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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.
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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.
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 xxi
List of Contributors xxiii
Foreword xxix
Preface xxxi
1 Pharmacokinetic Principles and Concepts: An Overview 1Seth 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 11Manish 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 53Mahesh 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 75James 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 133Vivek 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 161Surovi 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 179David 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 203Aparoop Das, Kalyani Pathak, Riya Saikia, Manash P. Pathak, Urvashee Gogoi, Jon J. Sahariah, Dibyajyoti Das, Md Ariful Islam, and Pallab Pramanik
8.1 Introduction 203
8.2 Physiological Considerations in Adolescents 206
8.2.1 Organ Development: Liver and Kidney Maturation 206
8.2.2 Variations in Body Composition 208
8.2.3 Hormonal Changes 208
8.2.3.1 Males 208
8.2.3.2 Females 209
8.2.4 Other Physiological Changes 210
8.3 Medication Adherence Challenges in Adolescents 211
8.4 Psychological Development on Drug Disposition 212
8.5 Risk-Taking behaviors and Their Implications on Medication Use 213
8.6 Drug Use Among Adolescents 215
8.6.1 Acetaminophen Use in Adolescents 215
8.6.2 Antidepressant Use in Adolescents 215
8.6.3 Drugs for ADHD 216
8.7 Pharmacokinetic Variability in Adolescents Drug Examples 217
8.7.1 Acetaminophen 217
8.7.2 Theophylline 217
8.7.3 Antidepressants 218
8.7.4 Drugs for ADHD 218
8.8 Legal and Ethical Considerations 219
8.8.1 Consent and Confidentiality in Adolescent Healthcare 219
8.8.2 Involving Adolescents in Treatment Decisions 220
8.8.3 Regulatory Aspects of Adolescents Drug Prescribing 221
8.9 Conclusion 221
References 222
9 Drug Disposition in Pregnancy 229Jacob Treanor, Stefanos Belavilas, Dominique Cook, Justin Cole, Amruta Potdar, and Charles Preuss
9.1 Introduction 229
9.2 Physiological Changes in Pregnancy 230
9.2.1 Changes in Absorption 231
9.2.2 Changes in Distribution and Free Medication 231
9.2.3 Changes in Cytochrome Metabolism 233
9.2.4 Changes in Renal Excretion 233
9.2.5 General Considerations in Drug Dosing with Pregnancy 234
9.3 Placental Drug Disposition 234
9.3.1 Placental Barrier Anatomy and Physiology 235
9.3.2 Placental Transport Mechanisms 237
9.3.3 Methods of Study for Placental Drug Transfer 238
9.4 Drug Classification in Pregnancy 239
9.5 Pharmacokinetic (PK) Modeling 241
9.6 Physiologically Based Pharmacokinetic (PBPK) Modeling 242
9.7 Limitations in PK and PBPK Models 244
9.8 PBPK Model Variables 244
9.9 Determining Treatment During Pregnancy 245
9.10 Fetal Blood Flow and Drug Processing 245
9.10.1 Hepatic and Renal Processing 246
9.10.2 Embryonic Staging 248
9.11 Teratogens 249
9.11.1 Thalidomide 250
9.11.2 Alcohol 251
9.11.3 Smoking and E-cigarettes 251
9.11.4 Caffeine 252
9.11.5 Antibiotics 253
9.11.6 Retinoids 254
9.12 Conclusion 257
Abbreviations 257
References 258
10 Drug Disposition in Obesity 265Seema Kohli and Ankita A. Singh
10.1 Introduction 265
10.2 Index of Obesity 265
10.3 Pathogenesis of Obesity/Overweight 266
10.4 Drug Disposition in Obesity 267
10.4.1 Absorption 267
10.4.2 Distribution 268
10.4.3 Metabolism 268
10.4.4 Renal Excretion 270
10.5 Drug Dose Calculations in Obese Patients 270
10.5.1 Volume of Distribution (Vd) 270
10.5.2 Drug Clearance 271
10.5.3 Body Size Description 271
10.5.4 Drug Dose Calculation 272
10.6 Disposition of Drugs in Obesity 273
10.6.1 Volatile Agents 273
10.6.2 Thiopental 274
10.6.3 Propofol 274
10.6.4 Midazolam 274
10.6.5 Acetaminophen 274
10.6.6 Opioids 275
10.6.7 Unfractionated Heparin 275
10.6.8 Cephazolin 275
10.6.9 Enoxaparin 275
10.7 Conclusion 276
References 276
11 Drug Disposition in Critical Care Patients 281Chinenye E. Muolokwu, Benjamin Tagoe, Michael M. Attah, and Seth K. Amponsah
11.1 Introduction 281
11.2 Pharmacokinetic Considerations in Critical Care Patients 282
11.2.1 Drug Absorption Considerations in Critical Care Patients 282
11.2.2 Drug Distribution Considerations in Critical Care Patients 283
11.2.3 Drug Metabolism Considerations in Critical Care Patients 284
11.2.4 Drug Excretion Considerations in Critical Care Patients 285
11.3 Dosing Algorithms for Commonly Administered Drugs in Critical Care Patients 286
11.3.1 Antibacterial and Antifungal Agents 286
11.3.1.1 Aminoglycosides 287
11.3.1.2 ß-Lactam Antibiotics 288
11.3.1.3 Fluoroquinolones 288
11.3.1.4 Oxazolidinones 289
11.3.1.5 Antifungal Agents 289
11.3.2 Inotropes 291
11.3.3 Antiviral Drugs 292
11.3.4 Narcotic Analgesics 292
11.3.4.1 Morphine and Pethidine 292
11.3.4.2 Fentanyl and Derivatives 293
11.3.5 Sedatives and Hypnotics 293
11.3.5.1 Midazolam 294
11.3.5.2 Lorazepam 295
11.3.6 Neuromuscular Blockers 295
11.4 Conclusion 297
References 297
12 Drug Disposition in Renal Insufficiency 305Sarah Nestler, Deborah Liaw, Gabriella Blanco, Rana Hanna, Ellen Si, and Charles Preuss
12.1 Renal Physiology 305
12.1.1 General Anatomical Structure 305
12.1.2 General Function of the Nephron 306
12.1.3 Water Regulation 306
12.1.4 Glomerular Filtration Rate (GFR) 307
12.1.5 Acid-Base Regulation 307
12.2 Glomerular Filtration Rate 307
12.3 Acute Kidney Injury 308
12.3.1 Diagnostic Criteria and Classification 308
12.3.2 Causes of AKI 310
12.3.3 Prerenal 310
12.3.4 Intrinsic 310
12.3.5 Postrenal 311
12.4 Chronic Kidney Disease 311
12.4.1 Diagnostic Criteria and Classification 311
12.4.2 Causes of Chronic Kidney Disease 312
12.5 Medication Dosing Modifications 313
12.5.1 Medication Dosing in Patients with CKD 313
12.5.2 Medications to Treat CKD-Induced HTN and Medications to Avoid in CKD 314
12.5.2.1 Antihypertensives 314
12.5.2.2 Hypoglycemics 316
12.5.2.3 Antimicrobials 317
12.5.2.4 Statins 321
12.5.2.5 NSAIDs 322
12.5.2.6 Analgesics 322
12.6 Epidemiology and Outcomes of Patients with CKD 323
References 324
13 Drug Disposition in Hepatic Insufficiency 327Fried A. Abilba, Jacob A. Ayembilla, and Raphael N. Alolga
13.1 Introduction 327
13.2 The Spectrum of Liver Diseases 328
13.3 Liver Function and Drug Metabolism 330
13.3.1 Impact of Hepatic Insufficiency on Drug Metabolism 331
13.3.2 Pharmacokinetic Changes in Hepatic Insufficiency 332
13.3.3 Effect of Liver Diseases on Pharmacokinetics of Drugs 333
13.4 Dosing Algorithms in Clinical Practice 334
13.4.1 Drug Selection 335
13.4.2 Dosing Adjustments 336
13.4.3 Pharmacokinetic Considerations 336
13.5 Drug Disposition and Factors That Influence Drug Disposition 336
13.6 Major Classes of Drugs and Hepatic Insufficiency 337
13.6.1 Anticoagulants 337
13.6.2 Antibiotics 338
13.6.3 Analgesics 338
13.6.4 Anticonvulsants 338
13.6.5 Antidepressants 339
13.6.6 Antiretrovirals 339
13.7 Cases Demonstrating Application of Dosing Algorithms 339
13.7.1 Case 1: Warfarin for Anticoagulation 339
13.7.1.1 The Use of Warfarin in a Patient with Hereditary Bleeding Disorder 339
13.7.1.2 Dosing Algorithm of Warfarin 340
13.7.2 Case 2: Acetaminophen for Pain Management 340
13.7.2.1 Dosing Algorithm for Paracetamol and Other Cytochrome p 450
Enzyme-inducing Drugs in Hepatic Insufficiency Using Child-Pugh Score 341
13.7.3 Case 3: Valproic Acid for Seizure Control 341
13.7.4 Case 4: Metronidazole for Infection 342
13.7.5 Case 5: Efavirenz for HIV Treatment 342
13.8 Limitations of Current Dosing Strategies 342
13.9 Conclusion and Future Perspectives 343
13.9.1 Emerging Technologies and Precision Medicine 343
13.9.2 Potential Impact of Pharmacogenomics 344
13.9.3 Areas of Research Interest 344
References 345
14 Drug Disposition in Geriatrics 349Ali Karimi, Samuel Cockey, Millena Levin, Teresa Travnicek, Nishanth Chalasani, and Charles Preuss
14.1 Introduction 349
14.2 Absorption 351
14.3 Distribution 352
14.4 Metabolism 354
14.5 Excretion 356
14.6 Hepatic 360
14.7 Renal 361
14.8 Cardiac 363
14.9 Sex Differences 363
14.10 Psychoactive Drugs 365
14.11 Anesthesiology Drugs 366
14.12 Drug Interactions 367
14.13 Drug Side Effects 368
14.14 Conclusion 371
Abbreviations 372
References 373
15 Considerations and Regulatory Affairs for Clinical Research in Special Populations 377Stephanie Leigh, Maxine Turner, and Goonaseelan C. Pillai
15.1 Introduction 377
15.2 Regulatory Frameworks for Clinical Research in Special Populations 378
15.2.1 The Historical Evolution of Regulatory Frameworks for Special Population Research 378
15.2.2 Current Global Regulatory Frameworks for Special Population Research 380
15.2.3 Current Regional Regulations Concerning Clinical Research Involving Special Populations 382
15.2.3.1 The United States: Food and Drug Regulatory Authority (us Fda) 382
15.2.3.2 Europe: European Medicines Agency (EMA) 383
15.2.3.3 The United Kingdom: The Medicines and Healthcare Products Regulatory Agency (MHRA) 383
15.2.3.4 Australia: The Therapeutic Goods Administration (TGA) 384
15.2.3.5 Brazil: National Health Surveillance Agency (ANVISA) 385
15.2.3.6 India: Central Drugs Standard Control Organization (CDSCO) 387
15.2.3.7 China: National Medical Products Administration (NMPA) 388
15.2.3.8 South Africa: The South African Health Products Regulatory Authority (SAHPRA) 389
15.2.4 Holistic Analysis of Regional Regulations Concerning Clinical Research Involving Special Populations 391
15.3 Key Considerations for Clinical Trials in Special Population Groups 392
15.3.1 Pediatric Population Groups 392
15.3.1.1 Regulatory Guidelines Governing Pediatric Clinical Research 392
15.3.2 Regional Legislations Governing Clinical Research in Pediatric Populations 393
15.3.2.1 The United States: Food and Drug Regulatory Authority (us Fda) 393
15.3.2.2 Europe: European Medicines Agency (EMA) 395
15.3.2.3 The United Kingdom: The Medicines and Healthcare Products Regulatory Agency (MHRA) 396
15.3.2.4 India: Central Drugs Standard Control Organization (CDSCO) 396
15.3.2.5 Other Global Jurisdictions 397
15.3.3 Holistic Analysis of Regional Regulations Concerning Clinical Research Involving Pediatric Populations 398
15.3.4 Ethical Considerations for Clinical Research in Pediatric Populations 398
15.3.4.1 Assent and Informed Consent 399
15.3.4.2 Participant Recruitment 402
15.4 Pregnant Population Groups 403
15.4.1 Historical Exclusion of Pregnant Persons in Clinical Research 403
15.4.2 Regulatory Guidelines Governing Clinical Research in Pregnant Persons 404
15.4.3 Regional Legislations Governing Clinical Research in Pregnant Persons 406
15.4.3.1 The United States: Food and Drug Regulatory Authority (us Fda) 406
15.4.3.2 Europe: European Medicines Agency (EMA) 406
15.4.3.3 Australia: The Therapeutic Goods Administration (TGA) 407
15.4.3.4 Brazil: National Health Surveillance Agency (ANVISA) 407
15.4.3.5 India: Central Drugs Standard Control Organization (CDSCO) 408
15.4.3.6 China: National Medical Products Administration (NMPA) 409
15.4.4 Challenges and Barriers to Clinical Research in Pregnant Persons 409
15.5 Geriatric Populations 410
15.5.1 Key Regulatory Guidelines Governing Geriatric Clinical Research 411
15.5.2 Regional Legislations Governing Clinical Research in Geriatric Populations 412
15.5.2.1 The United States: Food and Drug Regulatory Authority (us Fda) 412
15.5.2.2 Europe: European Medicines Agency (EMA) 414
15.5.2.3 The United Kingdom: The Medicines and Healthcare Products Regulatory Agency (MHRA) 415
15.5.2.4 India: Central Drugs Standard Control Organization (CDSCO) 416
15.5.2.5 Other Global Jurisdictions 417
15.5.3 Challenges and Barriers to Clinical Research in Geriatric Populations 417
15.6 Critical Care 417
15.6.1 Key Regulatory Guidelines Governing Critical Care Clinical Research 418
15.6.2 Regional Legislations Governing Clinical Research in Critical Care Populations 418
15.6.2.1 The United States: Food and Drug Regulatory Authority (us Fda) 418
15.6.2.2 Europe: European Medicines Agency (EMA) 420
15.6.2.3 The United Kingdom: The Medicines and Healthcare Products Regulatory Agency (MHRA) 420
15.6.2.4 India: Central Drugs Standard Control Organization (CDSCO) 421
15.6.2.5 Other Global Jurisdictions 421
15.6.3 Challenges and Barriers to Clinical Research in Critical Care Populations 422
15.7 Summary Points 422
15.7.1 Regulatory Guidelines 422
15.7.2 Ethical Considerations 423
15.7.3 Participant Recruitment 423
15.8 Conclusion 423
References 424
Index 435
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
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.
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].
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].
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.
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,...
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