Essentials of Pharmacokinetics and Pharmacodynamics-2판

Front Matter
ABOUT THE AUTHORS
THOMAS N. TOZER
MALCOLM ROWLAND
PREFACE
CHAPTER 1: Opening Comments
THE CLINICAL SETTING
FIGURE 1-1
Components of the Dose–Response Relationship
FIGURE 1-2
FIGURE 1-3
FIGURE 1-4
FIGURE 1-5
FIGURE 1-6
Variability in Drug Response
FIGURE 1-7
FIGURE 1-8
Adherence to Regimen
FIGURE 1-9
FIGURE 1-10
THE INDUSTRIAL PERSPECTIVE
FIGURE 1-11
ORGANIZATION OF THE BOOK
SECTION I: Basic Considerations
CHAPTER 2: Input–Exposure Relationships
OBJECTIVES
SYSTEMIC EXPOSURE
Sites of Measurement
TABLE 2-1 | Differences Among Plasma, Serum, and Whole Blood Drug Concentrations
Unbound Drug Concentration
Exposure–Time Profile
FIGURE 2-1
PERIOD OF OBSERVATION
ANATOMIC AND PHYSIOLOGIC CONSIDERATIONS
FIGURE 2-2
Sites of Administration
Events After Entering Systemically
CHEMICAL PURITY AND ANALYTIC SPECIFICITY
DEFINITIONS
Systemic Absorption
FIGURE 2-3
Disposition
Distribution
FIGURE 2-4
Elimination
BASIC MODEL FOR DRUG ABSORPTION AND DISPOSITION
FIGURE 2-5
Compartments
FIGURE 2-6
Metabolites
SUMMARY
KEY TERM REVIEW
KEY RELATIONSHIPS
STUDY PROBLEMS
FIGURE 2–7
CHAPTER 3: Exposure–Response Relationships
OBJECTIVES
CLASSIFICATION OF RESPONSE
FIGURE 3-1
ASSESSMENT OF DRUG EFFECT
FIGURE 3-2
FIGURE 3-3
FIGURE 3-4
RELATING RESPONSE TO CONCENTRATION
Graded Response
FIGURE 3-5
FIGURE 3-6
Quantal Response
FIGURE 3-7
Desirable Characteristics
EXPOSURE–RESPONSE RELATIONSHIPS
FIGURE 3-8
SUMMARY
KEY TERM REVIEW
KEY RELATIONSHIPS
STUDY PROBLEMS
FIGURE 3-9
FIGURE 3-10
FIGURE 3-11
FIGURE 3-12
SECTION II: Exposure and Response After a Single Dose
CHAPTER 4: Membranes: A Determining Factor
OBJECTIVES
MEMBRANES
FIGURE 4-1
THE PROCESSES OF DRUG PERMEATION
FIGURE 4-2
Protein Binding
Diffusion
Drug Properties Determining Passive Permeability
FIGURE 4-3
FIGURE 4-4
FIGURE 4-5
Membrane Characteristics
TABLE 4-1 | Properties of Different Membranes
FIGURE 4-6
Carrier-Mediated Transport
FIGURE 4-7
TABLE 4-2 | Examples of Transporters and Their Substrates
FIGURE 4-8
FIGURE 4-9
FIGURE 4-10
BLOOD FLOW VERSUS PERMEABILITY
Perfusion-Rate Limitation
FIGURE 4-11
FIGURE 4-12
Permeability-Rate Limitation
REVERSIBLE NATURE OF DRUG PERMEATION
TABLE 4-3 | Time to Reduce the Plasma Concentration of the Active Metabolite of the Prodrug Leflunomide by
50% in the Presence and Absence of Activated Charcoal Treatment
SUMMARY
KEY TERM REVIEW
STUDY PROBLEMS
CHAPTER 5: Quantifying Events Following an Intravenous Bolus
OBJECTIVES
APPRECIATION OF KINETIC CONCEPTS
FIGURE 5-1
FIGURE 5-2
Volume of Distribution and Clearance
FIGURE 5-3
First-Order Elimination
TABLE 5-1 | Amount Remaining in the Reservoir Over a 5-Hour Period (After Introduction of a 100-mg Dose of
a Drug With an Elimination Rate Constant of 0.1 /hr)
Half-Life
Fraction of Dose Remaining
Clearance, Area, and Volume of Distribution
A CASE STUDY
FIGURE 5-4
Distribution Phase
Terminal Phase
Elimination Half-Life
Clearance
Volume of Distribution
Clearance and Elimination
FIGURE 5-5
Distribution and Elimination: Competing Processes
FIGURE 5-6
FIGURE 5-7
PATHWAYS OF ELIMINATION
Renal Excretion as a Fraction of Total Elimination
Additivity of Clearance
HALF-LIFE, CLEARANCE, AND DISTRIBUTION
FIGURE 5-8
SUMMARY
Estimation of Disposition Parameters
KEY TERM REVIEW
KEY RELATIONSHIPS
STUDY PROBLEMS
FIGURE 5-9
FIGURE 5-10
TABLE 5-2 | Estimated Pharmacokinetic Paramenters for Diazepam, Nortryptyline, and Warfarin from data in
Fig. 5-8
FIGURE 5-11
TABLE 5-3 | Plasma Concentrations of Cocaine Base After a Single IV Dose of 33 mg Cocaine Hydrochloride
CHAPTER 6: Physiologic and Physicochemical Determinants of Distribution and Elimination
OBJECTIVES
WHY DOES DISTRIBUTION VARY SO WIDELY AMONG DRUGS?
Kinetics of Drug Distribution
FIGURE 6-1
Perfusion-Rate Limitation
TABLE 6-1 | Blood Flow, Perfusion Rate, and Relative Sizes of Different Organs and Tissues Under Basal
Conditions in a Standard 70-kg Human
FIGURE 6-2
TABLE 6-2 | Influence of Changes in Perfusion Rates and Tissue Affinity on the Time to Achieve Distribution
Equilibrium
Permeability Limitation
FIGURE 6-3
Extent of Distribution
TABLE 6-3 | Representative Proteins to Which Drugs Bind in Plasma
Apparent Volume of Distribution
FIGURE 6-4
Plasma Protein Binding
FIGURE 6-5
Tissue Binding
FIGURE 6-6
FIGURE 6-7
Amount in Body and Unbound Concentration
WHY DOES CLEARANCE VARY SO WIDELY AMONG DRUGS?
Processes of Elimination
FIGURE 6-8
TABLE 6-4 | Patterns of Biotransformationa of Representative Drugsb
FIGURE 6-9
Clearance in General
Plasma Versus Blood Clearance
Hepatic Clearance
Perfusion, Protein Binding, and Hepatocellular Activity
FIGURE 6-10
TABLE 6-5 | Hepatic and Renal Extraction Ratios of Representative Drugs
Intrinsic Clearance
High Extraction Ratio
FIGURE 6-11
Low Extraction Ratio
FIGURE 6-12
Biliary Excretion and Enterohepatic Cycling
FIGURE 6-13
Hepatic Handling of Protein Drugs
Renal Clearance
The Nephron: Anatomy and Function
FIGURE 6-14
Glomerular Filtration
Active Secretion
Active Reabsorption
Passive Reabsorption
Renal Handling of Protein Drugs
Clearance by Other Organs
TARGET-MEDIATED DISPOSITION
SUMMARY
Kinetics of Distribution
Extent of Distribution
Elimination
KEY TERM REVIEW
KEY RELATIONSHIPS
STUDY PROBLEMS
TABLE 6-6 | Equilibrium Distribution Ratio and Perfusion Rate of Selected Tissues
CHAPTER 7: Quantifying Events Following an Extravascular Dose
OBJECTIVES
TABLE 7-1 | Extravascular Routes of Administration for Systemic Drug Deliverya
KINETICS OF ABSORPTION
FIGURE 7-1
FIGURE 7-2
EXPOSURE–TIME AND EXPOSURE–DOSE RELATIONSHIPS
Extravascular Versus Intravenous Administration
FIGURE 7-3
FIGURE 7-4
Bioavailability
Relative Bioavailability
CHANGES IN DOSE OR ABSORPTION KINETICS
Changing Dose
Changing Absorption Kinetics
FIGURE 7-5
Disposition is Rate Limiting
Absorption Is Rate Limiting
Distinguishing Between Absorption and Disposition Rate Limitations
ASSESSMENT OF PRODUCT PERFORMANCE
Formulation
Bioequivalence Testing
FIGURE 7-6
SUMMARY
KEYTERM REVIEW
KEY RELATIONSHIPS
STUDY PROBLEMS
TABLE 7-2 | Peak Concentration, AUC, and Peak Times After a 250-mg Oral Dose of PJT483 Under Various
Conditions
FIGURE 7-7
FIGURE 7-8
TABLE 7-3 | Total Systemic Exposure (AUC), Peak Exposure (Cmax), Time of Peak Exposure (tmax), and Terminal
Half-life of Sumatriptan Following Administration by the Subcutaneous, Oral, Rectal, and Intranasal Routes
TABLE 7-4 | Mean Acetaminophen Concentrations in Subjects Standing and Lying Down after a Single 500-mg
Oral Dose
FIGURE 7-9
CHAPTER 8: Physiologic and Physicochemical Determinants of Drug Absorption
OBJECTIVES
ABSORPTION FROM SOLUTION
Gastrointestinal Absorption
Gastric Emptying
FIGURE 8-1
Intestinal Absorption and Permeability
FIGURE 8-2
FIGURE 8-3
Insufficient Time for Absorption
FIGURE 8-4
TABLE 8-1 | Examples of Drugs Showing Low Oral Bioavailability Due to Low Intestinal Permeability
Causes of Changes in Oral Bioavailability
FIGURE 8-5
First-Pass Loss
TABLE 8-2 | Availabilities of Various Substrates of CYP3A4 Across the Gut Wall and the Liver
Competing Gastrointestinal Reactions
TABLE 8-3 | Representative Reactions Within the Gastrointestinal Tract that Compete With Drug Absorption
From Solution
FIGURE 8-6
TABLE 8-4 | Mean (± SD) Peak Concentrations (Cmax) and Total Area Under the Curve (AUC) After a Single 40-
mg Dose of Simvastatin With and Without Grapefruit Juice (GFJ)
FIGURE 8-7
Saturable First-Pass Metabolism
TABLE 8-5 | Examples of Drugs Showing Saturable First-Pass Metabolism in the Gut Wall, Liver, or both After
Oral Administration of Therapeutic Doses
Absorption From Intramuscular and Subcutaneous Sites
Small Molecular Weight Drugs
TABLE 8-6 | Influence of Site of Injection on the Peak Venous Lidocaine Concentration Following Injection
of a 100-mg Dose
Macromolecules and Lymphatic Transport
FIGURE 8-8
FIGURE 8-9
TABLE 8-7 | Bioavailability of Selected Monoclonal Antibody Drugs After Subcutaneous and Intramuscular
Administration of a Single Dosea
ABSORPTION FROM SOLID DOSAGE FORMS
FIGURE 8-10
TABLE 8-8 | Factors Determining the Release and Absorption Kinetics of a Drug Following Oral Administration
of a Solid Dosage Form
Dissolution
FIGURE 8-11
Gastric Emptying and Intestinal Transit
FIGURE 8-12
Rapid Dissolution in Stomach
Rapid Dissolution in Intestine
Poor Dissolution
Absorption From Other Sites
TABLE 8-9 | Examples of Unconventional Sites and Methods of Administration of Polypeptide and Protein Drugs
TABLE 8-10 | Examples of Transdermal Delivery Systems
SUMMARY
KEY TERM REVIEW
KEY RELATIONSHIPS
STUDY PROBLEMS
FIGURE 8-13
TABLE 8-11 | Mean AUC, Maximum Plasma Concentration, and Terminal Half-life of Erythropoietin in End-Stage
Renal Disease Patients Following Intravenous and Subcutaneous Administration
CHAPTER 9: Response Following a Single Dose
OBJECTIVES
TIME DELAYS BETWEEN CONCENTRATION AND RESPONSE
Detecting Time Delays
FIGURE 9-1
FIGURE 9-2
CAUSES OF TIME DELAY
Tissue Distribution
Pharmacodynamics
FIGURE 9-3
FIGURE 9-4
FIGURE 9-5
DECLINE OF RESPONSE WITH TIME
When Response Changes in Line With Plasma Concentration: A Pharmacokinetic Rate Limitation
FIGURE 9-6
FIGURE 9-7
When Response Changes More Slowly Than Plasma Concentration: A Pharmacodynamic Rate Limitation
FIGURE 9-8
FIGURE 9-9
REVEALING THE DIRECT CONCENTRATION–RESPONSE RELATIONSHIP
FIGURE 9-10
FIGURE 9-11
ONSET AND DURATION OF RESPONSE
Onset of Effect
Duration of Effect
FIGURE 9-12
FIGURE 9-13
SUMMARY
KEY TERM REVIEW
KEY RELATIONSHIPS
STUDY PROBLEMS
FIGURE 9-14
FIGURE 9-15
FIGURE 9-16
FIGURE 9-17
FIGURE 9-18
SECTION III: Therapeutic Regimens
CHAPTER 10: Therapeutic Window
OBJECTIVES
TABLE 10-1 | Selected Drugs and Their Plasma Concentrations Usually Associated With Successful Therapy
DOSAGE REGIMENS
FIGURE 10-1
THERAPEUTIC WINDOW
FIGURE 10-2
FIGURE 10-3
FIGURE 10-4
FIGURE 10-5
THERAPEUTIC CORRELATES
THERAPEUTIC INDEX
ADDITIONAL CONSIDERATIONS
Multiple Active Species
Single-Dose Therapy
Duration Versus Intensity of Exposure
Time Delays
ACHIEVING THERAPEUTIC GOALS
SUMMARY
KEY TERM REVIEW
STUDY PROBLEMS
CHAPTER 11: Constant-Rate Regimens
OBJECTIVES
Table 11-1 | Examples of Drugs Given by Intravenous Infusion
Table 11-2 | Representative Constant-Rate Devices or Systems and Their Applications
EXPOSURE–TIME RELATIONSHIPS
FIGURE 11-1
FIGURE 11-2
The Plateau Value
FIGURE 11-3
Time to Reach Plateau
FIGURE 11-4
Table 11-3 | Approach to Plateau with Time Following a Constant-Rate Drug Infusion
Postinfusion
Changing Infusion Rates
FIGURE 11-5
FIGURE 11-6
Bolus Plus Infusion
FIGURE 11-7
FIGURE 11-8
SHORT-TERM INFUSIONS
PARAMETER VALUES
CONSEQUENCE OF SLOW TISSUE DISTRIBUTION
FIGURE 11-9
FIGURE 11-10
Rapid Induction of Anesthesia
Decrease in Infusion Rate on Chronic Administration
Recovery From Anesthesia
PHARMACODYNAMIC CONSIDERATIONS
Onset of Response
Response on Stopping an Infusion
SUMMARY
KEY TERM REVIEW
KEY RELATIONSHIPS
STUDY PROBLEMS
FIGURE 11-11
FIGURE 11-12
TABLE 11-4 | Plasma Concentration During and Following Constant Rate Infusion of the Drug (Data Shown in
Fig. 11-12)
Table 11-5 | Plasma Concentration of a Drug During and After a Constant-Rate Infusion (120 mg/hr) for 16
Hours
FIGURE 11-13
FIGURE 11-14
FIGURE 11-15
Table 11-6 | Mean Plasma Droperidol Concentrations (mg/L) following an Intravenous Infusion and the Use of
a Rectal Device in Eight Subjects
FIGURE 11-16
CHAPTER 12: Multiple-Dose Regimens
OBJECTIVES
PRINCIPLES OF DRUG ACCUMULATION
Table 12-1 | Plasma Concentrations of a Drug Following a Regimen of 200 mg Once Daily for 5 Days
FIGURE 12-1
Maxima and Minima on Accumulation to the Plateau
FIGURE 12-2
Average Level at Plateau
Rate of Accumulation to Plateau
Table 12-2 | Approach to Plateau on Daily Administration of Phenobarbital
FIGURE 12-3
Accumulation Index
Change in Regimen
RELATIONSHIP BETWEEN INITIAL AND MAINTENANCE DOSES
FIGURE 12-4
MAINTENANCE OF DRUG IN THE THERAPEUTIC RANGE
TABLE 12-3 | Oral Dosage Regimens for Continuous Maintenance of Therapy
Half-Lives Less Than 30 Minutes
Half-Lives Between 30 Minutes and 8 Hours
Half-Lives Between 8 and 24 Hours
Half-Lives Greater Than 24 Hours
Reinforcing the Principles
TABLE 12-4 | Dosage Regimens and Half-lives of Three Drugs
TABLE 12-5 | Amount of Drug in Body (mg) on Regimens Given in Table 12-4
FIGURE 12-5
FIGURE 12-6
FIGURE 12-7
ADDITIONAL CONSIDERATIONS
Extravascular Administration
FIGURE 12-8
FIGURE 12-9
Plasma Concentration Versus Amount in Body
MODIFIED-RELEASE PRODUCTS
FIGURE 12-10
PHARMACODYNAMIC CONSIDERATIONS
FIGURE 12-11
Time to Achieve Therapeutic Effect
FIGURE 12-12
FIGURE 12-13
Intermittent Administration
Development of Tolerance
Modality of Administration
FIGURE 12-14
FIGURE 12-15
SUMMARY
KEY TERM REVIEW
KEY RELATIONSHIPS
STUDY PROBLEMS
TABLE 12-6 | Pharmacokinetic Parameters and Regimens of Three Drugs
FIGURE 12-16
FIGURE 12-17
TABLE 12-7 | Mean (±SD) Pharmacokinetic Measures and Parameters Obtained for Racemate (Rac-MQ) and (+) and
(−) Isomers of Mefloquine (MQ).
SECTION IV: Individualization
CHAPTER 13: Variability
OBJECTIVES
EXPRESSIONS OF INDIVIDUAL DIFFERENCES
FIGURE 13-1
FIGURE 13-2
FIGURE 13-3
Quantifying Variability
FIGURE 13-4
Describing Variability
FIGURE 13-5
WHY PEOPLE DIFFER
Genetics
Inherited Variability in Pharmacokinetics
TABLE 13-1 | Frequency of Genetic Polymorphisms Producing Slow Metabolism in Some Drug-Metabolizing Enzymes
and Representative Substrates
Oxidation
FIGURE 13-6
FIGURE 13-7
FIGURE 13-8
FIGURE 13-9
S-Methylation
FIGURE 13-10
Conjugation
Additional Clinical Considerations
Inherited Variability in Pharmacodynamics
FIGURE 13-11
TABLE 13-2 | Some Genetic Polymorphisms in Pharmacodynamics
Age and Weight
A Point of Reference
Pharmacodynamics
FIGURE 13-12
Pharmacokinetics
FIGURE 13-13
The Newborn
The Infant, Child, and Adolescent
The Adult and the Elderly
Disease
FIGURE 13-14
TABLE 13-3 | Influence of Renal Impairment on Clearance of Desirudin, a Recombinant Hirudin
Interacting Drugs
TABLE 13-4 | Classification and Examples of Drug Interactions to Be Avoided
TABLE 13-5 | Pharmacokinetically Driven Combination Products
FIGURE 13-15
FIGURE 13-16
Adherence to Regimen
TABLE 13-6 | Additional Factors Known to Contribute to Variability in Drug Response
FIGURE 13-17
Additional Factors
FIGURE 13-18
FIGURE 13-19
FIGURE 13-20
SUMMARY
KEY TERM REVIEW
KEY RELATIONSHIPS
STUDY PROBLEMS
TABLE 13-7 | Pharmacokinetic Data Following Intravenous Infusion to Steady State
TABLE 13-8 | Variability in Plasma Concentration and Pharmacokinetic Parameters and Measures
TABLE 13-9 | Demographic Data and Dosage Regimens of Montelukast
FIGURE 13-21
TABLE 13-10 | Verapamil Pharmacokinetics in Healthy Subjects and Cirrhotic Patients
CHAPTER 14: Initiating and Managing Therapy
OBJECTIVES
FIGURE 14-1
ANTICIPATING SOURCES OF VARIABILITY
Pharmacodynamic Variability
FIGURE 14-2
Pharmacokinetic Variability
TABLE 14-1 | Degree of Variability in the Oral Absorption and Disposition of Representative Drugs Within
the Patient Population
FIGURE 14-3
FIGURE 14-4
FIGURE 14-5
FIGURE 14-6
INITIATING THERAPY
Choosing the Starting Dose
When Is a Loading Dose Needed?
FIGURE 14-7
What Should the Loading Dose Be?
Dose Titration
MANAGING THERAPY
Low Therapeutic Index
TABLE 14-2 | Interpatient Variability and Monitoring of a Low Therapeutic Index Drug
Use of Biomarkers and Clinical and Surrogate Endpoints
Tolerance
Concentration Monitoring
When Is It Useful?
The Target Concentration
Adherence Issues
TABLE 14-3 | Patterns of Nonadherence to Prescribed Dosage
Missed Dose(s)
FIGURE 14-8
Make-Up Dose(s)
Doubling-Up of Doses
FIGURE 14-9
Changes in Therapy
DOSE STRENGTHS AND STRATIFICATION OF PATIENTS
DISCONTINUING THERAPY
SUMMARY
KEY TERM REVIEW
STUDY PROBLEMS
Back Matter
APPENDIX A: Definitions of Symbols
APPENDIX B: Medical Words and Terms
APPENDIX C: Ionization and the pH Partition Hypothesis
FIGURE C-1
FIGURE C-2
STUDY PROBLEMS
APPENDIX D: Assessment of AUC
TABLE D-1 | Calculation of Total AUC Using the Trapezoidal Rule
FIGURE D-1
STUDY PROBLEM
TABLE D-2 | Plasma Concentrations of Zileuton (Zyflo) Following a 600-mg Oral Dose
APPENDIX E: Amount of Drug in the Body on Accumulation to Plateau
DRUG ACCUMULATION
TABLE E-1 | Drug Remaining in the Body Just After Each of Four Successive Doses
STEADY STATE
STUDY PROBLEM
TABLE E-2 | Amount of Diazepam in the Body Just After Each of Four Successive Daily 10-mg Doses
APPENDIX F: Answers to Study Problems
CHAPTER 2
FIGURE F-1
CHAPTER 3
Measured, Drug, and Placebo Responses to Spiriva® 6 Hours after Its Inhalation*
CHAPTER 4
CHAPTER 5
FIGURE F-2
FIGURE F-3
FIGURE F-4
CHAPTER 6
CHAPTER 7
FIGURE F-5
CHAPTER 8
CHAPTER 9
FIGURE F-6
CHAPTER 10
CHAPTER 11
FIGURE F-7
CHAPTER 12
FIGURE F-8
CHAPTER 13
CHAPTER 14
FIGURE F-9
APPENDIX C
APPENDIX D
APPENDIX E
Amount of Diazepam (mg) in the Body Just After Each of four Successive Daily Doses
INDEX