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.
• Presents the essentials of pharmacokinetics and pharmacodynamics in a clear and progressive manner
• Helps students better appreciate important concepts and gain a greater understanding of the mechanism of action of drugs by reinforcing practical applications in both the book and the computer modules
• Features interactive computer simulations, available online through a companion website at: http://www.uri.edu/pharmacy/faculty/rosenbaum/basicmodels.html• Adds new chapters on physiologically based pharmacokinetic models, predicting drug-drug interactions, and pharmacogenetics while also strengthening original chapters to better prepare students for more advanced applications
• 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 students because it is written from a perspective of drug action . . . Overall, this is a well-written introduction to PK/PD …. “ (British Toxicology Society Newsletter)
Contents
1. INTRODUCTION TO PHARMACOKINETICS AND PHARMACODYNAMICS
1.1 Introduction: Drugs and Doses
1.2 Introduction to Pharmacodynamics
1.3 Introduction to Pharmacokinetics
1.4 Dose–Response Relationships
1.5 Therapeutic Range
1.6 Summary
2. PASSAGE OF DRUGS THROUGH MEMBRANES
2.1 Introduction
2.2 Structure and Properties of Membranes
2.3 Passive Diffusion
2.4 Carrier-Mediated Processes: Transport Proteins
3. DRUG ADMINISTRATION AND DRUG ABSORPTION
Steven Sutton
3.1 Introduction: Local and Systemic Drug Administration
3.2 Routes of Drug Administration
3.3 Overview of Oral Absorption
3.4 Extent of Drug Absorption
3.5 Determinants of the Fraction of the Dose Absorbed (F)
3.6 Factors Controlling the Rate of Drug Absorption
3.7 Biopharmaceutics Classification System
3.8 Food effects
Problems
References
4. DRUG DISTRIBUTION
4.1 Introduction
4.2 Extent of Drug Distribution
4.3 Rate of Drug Distribution
4.4 Distribution of Drugs to the Central Nervous System
Problems
References
5. DRUG ELIMINATION AND CLEARANCE
5.1 Introduction
5.2 Clearance
5.3 Renal Clearance
5.4 Hepatic Elimination and Clearance
Problems
References
6. COMPARTMENTAL MODELS IN PHARMACOKINETICS
6.1 Introduction
6.2 Expressions for Component Parts of the Dose–Plasma Concentration Relationship
6.3 Putting Everything Together: Compartments and Models
6.4 Examples of Complete Compartment Models
6.5 Use of Compartmental Models to Study Metabolite Pharmacokinetics
6.6 Selecting and Applying Models
Problems
Recommended Reading
7.PHARMACOKINETICS OF AN INTRAVENOUS BOLUS INJECTION IN A ONE-COMPARTMENT MODEL
7.1 Introduction
7.2 One-Compartment Model
7.3 Pharmacokinetic Equations
7.4 Simulation Exercise
7.5 Application of the Model
7.6 Determination of Pharmacokinetic Parameters Experimentally
7.7 Pharmacokinetic Analysis in Clinical Practice
Problems
8. PHARMACOKINETICS OF AN INTRAVENOUS BOLUS INJECTION IN A TWO-COMPARTMENT MODEL
8.1 Introduction
8.2 Tissue and Compartmental Distribution of a Drug
8.3 Basic Equation
8.4 Relationship Between Macro and Micro Rate Constants
8.5 Primary Pharmacokinetic Parameters
8.6 Simulation Exercise
8.7 Determination of the Pharmacokinetic Parameters of the Two-Compartment Model
8.8 Clinical Application of the Two-Compartment Model
Problems
9. PHARMACOKINETICS OF EXTRAVASCULAR DRUG ADMINISTRATION
Steven Sutton
9.1 Introduction
9.2 First-Order Absorption in a One-Compartment Model
9.3 Modified Release and Gastric Retention Formulation
9.4 Bioavailability
9.5 In Vitro-In Vivo Correlation (IVIVC)
9.6 Simulation Exercise
Problems
References
10.INTRODUCTION TO NONCOMPARTMENTAL ANALYSIS
10.1 Introduction
10.2 Mean Residence Time
10.3 Determination of Other Important Pharmacokinetic Parameters
10.4 Different Routes of Administration
10.5 Application of Noncompartmental Analysis to Clinical Studies
Problems
11. PHARMACOKINETICS OF INTRAVENOUS INFUSION IN A ONE-COMPARTMENT MODEL
11.1 Introduction
11.2 Model and Equations
11.3 Steady-State Plasma Concentration
11.4 Loading Dose
11.5 Termination of Infusion
11.6 Individualization of Dosing Regimens
Problems
12. MULTIPLE INTRAVENOUS BOLUS INJECTIONS IN THE ONE-COMPARTMENT MODEL
12.1 Introduction
12.2 Terms and Symbols Used in Multiple-Dosing Equations
12.3 Monoexponential Decay During a Dosing Interval
12.4 Basic Pharmacokinetic Equations for Multiple Doses
12.5 Steady State
12.6 Basic Formula Revisited
12.7 Pharmacokinetic-Guided Dosing Regimen Design
12.8 Simulation Exercise
Problems
13. MULTIPLE INTERMITTENT INFUSIONS
13.1 Introduction
13.2 Steady-State Equations for Multiple Intermittent Infusions
13.3 Monoexponential Decay During a Dosing Interval: Determination of Peaks, Troughs, and Elimination Half-Life
13.4 Determination of the Volume of Distribution
13.5 Individualization of Dosing Regimens
13.6 Simulation Exercise
Problems
14. MULTIPLE ORAL DOSES
14.1 Introduction
14.2 Steady-State Equations
14.3 Equations Used Clinically to Individualize Oral Doses
14.4 Simulation Exercise
15.NONLINEAR PHARMACOKINETICS
15.1 Linear Pharmacokinetics
15.2 Nonlinear Processes in Absorption, Distribution, Metabolism, and Elimination
15.3 Pharmacokinetics of Capacity-Limited Metabolism
15.4 Phenytoin
Problems
16. INTRODUCTION TO PHARMACOGENETICS
16.1 Introduction
16.2 Genetics Primer
16.3 Pharmacogenetics
16.4 Genetics and Pharmacodynamics
16.5 Summary
Reference and Recommended Reading
17. MODELS USED TO PREDICT DRUG-DRUG INTERACTIONS FOR ORALLY ADMINISTERED DRUGS
17.1 Introduction
17.2 Mathematical Models For In Vitro Data on Inhibitors and Inducers of Drug Metabolism
17. 3. Surrogate In Vivo Values For the Unbound Concentration of the Perpetrator at the Site of Action
17.4. Model To Predict DDIs In Vivo
17.5. Predictive Models For Transporter-Based DDIs
17.6. Application of Physiologically Based Modeling to DDI Prediction: the Dynamic Approach
17.7. Conclusion
Problems
References
18. INTRODUCTION TO PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELING
18.1 Introduction
18.2 Components of PBPK Models
18.3 Equations of PBPK Models
18.4 Building a Model
18.5 Simulations
18.6 Estimation of Drug Specific Parameters
18.7 More Detailed PBPK Models
18.8 Application of PBPK Models
Reference
19. INTRODUCTION TO PHARMACODYNAMIC MODELS AND INTEGRATED PHARMACOKINETIC–PHARMACODYNAMIC MODELS
Diane Mould and Paul Hutson
19.1 Introduction
19.2 Classic Pharmacodynamic Models Based On Receptor Theory
19.3 Direct Effect Pharmacodynamic Models
19.4 Integrated Pk–Pd Models: Intravenous Bolus Injection In The One-Compartment Mode And The Sigmoidal Emax Model
19.5 Pharmacodynamic Drug-Interactions
PROBLEMS
REFERENCES
20. SEMI-MECHANISTIC PHARMACOKINETIC–PHARMACODYNAMIC MODEL
Diane Mould and Paul Hutson
20.1 Introduction
20.2 Hysteresis and the Effect Compartment
20.3 Physiological Turnover Models and Their Characteristics
20.4 Indirect Effect Models
20.5 Other Indirect Effect Models
20.6 Models Of Tolerance
20.7 Irreversible Drug Effects
20.8 Disease Progression Models
Problems
References
APPENDIX A REVIEW OF EXPONENTS AND LOGARITHMS
A.1 Exponents
A.2 Logarithms: log and ln
A.3 Performing Calculations in the Logarithmic Domain
A.4 Calculations Using Exponential Expressions and Logarithms
A.5 Decay Function: e−kt
A.6 Growth Function: 1 − e−kt
A.7 Decay Function in Pharmacokinetics
Problems
APPENDIX B. RATES OF PROCESSES
B.1 Introduction
B.2 Order of a Rate Process
B.3 Zero-Order Processes
B.4 First-Order Processes
B.5 Comparison of Zero- and First-Order Processes
B.6 Detailed Example of First-Order Decay in Pharmacokinetics
B.7 Examples of the Application of First-Order Kinetics to Pharmacokinetics
APPENDIX C. CREATION OF EXCEL WORKSHEETS FOR PHARMACOKINETIC ANALYSIS
C.1 Measurement of AUC and Clearance
C.2 Analysis of Data from an Intravenous Bolus Injection in a One-Compartment Model
C.3 Analysis of Data from an Intravenous Bolus Injection in a Two-Compartment Model
C.4 Analysis of Oral Data in a One-Compartment Model
C.5 Noncompartmental Analysis of Oral Data
APPENDIX D. DERIVATION OF EQUATIONS FOR MULTIPLE INTRAVENOUS BOLUS INJECTIONS
D.1 Assumptions
D.2 Basic Equation for Plasma Concentration After Multiple Intravenous Bolus Injections
D.3 Steady-State Equations
APPENDIX E ENZYME KINETICS: MICHAELIS MENTEN EQUATION. AND MODELS FOR INHIBITORS AND INDUCERS OF DRUG METABOLISM
E.1 KINETIC OF DRUG METABOLISM: THE MICHAELIS MENTEN MODEL
E.2. Effect of Perpetrators of DDIs on Enzyme Kinetics and Intrinsic Clearance.
APPENDIX F. SUMMARY OF THE PROPERTIES OF THE FICTITIOUS DRUGS USED IN THE TEXT
APPENDIX G. COMPUTER SIMULATION MODELS
