavilas, Dominique Cook, Justin Cole, Amruta Potdar, and Charles Preuss9.1 Introduction 2299.2 Physiological Changes in Pregnancy 2309.2.1 Changes in Absorption 2319.2.2 Changes in Distribution and Free Medication 2319.2.3 Changes in Cytochrome Metabolism 2339.2.4 Changes in Renal Excretion 2339.2.5 General Considerations in Drug Dosing with Pregnancy 2349.3 Placental Drug Disposition 2349.3.1 Placental Barrier Anatomy and Physiology 2359.3.2 Placental Transport Mechanisms 2379.3.3 Methods of Study for Placental Drug Transfer 2389.4 Drug Classification in Pregnancy 2399.5 Pharmacokinetic (PK) Modeling 2419.6 Physiologically Based Pharmacokinetic (PBPK) Modeling 2429.7 Limitations in PK and PBPK Models 2449.8 PBPK Model Variables 2449.9 Determining Treatment During Pregnancy 2459.10 Fetal Blood Flow and Drug Processing 2459.10.1 Hepatic and Renal Processing 2469.10.2 Embryonic Staging 2489.11 Teratogens 2499.11.1 Thalidomide 2509.11.2 Alcohol 2519.11.3 Smoking and E-cigarettes 2519.11.4 Caffeine 2529.11.5 Antibiotics 2539.11.6 Retinoids 2549.12 Conclusion 257Abbreviations 257References 25810 Drug Disposition in Obesity 265Seema Kohli and Ankita A. Singh10.1 Introduction 26510.2 Index of Obesity 26510.3 Pathogenesis of Obesity/Overweight 26610.4 Drug Disposition in Obesity 26710.4.1 Absorption 26710.4.2 Distribution 26810.4.3 Metabolism 26810.4.4 Renal Excretion 27010.5 Drug Dose Calculations in Obese Patients 27010.5.1 Volume of Distribution (Vd) 27010.5.2 Drug Clearance 27110.5.3 Body Size Description 27110.5.4 Drug Dose Calculation 27210.6 Disposition of Drugs in Obesity 27310.6.1 Volatile Agents 27310.6.2 Thiopental 27410.6.3 Propofol 27410.6.4 Midazolam 27410.6.5 Acetaminophen 27410.6.6 Opioids 27510.6.7 Unfractionated Heparin 27510.6.8 Cephazolin 27510.6.9 Enoxaparin 27510.7 Conclusion 276References 27611 Drug Disposition in Critical Care Patients 281Chinenye E. Muolokwu, Benjamin Tagoe, Michael M. Attah, and Seth K. Amponsah11.1 Introduction 28111.2 Pharmacokinetic Considerations in Critical Care Patients 28211.2.1 Drug Absorption Considerations in Critical Care Patients 28211.2.2 Drug Distribution Considerations in Critical Care Patients 28311.2.3 Drug Metabolism Considerations in Critical Care Patients 28411.2.4 Drug Excretion Considerations in Critical Care Patients 28511.3 Dosing Algorithms for Commonly Administered Drugs in Critical Care Patients 28611.3.1 Antibacterial and Antifungal Agents 28611.3.1.1 Aminoglycosides 28711.3.1.2 β-Lactam Antibiotics 28811.3.1.3 Fluoroquinolones 28811.3.1.4 Oxazolidinones 28911.3.1.5 Antifungal Agents 28911.3.2 Inotropes 29111.3.3 Antiviral Drugs 29211.3.4 Narcotic Analgesics 29211.3.4.1 Morphine and Pethidine 29211.3.4.2 Fentanyl and Derivatives 29311.3.5 Sedatives and Hypnotics 29311.3.5.1 Midazolam 29411.3.5.2 Lorazepam 29511.3.6 Neuromuscular Blockers 29511.4 Conclusion 297References 29712 Drug Disposition in Renal Insufficiency 305Sarah Nestler, Deborah Liaw, Gabriella Blanco, Rana Hanna, Ellen Si, and Charles Preuss12.1 Renal Physiology 30512.1.1 General Anatomical Structure 30512.1.2 General Function of the Nephron 30612.1.3 Water Regulation 30612.1.4 Glomerular Filtration Rate (GFR) 30712.1.5 Acid–Base Regulation 30712.2 Glomerular Filtration Rate 30712.3 Acute Kidney Injury 30812.3.1 Diagnostic Criteria and Classification 30812.3.2 Causes of AKI 31012.3.3 Prerenal 31012.3.4 Intrinsic 31012.3.5 Postrenal 31112.4 Chronic Kidney Disease 31112.4.1 Diagnostic Criteria and Classification 31112.4.2 Causes of Chronic Kidney Disease 31212.5 Medication Dosing Modifications 31312.5.1 Medication Dosing in Patients with CKD 31312.5.2 Medications to Treat CKD-Induced HTN and Medications to Avoid in CKD 31412.5.2.1 Antihypertensives 31412.5.2.2 Hypoglycemics 31612.5.2.3 Antimicrobials 31712.5.2.4 Statins 32112.5.2.5 NSAIDs 32212.5.2.6 Analgesics 32212.6 Epidemiology and Outcomes of Patients with CKD 323References 32413 Drug Disposition in Hepatic Insufficiency 327Fried A. Abilba, Jacob A. Ayembilla, and Raphael N. Alolga13.1 Introduction 32713.2 The Spectrum of Liver Diseases 32813.3 Liver Function and Drug Metabolism 33013.3.1 Impact of Hepatic Insufficiency on Drug Metabolism 33113.3.2 Pharmacokinetic Changes in Hepatic Insufficiency 33213.3.3 Effect of Liver Diseases on Pharmacokinetics of Drugs 33313.4 Dosing Algorithms in Clinical Practice 33413.4.1 Drug Selection 33513.4.2 Dosing Adjustments 33613.4.3 Pharmacokinetic Considerations 33613.5 Drug Disposition and Factors That Influence Drug Disposition 33613.6 Major Classes of Drugs and Hepatic Insufficiency 33713.6.1 Anticoagulants 33713.6.2 Antibiotics 33813.6.3 Analgesics 33813.6.4 Anticonvulsants 33813.6.5 Antidepressants 33913.6.6 Antiretrovirals 33913.7 Cases Demonstrating Application of Dosing Algorithms 33913.7.1 Case 1: Warfarin for Anticoagulation 33913.7.1.1 The Use of Warfarin in a Patient with Hereditary Bleeding Disorder 33913.7.1.2 Dosing Algorithm of Warfarin 34013.7.2 Case 2: Acetaminophen for Pain Management 34013.7.2.1 Dosing Algorithm for Paracetamol and Other Cytochrome p 450Enzyme-inducing Drugs in Hepatic Insufficiency Using Child-Pugh Score 34113.7.3 Case 3: Valproic Acid for Seizure Control 34113.7.4 Case 4: Metronidazole for Infection 34213.7.5 Case 5: Efavirenz for HIV Treatment 34213.8 Limitations of Current Dosing Strategies 34213.9 Conclusion and Future Perspectives 34313.9.1 Emerging Technologies and Precision Medicine 34313.9.2 Potential Impact of Pharmacogenomics 34413.9.3 Areas of Research Interest 344References 34514 Drug Disposition in Geriatrics 349Ali Karimi, Samuel Cockey, Millena Levin, Teresa Travnicek, Nishanth Chalasani, and Charles Preuss14.1 Introduction 34914.2 Absorption 35114.3 Distribution 35214.4 Metabolism 35414.5 Excretion 35614.6 Hepatic 36014.7 Renal 36114.8 Cardiac 36314.9 Sex Differences 36314.10 Psychoactive Drugs 36514.11 Anesthesiology Drugs 36614.12 Drug Interactions 36714.13 Drug Side Effects 36814.14 Conclusion 371Abbreviations 372References 37315 Considerations and Regulatory Affairs for Clinical Research in Special Populations 377Stephanie Leigh, Maxine Turner, and Goonaseelan C. Pillai15.1 Introduction 37715.2 Regulatory Frameworks for Clinical Research in Special Populations 37815.2.1 The Historical Evolution of Regulatory Frameworks for Special Population Research 37815.2.2 Current Global Regulatory Frameworks for Special Population Research 38015.2.3 Current Regional Regulations Concerning Clinical Research Involving Special Populations 38215.2.3.1 The United States: Food and Drug Regulatory Authority (us Fda) 38215.2.3.2 Europe: European Medicines Agency (EMA) 38315.2.3.3 The United Kingdom: The Medicines and Healthcare Products Regulatory Agency (MHRA) 38315.2.3.4 Australia: The Therapeutic Goods Administration (TGA) 38415.2.3.5 Brazil: National Health Surveillance Agency (ANVISA) 38515.2.3.6 India: Central Drugs Standard Control Organization (CDSCO) 38715.2.3.7 China: National Medical Products Administration (NMPA) 38815.2.3.8 South Africa: The South African Health Products Regulatory Authority (SAHPRA) 38915.2.4 Holistic Analysis of Regional Regulations Concerning Clinical Research Involving Special Populations 39115.3 Key Considerations for Clinical Trials in Special Population Groups 39215.3.1 Pediatric Population Groups 39215.3.1.1 Regulatory Guidelines Governing Pediatric Clinical Research 39215.3.2 Regional Legislations Governing Clinical Research in Pediatric Populations 39315.3.2.1 The United States: Food and Drug Regulatory Authority (us Fda) 39315.3.2.2 Europe: European Medicines Agency (EMA) 39515.3.2.3 The United Kingdom: The Medicines and Healthcare Products Regulatory Agency (MHRA) 39615.3.2.4 India: Central Drugs Standard Control Organization (CDSCO) 39615.3.2.5 Other Global Jurisdictions 39715.3.3 Holistic Analysis of Regional Regulations Concerning Clinical Research Involving Pediatric Populations 39815.3.4 Ethical Considerations for Clinical Research in Pediatric Populations 39815.3.4.1 Assent and Informed Consent 39915.3.4.2 Participant Recruitment 40215.4 Pregnant Population Groups 40315.4.1 Historical Exclusion of Pregnant Persons in Clinical Research 40315.4.2 Regulatory Guidelines Governing Clinical Research in Pregnant Persons 40415.4.3 Regional Legislations Governing Clinical Research in Pregnant Persons 40615.4.3.1 The United States: Food and Drug Regulatory Authority (us Fda) 40615.4.3.2 Europe: European Medicines Agency (EMA) 40615.4.3.3 Australia: The Therapeutic Goods Administration (TGA) 40715.4.3.4 Brazil: National Health Surveillance Agency (ANVISA) 40715.4.3.5 India: Central Drugs Standard Control Organization (CDSCO) 40815.4.3.6 China: National Medical Products Administration (NMPA) 40915.4.4 Challenges and Barriers to Clinical Research in Pregnant Persons 40915.5 Geriatric Populations 41015.5.1 Key Regulatory Guidelines Governing Geriatric Clinical Research 41115.5.2 Regional Legislations Governing Clinical Research in Geriatric Populations 41215.5.2.1 The United States: Food and Drug Regulatory Authority (us Fda) 41215.5.2.2 Europe: European Medicines Agency (EMA) 41415.5.2.3 The United Kingdom: The Medicines and Healthcare Products Regulatory Agency (MHRA) 41515.5.2.4 India: Central Drugs Standard Control Organization (CDSCO) 41615.5.2.5 Other Global Jurisdictions 41715.5.3 Challenges and Barriers to Clinical Research in Geriatric Populations 41715.6 Critical Care 41715.6.1 Key Regulatory Guidelines Governing Critical Care Clinical Research 41815.6.2 Regional Legislations Governing Clinical Research in Critical Care Populations 41815.6.2.1 The United States: Food and Drug Regulatory Authority (us Fda) 41815.6.2.2 Europe: European Medicines Agency (EMA) 42015.6.2.3 The United Kingdom: The Medicines and Healthcare Products Regulatory Agency (MHRA) 42015.6.2.4 India: Central Drugs Standard Control Organization (CDSCO) 42115.6.2.5 Other Global Jurisdictions 42115.6.3 Challenges and Barriers to Clinical Research in Critical Care Populations 42215.7 Summary Points 42215.7.1 Regulatory Guidelines 42215.7.2 Ethical Considerations 42315.7.3 Participant Recruitment 42315.8 Conclusion 423References 424Index 435

Seth Kwabena Amponsah, PhD, is an Associate Professor at the Department of Medical Pharmacology at the University of Ghana Medical School. He has published over 70 research articles, 20 book chapters, 4 books, and several conference abstracts. Yashwant V. Pathak, PhD, is Associate Dean for Faculty Affairs and Tenured Professor of Pharmaceutical Sciences at the University of South Florida. He has published over 410 research articles, reviews, book chapters, and books.

• About the Editors xxiList of Contributors xxiiiForeword xxixPreface xxxi1 Pharmacokinetic Principles and Concepts: An Overview 1Seth K. Amponsah and Yahwant V. Pathak1.1 Introduction 11.2 Pharmacokinetic Parameters 21.2.1 Absorption 21.2.2 Distribution 31.2.3 Metabolism 41.2.4 Excretion 51.3 Pharmacokinetic Models 51.4 Applications 61.5 Conclusion 7References 72 Model-Based Pharmacokinetic Approaches 11Manish P. Patel, Kashyap M. Patel, Shakil Z. Vhora, Anuradha K. Gajjar, Jayvadan K. Patel, and Amitkumar K. Patel2.1 Introduction 112.1.1 Importance of PK 122.1.2 Overview of Model-Based Approaches 132.2 Basics of Pharmacokinetics 142.2.1 Key Pharmacokinetic Parameters 142.2.1.1 Absorption 142.2.1.2 Key Parameter 142.2.1.3 Distribution 142.2.1.4 Key Parameter 152.2.1.5 Metabolism 152.2.1.6 Key Parameter 152.2.1.7 Excretion 152.2.1.8 Key Parameter 152.2.2 Differences Between Traditional and Model-Based Pharmacokinetic Approaches 162.3 Pharmacokinetic (PK) Models 172.3.1 Introduction 172.3.2 Compartment Modeling 182.3.2.1 One-Compartment Model 212.3.2.2 Multi-Compartment Model 212.3.2.3 Two-Compartment Model 242.3.3 Population PK Model 252.3.4 Physiologically Based PK (PBPK) Model 262.4 Model Development and Validation 272.4.1 Data Requirements for Model Development 272.4.2 Data Requirements for Model Validation 292.4.3 Steps in Model Building (E.g., Model Selection and Parameter Estimation) 292.5 Applications of Model-Based Approaches 312.5.1 Dose Optimization 312.5.2 Predicting Drug Interactions 322.5.3 Drug Tailoring in Special Populations (E.g., Pediatrics, Geriatrics, and Renal Impairment) 332.5.4 Translational PK from Preclinical to Clinical Settings 342.6 Modeling in Special Populations 362.6.1 Challenges and Considerations 362.6.1.1 Challenges in PK Modeling 362.6.1.2 Considerations in PK Modeling 362.7 Software and Tools for PK Modeling 372.7.1 Gastroplus™ 382.7.2 Berkeley Madonna 382.7.3 MATLAB 382.7.4 PK-Sim® 392.7.5 Simcyp® 392.7.6 Auxiliary PBPK Modeling Software 392.7.6.1 Julia 392.7.6.2 Nonmem 392.7.6.3 Phoenix WinNonlin 402.7.6.4 GraphPad Prism 402.7.6.5 Minitab 402.7.6.6 PlotDigitizer 402.7.6.7 GNU MCSim 402.7.6.8 WebPlotDigitizer 402.8 Regulatory Perspectives of PK Modeling 402.9 Future Directions of PK Modeling 432.10 Conclusion 43Abbreviations 44References 453 Physiologically Based Pharmacokinetic Modeling 53Mahesh P. More and Rahul S. Tade3.1 Introduction 533.2 Significance of PBPK Modeling 563.3 Principles for the Development of PBPK for Special Populations 573.4 Data Integration for Special Populations 573.4.1 Demographic Data 583.4.2 Physiological Consideration 583.4.3 Ontogeny 583.4.4 Age and Maturation Changes 593.4.5 Steady State Volume of Distribution (Vdss) 593.5 Applications of PBPK Modeling 603.5.1 Dose Optimization/Regimen/Selection 603.5.2 Dose Individualization/Precision Dosing 613.5.3 Biopharmaceutics 623.6 Regulatory Applications/Pre–Post Market Utilization 623.7 Case Studies 643.7.1 Simulation Application 643.7.2 Successful Applications 673.8 Lessons Learned 683.9 Conclusion 68References 704 Therapeutic Drug Monitoring in Special Populations 75James A. Akingbasote, Sandra K. Szlapinski, Elora Hilmas, Kyle Weston, Yelena Wu, and Alexandra Burton4.1 Introduction 754.2 Pediatrics 764.2.1 Importance of TDM in Pediatrics 764.2.2 Pharmacokinetic Differences in Pediatric Patients 774.2.3 Drug Absorption in the Pediatric Population 774.2.4 Drug Distribution in the Pediatric Population 784.2.5 Drug Metabolism and Elimination in the Pediatric Population 794.3 TDM Practices in Pediatrics 794.3.1 Vancomycin 804.3.2 Aminoglycosides 814.3.3 Ganciclovir/Valganciclovir 824.3.4 Antiepileptic Drugs (AEDs) 834.3.5 Enoxaparin 844.4 Conclusion 854.5 Pregnancy 854.5.1 Physiological Adaptations in Pregnancy 854.5.2 Current State of Clinical Practice of TDM in Pregnancy 874.5.3 TDM in Pregnancy 894.5.3.1 Antiepileptics 894.5.3.2 Antidepressants 904.5.3.3 Antiretroviral Drugs 914.5.3.4 Immunomodulatory Drugs 934.5.4 Challenges in the Implementation of TDM in the Pregnant Population 944.6 The Elderly 954.6.1 Physiological Changes in the Elderly 954.6.2 Effect of Aging on Drug Pharmacokinetics 954.6.3 Application of TDM in the Elderly 974.6.3.1 Cardiac Glycosides 984.6.3.2 Serotonin–Norepinephrine Reuptake Inhibitor (SNRI) 984.6.3.3 Anticoagulants 994.6.3.4 Benzodiazepines 994.7 Conclusion 1014.8 Hepatic and Renal Impairments 1014.8.1 Hepatic Impairment 1024.8.2 TDM in Patients with Hepatic Impairment 1044.8.2.1 Meropenem 1054.8.2.2 Metoprolol 1054.8.2.3 Midazolam 1064.8.3 Renal Impairment 1074.8.4 Prerenal Disease 1094.8.5 Intrinsic Renal Vascular Disease 1094.8.6 Intrinsic Glomerular Disease (Nephritic or Nephrotic) 1094.8.7 TDM in Renal Impairment 1094.8.7.1 Vancomycin 1114.8.7.2 Metformin 1114.9 Conclusion 1124.10 Overall Conclusion and Future Direction 112Acknowledgment 113References 1145 Optimization of Drug Dosing Regimen 133Vivek Patel, Kartik Hariharan, Dhruv Shah, Arindam Halder, Ajay J. Khopade, Amitkumar K. Patel, and Jayvadan K. Patel5.1 Introduction 1335.2 Dosing Regimen Optimization Approaches and Strategies 1345.2.1 Models Used for Dosing Regimen Selection 1345.2.1.1 Pharmacometric Models 1345.2.1.2 PK Models 1355.2.1.3 Empirical Dose–Response Models 1365.2.1.4 Multiple Comparison Procedures Models (MCP-Mod) 1365.2.1.5 Model Averaging 1375.2.2 Role of Patient Characteristics in Dose Selection 1375.2.2.1 Phenotype-Guided Dosing 1375.2.2.2 Genotype-Guided Drug Dosing 1385.2.3 Therapeutic Drug Monitoring (TDM) 1385.3 Dosing Regimen in Special Populations 1395.3.1 Dosing Regimen in Cancer Patients 1395.3.1.1 Metronomic Chemotherapy 1405.3.2 Dosing Regimen for Patients on Antimicrobial Therapy 1425.3.2.1 Antimicrobial Stewardship Strategy 1455.3.2.2 Mathematical Models for Optimizing Antimicrobial Therapy 1465.3.2.3 Antimicrobial Dosing Strategies During CRRT 1475.3.2.4 Methods for Enhancing Dosing of Antimicrobials via Nebulization 1495.3.3 Dosing Regimen in Pediatric Patients 1495.3.3.1 Physiological Differences Between Pediatric and Adult Patients 1495.3.3.2 Application of MIDD in Pediatric Dose Selection 1495.3.3.3 Scaling from Adults to Pediatric Patients 1505.3.3.4 Scaling from Animals to Pediatric Patients 1505.3.3.5 Integrating Mechanistic Models in Neonates and Infants 1505.3.3.6 Dose Optimization in Neonates and Infants 1515.4 Conclusion 151References 1526 Artificial Intelligence in Drug Development 161Surovi Saikia, Aparna Anandan, Unais Annenkottil, Vishnu P. Athilingam, Partha P. Kalita, and Viswanadha V. Padma6.1 Introduction 1616.2 Application of AI in Drug Design 1626.2.1 Target Identification and Validation 1626.2.2 Drug Candidate Design and Optimization 1626.2.3 Virtual Screening and Molecular Docking 1636.2.4 Synthesis Planning 1636.2.5 Predicting Drug Toxicity and Pharmacokinetics 1636.2.6 Personalized Medicine 1636.3 AI Use in Drug Formulation 1636.4 Drug Release Characterization Using AI 1646.5 AI-Based Dose/Dosing Regimen 1656.6 Dissolution Rate Predictions with AI 1666.7 Clinical End-Point Evaluation with AI 1666.8 AI in Prediction of Fate of Drugs Administered Via Mucosal, Transdermal, and Parenteral Routes 1676.9 AI-Integrated Mechanistic Modeling Platform for Drug Delivery and Monitoring 1696.10 AI-Based Tools for Metabolism and Clearance Prediction 1696.11 Limitations of Existing Tools 1716.12 Conclusions 1716.13 Conflict of Interest 171Acknowledgments 171References 1727 Drug Disposition in Neonates and Infants 179David Gyamfi, Emmanuel B. Amoafo, Awo A. Kwapong, Mansa Fredua-Agyeman, and Seth K. Amponsah7.1 Introduction 1797.2 Drug Absorption in Neonates and Infants 1807.3 Drug Distribution in Neonates and Infants 1827.4 Hepatic Metabolism of Drugs in Neonates and Infants 1857.4.1 Phase I Metabolism 1857.4.2 Phase II Metabolism 1877.5 Drug Excretion in Neonates and Infants 1887.6 Pharmacodynamics in Neonates and Infants 1907.7 Age-Related Dosing Regimen in Neonates and Infants 1907.8 Conclusion 192References 1938 Drug Disposition in Adolescents 203Aparoop Das, Kalyani Pathak, Riya Saikia, Manash P. Pathak, Urvashee Gogoi, Jon J. Sahariah, Dibyajyoti Das, Md Ariful Islam, and Pallab Pramanik8.1 Introduction 2038.2 Physiological Considerations in Adolescents 2068.2.1 Organ Development: Liver and Kidney Maturation 2068.2.2 Variations in Body Composition 2088.2.3 Hormonal Changes 2088.2.3.1 Males 2088.2.3.2 Females 2098.2.4 Other Physiological Changes 2108.3 Medication Adherence Challenges in Adolescents 2118.4 Psychological Development on Drug Disposition 2128.5 Risk-Taking behaviors and Their Implications on Medication Use 2138.6 Drug Use Among Adolescents 2158.6.1 Acetaminophen Use in Adolescents 2158.6.2 Antidepressant Use in Adolescents 2158.6.3 Drugs for ADHD 2168.7 Pharmacokinetic Variability in Adolescents Drug Examples 2178.7.1 Acetaminophen 2178.7.2 Theophylline 2178.7.3 Antidepressants 2188.7.4 Drugs for ADHD 2188.8 Legal and Ethical Considerations 2198.8.1 Consent and Confidentiality in Adolescent Healthcare 2198.8.2 Involving Adolescents in Treatment Decisions 2208.8.3 Regulatory Aspects of Adolescents Drug Prescribing 2218.9 Conclusion 221References 2229 Drug Disposition in Pregnancy 229Jacob Treanor, Stefanos Belavilas, Dominique Cook, Justin Cole, Amruta Potdar, and Charles Preuss9.1 Introduction 2299.2 Physiological Changes in Pregnancy 2309.2.1 Changes in Absorption 2319.2.2 Changes in Distribution and Free Medication 2319.2.3 Changes in Cytochrome Metabolism 2339.2.4 Changes in Renal Excretion 2339.2.5 General Considerations in Drug Dosing with Pregnancy 2349.3 Placental Drug Disposition 2349.3.1 Placental Barrier Anatomy and Physiology 2359.3.2 Placental Transport Mechanisms 2379.3.3 Methods of Study for Placental Drug Transfer 2389.4 Drug Classification in Pregnancy 2399.5 Pharmacokinetic (PK) Modeling 2419.6 Physiologically Based Pharmacokinetic (PBPK) Modeling 2429.7 Limitations in PK and PBPK Models 2449.8 PBPK Model Variables 2449.9 Determining Treatment During Pregnancy 2459.10 Fetal Blood Flow and Drug Processing 2459.10.1 Hepatic and Renal Processing 2469.10.2 Embryonic Staging 2489.11 Teratogens 2499.11.1 Thalidomide 2509.11.2 Alcohol 2519.11.3 Smoking and E-cigarettes 2519.11.4 Caffeine 2529.11.5 Antibiotics 2539.11.6 Retinoids 2549.12 Conclusion 257Abbreviations 257References 25810 Drug Disposition in Obesity 265Seema Kohli and Ankita A. Singh10.1 Introduction 26510.2 Index of Obesity 26510.3 Pathogenesis of Obesity/Overweight 26610.4 Drug Disposition in Obesity 26710.4.1 Absorption 26710.4.2 Distribution 26810.4.3 Metabolism 26810.4.4 Renal Excretion 27010.5 Drug Dose Calculations in Obese Patients 27010.5.1 Volume of Distribution (Vd) 27010.5.2 Drug Clearance 27110.5.3 Body Size Description 27110.5.4 Drug Dose Calculation 27210.6 Disposition of Drugs in Obesity 27310.6.1 Volatile Agents 27310.6.2 Thiopental 27410.6.3 Propofol 27410.6.4 Midazolam 27410.6.5 Acetaminophen 27410.6.6 Opioids 27510.6.7 Unfractionated Heparin 27510.6.8 Cephazolin 27510.6.9 Enoxaparin 27510.7 Conclusion 276References 27611 Drug Disposition in Critical Care Patients 281Chinenye E. Muolokwu, Benjamin Tagoe, Michael M. Attah, and Seth K. Amponsah11.1 Introduction 28111.2 Pharmacokinetic Considerations in Critical Care Patients 28211.2.1 Drug Absorption Considerations in Critical Care Patients 28211.2.2 Drug Distribution Considerations in Critical Care Patients 28311.2.3 Drug Metabolism Considerations in Critical Care Patients 28411.2.4 Drug Excretion Considerations in Critical Care Patients 28511.3 Dosing Algorithms for Commonly Administered Drugs in Critical Care Patients 28611.3.1 Antibacterial and Antifungal Agents 28611.3.1.1 Aminoglycosides 28711.3.1.2 β-Lactam Antibiotics 28811.3.1.3 Fluoroquinolones 28811.3.1.4 Oxazolidinones 28911.3.1.5 Antifungal Agents 28911.3.2 Inotropes 29111.3.3 Antiviral Drugs 29211.3.4 Narcotic Analgesics 29211.3.4.1 Morphine and Pethidine 29211.3.4.2 Fentanyl and Derivatives 29311.3.5 Sedatives and Hypnotics 29311.3.5.1 Midazolam 29411.3.5.2 Lorazepam 29511.3.6 Neuromuscular Blockers 29511.4 Conclusion 297References 29712 Drug Disposition in Renal Insufficiency 305Sarah Nestler, Deborah Liaw, Gabriella Blanco, Rana Hanna, Ellen Si, and Charles Preuss12.1 Renal Physiology 30512.1.1 General Anatomical Structure 30512.1.2 General Function of the Nephron 30612.1.3 Water Regulation 30612.1.4 Glomerular Filtration Rate (GFR) 30712.1.5 Acid–Base Regulation 30712.2 Glomerular Filtration Rate 30712.3 Acute Kidney Injury 30812.3.1 Diagnostic Criteria and Classification 30812.3.2 Causes of AKI 31012.3.3 Prerenal 31012.3.4 Intrinsic 31012.3.5 Postrenal 31112.4 Chronic Kidney Disease 31112.4.1 Diagnostic Criteria and Classification 31112.4.2 Causes of Chronic Kidney Disease 31212.5 Medication Dosing Modifications 31312.5.1 Medication Dosing in Patients with CKD 31312.5.2 Medications to Treat CKD-Induced HTN and Medications to Avoid in CKD 31412.5.2.1 Antihypertensives 31412.5.2.2 Hypoglycemics 31612.5.2.3 Antimicrobials 31712.5.2.4 Statins 32112.5.2.5 NSAIDs 32212.5.2.6 Analgesics 32212.6 Epidemiology and Outcomes of Patients with CKD 323References 32413 Drug Disposition in Hepatic Insufficiency 327Fried A. Abilba, Jacob A. Ayembilla, and Raphael N. Alolga13.1 Introduction 32713.2 The Spectrum of Liver Diseases 32813.3 Liver Function and Drug Metabolism 33013.3.1 Impact of Hepatic Insufficiency on Drug Metabolism 33113.3.2 Pharmacokinetic Changes in Hepatic Insufficiency 33213.3.3 Effect of Liver Diseases on Pharmacokinetics of Drugs 33313.4 Dosing Algorithms in Clinical Practice 33413.4.1 Drug Selection 33513.4.2 Dosing Adjustments 33613.4.3 Pharmacokinetic Considerations 33613.5 Drug Disposition and Factors That Influence Drug Disposition 33613.6 Major Classes of Drugs and Hepatic Insufficiency 33713.6.1 Anticoagulants 33713.6.2 Antibiotics 33813.6.3 Analgesics 33813.6.4 Anticonvulsants 33813.6.5 Antidepressants 33913.6.6 Antiretrovirals 33913.7 Cases Demonstrating Application of Dosing Algorithms 33913.7.1 Case 1: Warfarin for Anticoagulation 33913.7.1.1 The Use of Warfarin in a Patient with Hereditary Bleeding Disorder 33913.7.1.2 Dosing Algorithm of Warfarin 34013.7.2 Case 2: Acetaminophen for Pain Management 34013.7.2.1 Dosing Algorithm for Paracetamol and Other Cytochrome p 450Enzyme-inducing Drugs in Hepatic Insufficiency Using Child-Pugh Score 34113.7.3 Case 3: Valproic Acid for Seizure Control 34113.7.4 Case 4: Metronidazole for Infection 34213.7.5 Case 5: Efavirenz for HIV Treatment 34213.8 Limitations of Current Dosing Strategies 34213.9 Conclusion and Future Perspectives 34313.9.1 Emerging Technologies and Precision Medicine 34313.9.2 Potential Impact of Pharmacogenomics 34413.9.3 Areas of Research Interest 344References 34514 Drug Disposition in Geriatrics 349Ali Karimi, Samuel Cockey, Millena Levin, Teresa Travnicek, Nishanth Chalasani, and Charles Preuss14.1 Introduction 34914.2 Absorption 35114.3 Distribution 35214.4 Metabolism 35414.5 Excretion 35614.6 Hepatic 36014.7 Renal 36114.8 Cardiac 36314.9 Sex Differences 36314.10 Psychoactive Drugs 36514.11 Anesthesiology Drugs 36614.12 Drug Interactions 36714.13 Drug Side Effects 36814.14 Conclusion 371Abbreviations 372References 37315 Considerations and Regulatory Affairs for Clinical Research in Special Populations 377Stephanie Leigh, Maxine Turner, and Goonaseelan C. Pillai15.1 Introduction 37715.2 Regulatory Frameworks for Clinical Research in Special Populations 37815.2.1 The Historical Evolution of Regulatory Frameworks for Special Population Research 37815.2.2 Current Global Regulatory Frameworks for Special Population Research 38015.2.3 Current Regional Regulations Concerning Clinical Research Involving Special Populations 38215.2.3.1 The United States: Food and Drug Regulatory Authority (us Fda) 38215.2.3.2 Europe: European Medicines Agency (EMA) 38315.2.3.3 The United Kingdom: The Medicines and Healthcare Products Regulatory Agency (MHRA) 38315.2.3.4 Australia: The Therapeutic Goods Administration (TGA) 38415.2.3.5 Brazil: National Health Surveillance Agency (ANVISA) 38515.2.3.6 India: Central Drugs Standard Control Organization (CDSCO) 38715.2.3.7 China: National Medical Products Administration (NMPA) 38815.2.3.8 South Africa: The South African Health Products Regulatory Authority (SAHPRA) 38915.2.4 Holistic Analysis of Regional Regulations Concerning Clinical Research Involving Special Populations 39115.3 Key Considerations for Clinical Trials in Special Population Groups 39215.3.1 Pediatric Population Groups 39215.3.1.1 Regulatory Guidelines Governing Pediatric Clinical Research 39215.3.2 Regional Legislations Governing Clinical Research in Pediatric Populations 39315.3.2.1 The United States: Food and Drug Regulatory Authority (us Fda) 39315.3.2.2 Europe: European Medicines Agency (EMA) 39515.3.2.3 The United Kingdom: The Medicines and Healthcare Products Regulatory Agency (MHRA) 39615.3.2.4 India: Central Drugs Standard Control Organization (CDSCO) 39615.3.2.5 Other Global Jurisdictions 39715.3.3 Holistic Analysis of Regional Regulations Concerning Clinical Research Involving Pediatric Populations 39815.3.4 Ethical Considerations for Clinical Research in Pediatric Populations 39815.3.4.1 Assent and Informed Consent 39915.3.4.2 Participant Recruitment 40215.4 Pregnant Population Groups 40315.4.1 Historical Exclusion of Pregnant Persons in Clinical Research 40315.4.2 Regulatory Guidelines Governing Clinical Research in Pregnant Persons 40415.4.3 Regional Legislations Governing Clinical Research in Pregnant Persons 40615.4.3.1 The United States: Food and Drug Regulatory Authority (us Fda) 40615.4.3.2 Europe: European Medicines Agency (EMA) 40615.4.3.3 Australia: The Therapeutic Goods Administration (TGA) 40715.4.3.4 Brazil: National Health Surveillance Agency (ANVISA) 40715.4.3.5 India: Central Drugs Standard Control Organization (CDSCO) 40815.4.3.6 China: National Medical Products Administration (NMPA) 40915.4.4 Challenges and Barriers to Clinical Research in Pregnant Persons 40915.5 Geriatric Populations 41015.5.1 Key Regulatory Guidelines Governing Geriatric Clinical Research 41115.5.2 Regional Legislations Governing Clinical Research in Geriatric Populations 41215.5.2.1 The United States: Food and Drug Regulatory Authority (us Fda) 41215.5.2.2 Europe: European Medicines Agency (EMA) 41415.5.2.3 The United Kingdom: The Medicines and Healthcare Products Regulatory Agency (MHRA) 41515.5.2.4 India: Central Drugs Standard Control Organization (CDSCO) 41615.5.2.5 Other Global Jurisdictions 41715.5.3 Challenges and Barriers to Clinical Research in Geriatric Populations 41715.6 Critical Care 41715.6.1 Key Regulatory Guidelines Governing Critical Care Clinical Research 41815.6.2 Regional Legislations Governing Clinical Research in Critical Care Populations 41815.6.2.1 The United States: Food and Drug Regulatory Authority (us Fda) 41815.6.2.2 Europe: European Medicines Agency (EMA) 42015.6.2.3 The United Kingdom: The Medicines and Healthcare Products Regulatory Agency (MHRA) 42015.6.2.4 India: Central Drugs Standard Control Organization (CDSCO) 42115.6.2.5 Other Global Jurisdictions 42115.6.3 Challenges and Barriers to Clinical Research in Critical Care Populations 42215.7 Summary Points 42215.7.1 Regulatory Guidelines 42215.7.2 Ethical Considerations 42315.7.3 Participant Recruitment 42315.8 Conclusion 423References 424Index 435