About the Editors xxi List of Contributors xxiii Foreword xxix Preface xxxi 1 Pharmacokinetic Principles and Concepts: An Overview 1 Seth K. Amponsah and Yahwant V. Pathak 1.1 Introduction 1 1.2 Pharmacokinetic Parameters 2 1.2.1 Absorption 2 1.2.

2 Distribution 3 1.2.3 Metabolism 4 1.2.4 Excretion 5 1.3 Pharmacokinetic Models 5 1.4 Applications 6 1.5 Conclusion 7 References 7 2 Model-Based Pharmacokinetic Approaches 11 Manish P.

Patel, Kashyap M. Patel, Shakil Z. Vhora, Anuradha K. Gajjar, Jayvadan K. Patel, and Amitkumar K. Patel 2.1 Introduction 11 2.1.

1 Importance of PK 12 2.1.2 Overview of Model-Based Approaches 13 2.2 Basics of Pharmacokinetics 14 2.2.1 Key Pharmacokinetic Parameters 14 2.2.1.

1 Absorption 14 2.2.1.2 Key Parameter 14 2.2.1.3 Distribution 14 2.2.

1.4 Key Parameter 15 2.2.1.5 Metabolism 15 2.2.1.6 Key Parameter 15 2.

2.1.7 Excretion 15 2.2.1.8 Key Parameter 15 2.2.2 Differences Between Traditional and Model-Based Pharmacokinetic Approaches 16 2.

3 Pharmacokinetic (PK) Models 17 2.3.1 Introduction 17 2.3.2 Compartment Modeling 18 2.3.2.1 One-Compartment Model 21 2.

3.2.2 Multi-Compartment Model 21 2.3.2.3 Two-Compartment Model 24 2.3.3 Population PK Model 25 2.

3.4 Physiologically Based PK (PBPK) Model 26 2.4 Model Development and Validation 27 2.4.1 Data Requirements for Model Development 27 2.4.2 Data Requirements for Model Validation 29 2.4.

3 Steps in Model Building (E.g., Model Selection and Parameter Estimation) 29 2.5 Applications of Model-Based Approaches 31 2.5.1 Dose Optimization 31 2.5.2 Predicting Drug Interactions 32 2.

5.3 Drug Tailoring in Special Populations (E.g., Pediatrics, Geriatrics, and Renal Impairment) 33 2.5.4 Translational PK from Preclinical to Clinical Settings 34 2.6 Modeling in Special Populations 36 2.6.

1 Challenges and Considerations 36 2.6.1.1 Challenges in PK Modeling 36 2.6.1.2 Considerations in PK Modeling 36 2.7 Software and Tools for PK Modeling 37 2.

7.1 Gastroplus(tm) 38 2.7.2 Berkeley Madonna 38 2.7.3 MATLAB 38 2.7.4 PK-Sim® 39 2.

7.5 Simcyp® 39 2.7.6 Auxiliary PBPK Modeling Software 39 2.7.6.1 Julia 39 2.7.

6.2 Nonmem 39 2.7.6.3 Phoenix WinNonlin 40 2.7.6.4 GraphPad Prism 40 2.

7.6.5 Minitab 40 2.7.6.6 PlotDigitizer 40 2.7.6.

7 GNU MCSim 40 2.7.6.8 WebPlotDigitizer 40 2.8 Regulatory Perspectives of PK Modeling 40 2.9 Future Directions of PK Modeling 43 2.10 Conclusion 43 Abbreviations 44 References 45 3 Physiologically Based Pharmacokinetic Modeling 53 Mahesh P. More and Rahul S.

Tade 3.1 Introduction 53 3.2 Significance of PBPK Modeling 56 3.3 Principles for the Development of PBPK for Special Populations 57 3.4 Data Integration for Special Populations 57 3.4.1 Demographic Data 58 3.4.

2 Physiological Consideration 58 3.4.3 Ontogeny 58 3.4.4 Age and Maturation Changes 59 3.4.5 Steady State Volume of Distribution (Vdss) 59 3.5 Applications of PBPK Modeling 60 3.

5.1 Dose Optimization/Regimen/Selection 60 3.5.2 Dose Individualization/Precision Dosing 61 3.5.3 Biopharmaceutics 62 3.6 Regulatory Applications/Pre-Post Market Utilization 62 3.7 Case Studies 64 3.

7.1 Simulation Application 64 3.7.2 Successful Applications 67 3.8 Lessons Learned 68 3.9 Conclusion 68 References 70 4 Therapeutic Drug Monitoring in Special Populations 75 James A. Akingbasote, Sandra K. Szlapinski, Elora Hilmas, Kyle Weston, Yelena Wu, and Alexandra Burton 4.

1 Introduction 75 4.2 Pediatrics 76 4.2.1 Importance of TDM in Pediatrics 76 4.2.2 Pharmacokinetic Differences in Pediatric Patients 77 4.2.3 Drug Absorption in the Pediatric Population 77 4.

2.4 Drug Distribution in the Pediatric Population 78 4.2.5 Drug Metabolism and Elimination in the Pediatric Population 79 4.3 TDM Practices in Pediatrics 79 4.3.1 Vancomycin 80 4.3.

2 Aminoglycosides 81 4.3.3 Ganciclovir/Valganciclovir 82 4.3.4 Antiepileptic Drugs (AEDs) 83 4.3.5 Enoxaparin 84 4.4 Conclusion 85 4.

5 Pregnancy 85 4.5.1 Physiological Adaptations in Pregnancy 85 4.5.2 Current State of Clinical Practice of TDM in Pregnancy 87 4.5.3 TDM in Pregnancy 89 4.5.

3.1 Antiepileptics 89 4.5.3.2 Antidepressants 90 4.5.3.3 Antiretroviral Drugs 91 4.

5.3.4 Immunomodulatory Drugs 93 4.5.4 Challenges in the Implementation of TDM in the Pregnant Population 94 4.6 The Elderly 95 4.6.1 Physiological Changes in the Elderly 95 4.

6.2 Effect of Aging on Drug Pharmacokinetics 95 4.6.3 Application of TDM in the Elderly 97 4.6.3.1 Cardiac Glycosides 98 4.6.

3.2 Serotonin-Norepinephrine Reuptake Inhibitor (SNRI) 98 4.6.3.3 Anticoagulants 99 4.6.3.4 Benzodiazepines 99 4.

7 Conclusion 101 4.8 Hepatic and Renal Impairments 101 4.8.1 Hepatic Impairment 102 4.8.2 TDM in Patients with Hepatic Impairment 104 4.8.2.

1 Meropenem 105 4.8.2.2 Metoprolol 105 4.8.2.3 Midazolam 106 4.8.

3 Renal Impairment 107 4.8.4 Prerenal Disease 109 4.8.5 Intrinsic Renal Vascular Disease 109 4.8.6 Intrinsic Glomerular Disease (Nephritic or Nephrotic) 109 4.8.

7 TDM in Renal Impairment 109 4.8.7.1 Vancomycin 111 4.8.7.2 Metformin 111 4.9 Conclusion 112 4.

10 Overall Conclusion and Future Direction 112 Acknowledgment 113 References 114 5 Optimization of Drug Dosing Regimen 133 Vivek Patel, Kartik Hariharan, Dhruv Shah, Arindam Halder, Ajay J. Khopade, Amitkumar K. Patel, and Jayvadan K. Patel 5.1 Introduction 133 5.2 Dosing Regimen Optimization Approaches and Strategies 134 5.2.1 Models Used for Dosing Regimen Selection 134 5.

2.1.1 Pharmacometric Models 134 5.2.1.2 PK Models 135 5.2.1.

3 Empirical Dose-Response Models 136 5.2.1.4 Multiple Comparison Procedures Models (MCP-Mod) 136 5.2.1.5 Model Averaging 137 5.2.

2 Role of Patient Characteristics in Dose Selection 137 5.2.2.1 Phenotype-Guided Dosing 137 5.2.2.2 Genotype-Guided Drug Dosing 138 5.2.

3 Therapeutic Drug Monitoring (TDM) 138 5.3 Dosing Regimen in Special Populations 139 5.3.1 Dosing Regimen in Cancer Patients 139 5.3.1.1 Metronomic Chemotherapy 140 5.3.

2 Dosing Regimen for Patients on Antimicrobial Therapy 142 5.3.2.1 Antimicrobial Stewardship Strategy 145 5.3.2.2 Mathematical Models for Optimizing Antimicrobial Therapy 146 5.3.

2.3 Antimicrobial Dosing Strategies During CRRT 147 5.3.2.4 Methods for Enhancing Dosing of Antimicrobials via Nebulization 149 5.3.3 Dosing Regimen in Pediatric Patients 149 5.3.

3.1 Physiological Differences Between Pediatric and Adult Patients 149 5.3.3.2 Application of MIDD in Pediatric Dose Selection 149 5.3.3.3 Scaling from Adults to Pediatric Patients 150 5.

3.3.4 Scaling from Animals to Pediatric Patients 150 5.3.3.5 Integrating Mechanistic Models in Neonates and Infants 150 5.3.3.

6 Dose Optimization in Neonates and Infants 151 5.4 Conclusion 151 References 152 6 Artificial Intelligence in Drug Development 161 Surovi Saikia, Aparna Anandan, Unais Annenkottil, Vishnu P. Athilingam, Partha P. Kalita, and Viswanadha V. Padma 6.1 Introduction 161 6.2 Application of AI in Drug Design 162 6.2.

1 Target Identification and Validation 162 6.2.2 Drug Candidate Design and Optimization 162 6.2.3 Virtual Screening and Molecular Docking 163 6.2.4 Synthesis Planning 163 6.2.

5 Predicting Drug Toxicity and Pharmacokinetics 163 6.2.6 Personalized Medicine 163 6.3 AI Use in Drug Formulation 163 6.4 Drug Release Characterization Using AI 164 6.5 AI-Based Dose/Dosing Regimen 165 6.6 Dissolution Rate Predictions with AI 166 6.7 Clinical End-Point Evaluation with AI 166 6.

8 AI in Prediction of Fate of Drugs Administered Via Mucosal, Transdermal, and Parenteral Routes 167 6.9 AI-Integrated Mechanistic Modeling Platform for Drug Delivery and Monitoring 169 6.10 AI-Based Tools for Metabolism and Clearance Prediction 169 6.11 Limitations of Existing Tools 171 6.12 Conclusions 171 6.13 Conflict of Interest 171 Acknowledgments 171 References 172 7 Drug Disposition in Neonates and Infants 179 David Gyamfi, Emmanuel B. Amoafo, Awo A. Kwapong, Mansa Fredua-Agyeman, and Seth K.

Amponsah 7.1 Introduction 179 7.2 Drug Absorption in Neonates and Infants 180 7.3 Drug Distribution in Neonates and Infants 182 7.4 Hepatic Metabolism of Drugs in Neonates and Infants 185 7.4.1 Phase I Metabolism 185 7.4.

2 Phase II Metabolism 187 7.5 Drug Excretion in Neonates and Infants 188 7.6 Pharmacodynamics in Neonates and Infants 190 7.7 Age-Related Dosing Regimen in Neonates and Infants 190 7.8 Conclusion 192 References 193 8 Drug Disposition in Adolescents 203 Aparoop Das, Kalyani Pathak, Riya Saikia, Manash P. Pathak, Urvashee Gogoi, Jon J. Sahariah, Dibyajyoti Das, Md Ariful Islam, and Palla.