
BASIC PHARMACOKINETICS AND PHARMACODYNAMICS. AN INTEGRATED TEXTBOOK AND COMPUTER SIMULATIONSRosenbaum, S.
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Updated with new chapters and topics, this book provides a comprehensive description of all essential topics in contemporary pharmacokinetics and pharmacodynamics. It also features interactive computer simulations for students to experiment and observe PK/PD models in action.
Reviews of the 1st edition: “This is an ideal textbook for those starting out … and also for use as a reference book …." (International Society for the Study of Xenobiotics) and “I could recommend Rosenbaum’s book for pharmacology studentsbecause it is written from a perspective of drug action . . . Overall, this is a wellwritten introduction to PK/PD …. “ (British Toxicology Society Newsletter)
Preface xix
Contributors xxi
1 Introduction to Pharmacokinetics and Pharmacodynamics 1
Sara E. Rosenbaum
1.1 Introduction: Drugs and Doses, 2
1.2 Introduction to Pharmacodynamics, 3
1.3 Introduction to Pharmacokinetics, 9
1.4 Dose–Response Relationships, 12
1.5 Therapeutic Range, 14
1.6 Summary, 18
Reference, 18
2 Passage of Drugs Through Membranes 19
Sara E. Rosenbaum
2.1 Introduction, 20
2.2 Structure and Properties of Membranes, 20
2.3 Passive Diffusion, 21
2.4 CarrierMediated Processes: Transport Proteins, 26
References, 33
3 Drug Administration and Drug Absorption 35
Steven C. Sutton
3.1 Introduction: Local and Systemic Drug Administration, 36
3.2 Routes of Drug Administration, 37
3.3 Overview of Oral Absorption, 41
3.4 Extent of Drug Absorption, 44
3.5 Determinants of the Fraction of the Dose Absorbed (F), 46
3.6 Factors Controlling the Rate of Drug Absorption, 61
3.7 Biopharmaceutics Classification System, 64
3.8 Food Effects, 65
Problems, 66
References, 67
4 Drug Distribution 71
Sara E. Rosenbaum
4.1 Introduction, 72
4.2 Extent of Drug Distribution, 72
4.3 Rate of Drug Distribution, 89
4.4 Distribution of Drugs to the Central Nervous System, 93
Problems, 96
References, 98
5 Drug Elimination and Clearance 99
Sara E. Rosenbaum
5.1 Introduction, 100
5.2 Clearance, 102
5.3 Renal Clearance, 108
5.4 Hepatic Elimination and Clearance, 119
Problems, 139
References, 142
6 Compartmental Models in Pharmacokinetics 145
Sara E. Rosenbaum
6.1 Introduction, 146
6.2 Expressions for Component Parts of the Dose–Plasma Concentration Relationship, 146
6.3 Putting Everything Together: Compartments and Models, 149
6.4 Examples of Complete Compartment Models, 152
6.5 Use of Compartmental Models to Study Metabolite Pharmacokinetics, 155
6.6 Selecting and Applying Models, 156
Problems, 157
Suggested Readings, 157
7 Pharmacokinetics of an Intravenous Bolus Injection in a OneCompartment Model 159
Sara E. Rosenbaum
7.1 Introduction, 160
7.2 OneCompartment Model, 160
7.3 Pharmacokinetic Equations, 162
7.4 Simulation Exercise, 163
7.5 Application of the Model, 165
7.6 Determination of Pharmacokinetic Parameters Experimentally, 168
7.7 Pharmacokinetic Analysis in Clinical Practice, 173
Problems, 174
Suggested Reading, 176
8 Pharmacokinetics of an Intravenous Bolus Injection in a TwoCompartment Model 177
Sara E. Rosenbaum
8.1 Introduction, 178
8.2 Tissue and Compartmental Distribution of a Drug, 179
8.3 Basic Equation, 181
8.4 Relationship Between Macro and Micro Rate Constants, 183
8.5 Primary Pharmacokinetic Parameters, 183
8.6 Simulation Exercise, 188
8.7 Determination of the Pharmacokinetic Parameters of the TwoCompartment Model, 191
8.8 Clinical Application of the TwoCompartment Model, 194
Problems, 197
Suggested Readings, 199
9 Pharmacokinetics of Extravascular Drug Administration 201
Dr. Steven C. Sutton
9.1 Introduction, 202
9.2 FirstOrder Absorption in a OneCompartment Model, 203
9.3 Modified Release and Gastric Retention Formulations, 214
9.4 Bioavailability, 215
9.5 In VitroIn Vivo Correlation, 219
9.6 Simulation Exercise, 222
Problems, 223
References, 224
10 Introduction to Noncompartmental Analysis 225
Sara E. Rosenbaum
10.1 Introduction, 225
10.2 Mean Residence Time, 226
10.3 Determination of Other Important Pharmacokinetic Parameters, 229
10.4 Different Routes of Administration, 231
10.5 Application of Noncompartmental Analysis to Clinical Studies, 232
Problems, 234
11 Pharmacokinetics of Intravenous Infusion in a OneCompartment Model 237
Sara E. Rosenbaum
11.1 Introduction, 238
11.2 Model and Equations, 239
11.3 SteadyState Plasma Concentration, 242
11.4 Loading Dose, 246
11.5 Termination of Infusion, 248
11.6 Individualization of Dosing Regimens, 249
Problems, 252
12 Multiple Intravenous Bolus Injections in the OneCompartment Model 255
Sara E. Rosenbaum
12.1 Introduction, 256
12.2 Terms and Symbols Used in MultipleDosing Equations, 257
12.3 Monoexponential Decay During a Dosing Interval, 259
12.4 Basic Pharmacokinetic Equations for Multiple Doses, 260
12.5 Steady State, 262
12.6 Basic Formula Revisited, 270
12.7 PharmacokineticGuided Dosing Regimen Design, 270
12.8 Simulation Exercise, 276
Problems, 277
Reference, 278
13 Multiple Intermittent Infusions 279
Sara E. Rosenbaum
13.1 Introduction, 279
13.2 SteadyState Equations for Multiple Intermittent Infusions, 281
13.3 Monoexponential Decay During a Dosing Interval: Determination of Peaks, Troughs, and Elimination HalfLife, 284
13.4 Determination of the Volume of Distribution, 286
13.5 Individualization of Dosing Regimens, 289
13.6 Simulation, 289
Problems, 290
14 Multiple Oral Doses 293
Sara E. Rosenbaum
14.1 Introduction, 293
14.2 SteadyState Equations, 294
14.3 Equations Used Clinically to Individualize Oral Doses, 298
14.4 Simulation Exercise, 300
References, 301
15 Nonlinear Pharmacokinetics 303
Sara E. Rosenbaum
15.1 Linear Pharmacokinetics, 304
15.2 Nonlinear Processes in Absorption, Distribution, Metabolism, and Elimination, 306
15.3 Pharmacokinetics of CapacityLimited Metabolism, 307
15.4 Phenytoin, 310
Problems, 321
References, 322
16 Introduction to Pharmacogenetics 323
Dr. Daniel Brazeau
16.1 Introduction, 324
16.2 Genetics Primer, 324
16.3 Pharmacogenetics, 328
16.4 Genetics and Pharmacodynamics, 334
16.5 Summary, 335
Reference, 335
Suggested Readings, 335
17 Models Used to Predict Drug–Drug Interactions for Orally Administered Drugs 337
Sara E. Rosenbaum
17.1 Introduction, 338
17.2 Mathematical Models for Inhibitors and Inducers of Drug Metabolism Based on In Vitro Data, 340
17.3 Surrogate In Vivo Values for the Unbound Concentration of the Perpetrator at the Site of Action, 345
17.4 Models Used to Predict DDIs In Vivo, 347
17.5 Predictive Models for TransporterBased DDIs, 359
17.6 Application of Physiologically Based Pharmacokinetic Models to DDI Prediction: The Dynamic Approach, 362
17.7 Conclusion, 362
Problems, 363
References, 364
18 Introduction to Physiologically Based Pharmacokinetic Modeling 367
Sara E. Rosenbaum
18.1 Introduction, 368
18.2 Components of PBPK Models, 369
18.3 Equations for PBPK Models, 369
18.4 Building a PBPK Model, 373
18.5 Simulations, 377
18.6 Estimation of Human DrugSpecific Parameters, 378
18.7 More Detailed PBPK Models, 381
18.8 Application of PBPK Models, 387
References, 388
19 Introduction to Pharmacodynamic Models and Integrated Pharmacokinetic–Pharmacodynamic Models 391
Drs. Diane Mould and Paul Hutson
19.1 Introduction, 392
19.2 Classic Pharmacodynamic Models Based on Receptor Theory, 393
19.3 Direct Effect Pharmacodynamic Models, 402
19.4 Integrated PK–PD Models: Intravenous Bolus Injection in the OneCompartment Mode and the Sigmoidal Emax Model, 406
19.5 Pharmacodynamic Drug–Drug Interactions, 410
Problems, 411
References, 412
20 Semimechanistic Pharmacokinetic–Pharmacodynamic Models 413
Drs. Diane Mould and Paul Hutson
20.1 Introduction, 414
20.2 Hysteresis and the Effect Compartment, 416
20.3 Physiological Turnover Models and Their Characteristics, 419
20.4 Indirect Effect Models, 422
20.5 Other Indirect Effect Models, 432
20.6 Models of Tolerance, 442
20.7 Irreversible Drug Effects, 450
20.8 Disease Progression Models, 452
Problems, 459
References, 465
Appendix A Review of Exponents and Logarithms 469
Sara E. Rosenbaum
A.1 Exponents, 469
A.2 Logarithms: Log and Ln, 470
A.3 Performing Calculations in the Logarithmic Domain, 471
A.4 Calculations Using Exponential Expressions and Logarithms, 472
A.5 Decay Function: e−kt, 474
A.6 Growth Function: 1 − e−kt, 475
A.7 Decay Function in Pharmacokinetics, 475
Problems, 476
Appendix B Rates of Processes 479
Sara E. Rosenbaum
B.1 Introduction, 479
B.2 Order of a Rate Process, 480
B.3 ZeroOrder Processes, 480
B.4 FirstOrder Processes, 482
B.5 Comparison of Zero and FirstOrder Processes, 484
B.6 Detailed Example of FirstOrder Decay in Pharmacokinetics, 484
B.7 Examples of the Application of FirstOrder Kinetics to Pharmacokinetics, 487
Appendix C Creation of Excel Worksheets for Pharmacokinetic Analysis 489
Sara E. Rosenbaum
C.1 Measurement of AUC and Clearance, 489
C.2 Analysis of Data from an Intravenous Bolus Injection in a OneCompartment Model, 494
C.3 Analysis of Data from an Intravenous Bolus Injection in a TwoCompartment Model, 496
C.4 Analysis of Oral Data in a OneCompartment Model, 498
C.5 Noncompartmental Analysis of Oral Data, 501
Appendix D Derivation of Equations for Multiple Intravenous Bolus Injections 505
Sara E. Rosenbaum
D.1 Assumptions, 505
D.2 Basic Equation for Plasma Concentration After Multiple Intravenous Bolus Injections, 505
D.3 SteadyState Equations, 508
Appendix E Enzyme Kinetics: Michaelis–Menten Equation and Models for Inhibitors and Inducers of Drug Metabolism 509
Sara E. Rosenbaum and Roberta S. King
E.1 Kinetics of Drug Metabolism: The Michaelis–Menten Model, 510
E.2 Effect of Perpetrators of DDI on Enzyme Kinetics and Intrinsic Clearance, 515
References, 526
Appendix F Summary of the Properties of the Fictitious Drugs Used in the Text 527
Sara E. Rosenbaum
Appendix G Computer Simulation Models 529
Sara E. Rosenbaum
Glossary of Terms 531
Index 537
Author Information
Sara E. Rosenbaum, PhD, is Professor of Biomedical and Pharmaceutical Sciences at the University of Rhode Island, where she teaches courses in pharmacokinetics and pharmacodynamics. Her research interests concentrate on thedevelopment and application of pharmacokinetic and pharmacodynamic models to better understand the drug doseresponse relationship.