Basic Pharmacokinetics - 3rd Edition

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Third edition published 2024 by Routledge
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© 2024 Mohsen A. Hedaya
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First edition published by CRC Press 2007
Second edition published by Routledge 2012
Library of Congress Cataloging-in-Publication Data
Names: Hedaya, Mohsen A, author.
Title: Basic pharmacokinetics / Mohsen A Hedaya.
Description: Third Edition. | New York : Routledge, 2023. |
Revised edition of the author’s Basic pharmacokinetics, c2012. |
Includes bibliographical references and index.
Identifiers: LCCN 2023005241 | ISBN 9780367752149 (hardback) |
ISBN 9780367752156 (paperback) | ISBN 9781003161523 (ebook)
Subjects: LCSH: Pharmacokinetics.
Classification: LCC RM301.5 .H43 2023 |
DDC 615/.7--dc23/eng/20230403
LC record available at https://lccn.loc.gov/2023005241

ISBN: 978-0-367-75214-9 (hbk)

ISBN: 978-0-367-75215-6 (pbk)
ISBN: 978-1-003-16152-3 (ebk)
DOI: 10.4324/9781003161523

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To the memory of my parents, may God have mercy on their souls.
Contents

List of Figures xxv

1 Introduction to Pharmacokinetics1
1.1 Introduction 1
1.2 Pharmacokinetics and Its Related Fields 2
1.2.1 Biopharmaceutics 2
1.2.2 Pharmacokinetics 2
1.2.3 Clinical Pharmacokinetics 3
1.2.4 Pharmacodynamics 4
1.2.5 Population Pharmacokinetics 4
1.2.6 Toxicokinetics 5
1.2.7 Pharmacogenetics 5
1.3 Application of the Pharmacokinetic Principles
in the Biomedical Fields 5
1.3.1 Design and Evaluation of Dosage Forms 5
1.3.2 Evaluation of Generic Drug Products 6
1.3.3 Pharmacological Testing 6
1.3.4 Toxicological Testing 6
1.3.5 Evaluation of Organ Function 6
1.3.6 Therapeutic Drug Monitoring 6
1.4 The Blood Drug Concentration-Time Profile 7
1.5 Linear and Nonlinear Pharmacokinetics 8
1.5.1 Linear Pharmacokinetics 8
1.5.2 Nonlinear Pharmacokinetics 8
1.6 Pharmacokinetic Modeling 9
1.6.1 Compartmental Modeling 10
1.6.2 Physiological Modeling 10
1.6.3 Population Pharmacokinetic Modeling 11
1.6.4 Noncompartmental Data Analysis Approach 12
1.6.5 Pharmacokinetic-Pharmacodynamic Modeling 12
viii Contents
1.7 Pharmacokinetic Simulations 12
1.8 Essential Graphical, Mathematical, and Statistical
Fundamentals Used in Pharmacokinetics 14
1.8.1 Graphs 14
1.8.2 Curve Fitting 16
1.8.3 Determination of the Straight-Line Parameters 16
1.8.3.1 Graphical Determination
of the Straight-Line Parameters 17
1.8.3.2 The Least Squares Method 17
1.8.4 Application of Basic Calculus Principles
in Pharmacokinetics 18

2 Drug Pharmacokinetics Following Single Intravenous Bolus

Administration: Drug Distribution21
2.1 Introduction 21
2.2 Drug Distribution 21
2.2.1 The Rate and Extent of Drug Distribution 22
2.3 The Volume of Distribution 23
2.4 Drug Distribution after Single IV Bolus Drug
Administration 26
2.5 Drug Protein Binding 28
2.5.1 Effect of Changing the Plasma Protein Binding 29
2.5.2 Determination of Plasma Protein Binding 30
2.6 Drug Partitioning to Blood Cells 31
2.7 Summary 32

3 Drug Pharmacokinetics Following Single IV Bolus

Administration: Drug Clearance34
3.1 Introduction 34
3.2 Drug Clearance 34
3.2.1 The Total Body Clearance 35
3.2.2 Physiological Approach to Drug Clearance 35
3.2.3 The Plasma Drug Concentration-Time Profile 37
3.3 Total Body Clearance and Volume of Distribution
Are the Independent Pharmacokinetic Parameters 38
3.4 Determination of the Total Body Clearance 39
3.5 Summary 40

4 Drug Pharmacokinetics Following Single IV Bolus

Administration: The Rate of Drug Elimination41
4.1 Introduction 41
4.2 Drug Elimination 41
 Contents ix
4.3 The Kinetics of the Drug Elimination Process 42
4.3.1 Zero-Order Elimination 42
4.3.1.1 The Zero-Order Elimination
Rate Constant 42
4.3.1.2 The Half-Life In Zero-Order
Elimination 44
4.3.2 First-Order Elimination 46
4.3.2.1 The First-Order Elimination
Rate Constant 46
4.3.2.2 Determination of the First-Order
Elimination Rate Constant, k 49
4.3.2.3 The Half-Life in First-Order Drug
Elimination 51
4.4 The Mathematical Expressions for Plasma Drug
Concentrations after Single IV Bolus Dose when
the Elimination Process Follows First-Order Kinetics 52
4.5 The Relationship between the First-Order Elimination Rate
Constant, Total Body Clearance, and Volume of Distribution 54
4.6 The Area under the Drug Concentration-Time Curve 54
4.7 Calculation of Pharmacokinetic Parameters after
Single IV Bolus Dose 55
4.8 The Effect of Changing the Pharmacokinetic
Parameters on the Plasma Drug Concentration-
Time Profile after Single IV Bolus Dose 58
4.8.1 Dose 58
4.8.2 Volume of Distribution 58
4.8.3 Total Body Clearance 59
4.9 Summary 59

5 Drug Absorption Following Extravascular Administration:

Biological, Physicochemical, and Formulation Considerations65
5.1 Introduction 65
5.2 The Drug Absorption Process 66
5.2.1 The Absorption Barriers 66
5.2.2 Mechanisms of Drug Absorption 66
5.2.2.1 Passive Diffusion 67
5.2.2.2 Carrier-Mediated Transport 68
5.2.2.3 Paracellular 69
5.2.2.4 Other Mechanisms 69
5.3 Molecular and Physicochemical Properties Affecting
Drug Absorption 69
5.3.1 Molecular Structure Features Affecting Drug
Absorption 69
x Contents
5.3.2 The Physicochemical Drug Properties 70
5.3.2.1 Drug Solubility 70
5.3.2.2 Drug Dissolution Rate 72
5.3.3 Drug Stability 73
5.4 Physiological Factors Affecting Drug Absorption After
Different Routes of Administration and Formulation
Strategies to Accommodate These Factors 74
5.4.1 Parenteral Drug Administration 74
5.4.2 Oral Drug Administration 74
5.4.3 Rectal Drug Administration 77
5.4.4 Intranasal Drug Administration 78
5.4.5 Pulmonary Drug Administration 78
5.4.6 Transdermal Drug Administration 79
5.5 Integration of the Physical, Chemical, and Physiological
Factors Affecting Drug Absorption 80
5.5.1 The Biopharmaceutics Classification
System 81
5.5.2 The Biopharmaceutics Drug Disposition
Classification System (BDDCS) 83
5.6 Summary 84
References 85

6 Drug Pharmacokinetics Following Single Oral Drug

Administration: The Rate of Drug Absorption87
6.1 Introduction 87
6.2 Drug Absorption after Oral
Administration 88
6.2.1 Zero-Order Drug Absorption 89
6.2.2 First-Order Drug Absorption 89
6.3 The Plasma Concentration-Time Profile After
Single Oral Dose 91
6.4 Determination of the Absorption
Rate Constant 94
6.4.1 The Method of Residuals 95
6.4.1.1 Lag Time 97
6.4.1.2 Flip-Flop of ka and k 98
6.4.2 Wagner-Nelson Method 100
6.4.2.1 Application of the
Wagner-Nelson Method 101
6.5 Summary 104
References 107
 Contents xi
7 Drug Pharmacokinetics Following Single Oral Drug
Administration: The Extent of Drug Absorption108
7.1 Introduction 108
7.2 Causes of Incomplete Drug Bioavailability 109
7.2.1 The First-Pass Effect 109
7.2.2 The GIT Drug Transporters 110
7.2.3 Intestinal Drug Metabolism 111
7.3 The Rationale for Bioavailability
Determination 112
7.4 Determination of the Drug In Vivo
Bioavailability 113
7.4.1 Drug Bioavailability 113
7.4.1.1 Absolute Bioavailability 114
7.4.1.2 Relative Bioavailability 115
7.4.2 Calculation of the Drug Bioavailability 115
7.4.3 Determination of the Drug Bioavailability
from Urinary Excretion Data 117
7.5 In Vivo Bioavailability Basic Study Design 119
7.6 Calculation of the AUC Using the Linear
Trapezoidal Rule 120
7.7 The Effect of Changing the Pharmacokinetic
Parameters on the Plasma Drug Concentration-
Time Profile after Single Oral Dose 124
7.7.1 Dose 125
7.7.2 Bioavailability 125
7.7.3 Total Body Clearance 126
7.7.4 Volume of Distribution 126
7.7.5 Absorption Rate Constant 127
7.8 Summary 127
References 131

8 Bioequivalence132
8.1 Introduction 132
8.2 General Definitions 133
8.3 Regulatory Requirement for Bioequivalence 133
8.4 Criteria for Requesting a Waiver of the
In Vivo Bioequivalence Determination 134
8.5 Approaches for Demonstrating Product
Bioequivalence 135
8.5.1 In Vivo Pharmacokinetic Studies 136
8.5.2 In Vitro Test Predictive of In Vivo
Human Bioavailability 136
xii Contents
8.5.3 Acute Pharmacodynamic Effect 136
8.5.4 Comparative Clinical Studies 137
8.5.5 In Vitro Dissolution Testing 137
8.6 Pharmacokinetic Approach to Demonstrate
Product Bioequivalence 138
8.6.1 Planning for the In Vivo Bioequivalence Study 138
8.6.2 Selection of the Reference Drug Product 138
8.6.3 In Vitro Testing of the Study Products 138
8.6.4 In Vivo Bioequivalence Study Design 139
8.6.4.1 Basic Principles 139
8.6.4.2 Ethical Approval 139
8.6.4.3 The Study Subjects 139
8.6.4.4 Number of Volunteers 140
8.6.4.5 Drug Administration 140
8.6.4.6 Experimental Protocol 140
8.6.4.7 Collection of Blood Samples 141
8.6.4.8 Analysis of Bioequivalence
Study Samples 141
8.6.4.9 Pharmacokinetic Parameter
Determination 142
8.6.4.10 Statistical Analysis 142
8.6.4.11 Documentation and Reporting 143
8.7 Special Issues Related to Bioequivalence
Determination 143
8.7.1 Multiple-Dose Bioequivalence Studies 143
8.7.2 Food-Effect Bioequivalence Studies 144
8.7.3 Drugs with Long Half-Lives 144
8.7.4 Determination of Bioequivalence
from the Drug Urinary Excretion Data 145
8.7.5 Fixed-Dose Combination 145
8.7.6 Measuring Drug Metabolites in
Bioequivalence Studies 146
8.7.7 Highly Variable Drugs 146
8.7.8 Drugs Following Nonlinear
Pharmacokinetics 147
8.7.9 Endogenous Substances 147
8.7.10 Enantiomers versus Racemates 147
8.7.11 Narrow Therapeutic Range Drugs 148
8.7.12 Oral Products Intended for the Local
Effect of the Drug 148
8.7.13 First Point Cpmax 148
8.7.14 Biological Products 148
8.8 Summary 149
References 149
 Contents xiii
9 Drug Pharmacokinetics during Constant Rate IV Infusion,
the Steady-State Concept151
9.1 Introduction 151
9.2 The Steady State 152
9.3 The Time Required to Achieve Steady State 155
9.3.1 Changing the Drug Infusion Rate 156
9.4 Loading Dose 157
9.5 Termination of the Constant Rate IV Infusion 159
9.6 Determination of the Pharmacokinetic
Parameters 159
9.6.1 Total Body Clearance 160
9.6.2 Elimination Rate Constant 160
9.6.3 Volume of Distribution 160
9.7 Dosage Forms with Zero-Order Input Rate 162
9.8 The Effect of Changing the Pharmacokinetic Parameters
on the Plasma Drug Concentration-Time Profile during
Constant Rate IV Infusion 163
9.8.1 Infusion Rate 163
9.8.2 Total Body Clearance 163
9.8.3 Volume of Distribution 164
9.8.4 Loading Dose 164
9.9 Summary 164

10 Steady State during Multiple Drug Administration167

10.1 Introduction 167
10.2 The Plasma Drug Concentration-Time Profile
during Multiple Drug Administration 168
10.3 The Time Required to Achieve Steady State 172
10.4 The Loading Dose 173
10.4.1 IV Loading Dose 173
10.4.2 Oral Loading Dose 174
10.5 The Average Plasma Concentration
at Steady State 175
10.6 Drug Accumulation 178
10.7 Controlled Release Formulations 179
10.8 The Effect of Changing the Pharmacokinetic Parameters
on the Steady-State Plasma Drug Concentration during
Multiple Drug Administration 180
10.8.1 Dosing Rate 180
10.8.2 Total Body Clearance 181
10.8.3 Volume of Distribution 181
10.8.4 Absorption Rate Constant 181
xiv Contents
10.9 Dosing Regimen Design 182
10.9.1 Factors to Be Considered 182
10.9.1.1 The Therapeutic Range of the Drug 182
10.9.1.2 The Required Onset of Effect 182
10.9.1.3 The Drug Product 182
10.9.1.4 Progression of the Patient Disease State 183
10.9.2 Estimation of the Patient Pharmacokinetic
Parameters 183
10.9.3 Selection of Dose and Dosing Interval 183
10.9.3.1 Multiple Controlled Release Oral
Formulation 184
10.9.3.2 Multiple IV or Fast-Release Oral
Formulations 184
10.9.4 Selection of the Loading Dose 185
10.10 Summary 186

11 Renal Drug Excretion190

11.1 Introduction 190
11.2 Studying Drug Elimination through a Specific Pathway 191
11.3 The Renal Excretion of Drugs 192
11.4 Determination of the Drug Renal Excretion Rate 193
11.4.1 Experimental Determination of the Renal
Excretion Rate 194
11.4.2 The Drug Renal Excretion Rate-Time Profile 195
11.5 The Renal Clearance 196
11.6 The Cumulative Amount of the Drug
Excreted in Urine 199
11.7 Determination of the Pharmacokinetic Parameters
from the Renal Excretion Rate Data 201
11.7.1 The Elimination Rate Constant and Half-Life 201
11.7.2 The Renal Excretion Rate Constant 201
11.7.3 The Volume of Distribution 201
11.7.4 The Renal Clearance 201
11.7.5 The Fraction of Dose Excreted Unchanged
in Urine 201
11.7.6 Bioavailability 201
11.8 The Effect of Changing the Pharmacokinetic Parameters
on the Urinary Excretion of Drugs 204
11.8.1 Dose 204
11.8.2 The Total Body Clearance 204
11.8.3 The Renal Clearance 205
11.9 Summary 205
References 207
 Contents xv
12 Metabolite Pharmacokinetics208
12.1 Introduction 208
12.2 Drug Metabolism 209
12.2.1 Metabolizing Enzymes 209
12.2.2 Formation of Active Metabolites 210
12.2.3 Formation of Toxic Metabolites 210
12.2.4 Metabolic Activation of Prodrugs 211
12.3 Metabolite Pharmacokinetics 211
12.4 A Simple Model for Metabolite Pharmacokinetics 213
12.4.1 Metabolite Concentration-Time Profile 215
12.5 The General Model for Metabolite Kinetics 216
12.6 Determination of the Metabolite Pharmacokinetic
Parameters 218
12.6.1 Metabolite Elimination Rate Constant, k(m) 218
12.6.2 Fraction of the Parent Drug Dose Converted
to a Specific Metabolite, fm 218
12.6.3 Metabolite Clearance, CL(m) 219
12.6.4 Metabolite Volume of Distribution, Vd(m) 219
12.6.5 Metabolite Formation Clearance, fm CLT 219
12.7 Steady-State Metabolite Concentration during
Repeated Administration of the Drug 222
12.8 Metabolite Pharmacokinetics after Extravascular
Administration of the Parent Drug 225
12.9 Kinetics of Sequential Metabolism 226
12.10 The Effect of Changing the Pharmacokinetic Parameters
on the Drug and Metabolite Concentration-Time Profiles
after Single IV Drug Administration and during
Multiple Drug Administration 227
12.10.1 Drug Dose 227
12.10.2 Drug Total Body Clearance 228
12.10.3 Drug Volume of Distribution 229
12.10.4 Fraction of the Drug Dose Converted
to the Metabolite 229
12.10.5 Metabolite Total Body Clearance 230
12.10.6 Metabolite Volume of Distribution 230
12.11 Summary 231
References 234

13 Nonlinear Pharmacokinetics236
13.1 Introduction 236
13.2 Causes of Nonlinear Pharmacokinetics 236
13.2.1 Dose-Dependent Drug Absorption 237
13.2.2 Dose-Dependent Drug Distribution 238
xvi Contents
13.2.3 Dose-Dependent Renal Excretion 239
13.2.4 Dose-Dependent Drug Metabolism 239
13.2.5 Other Conditions That Can Lead to
Nonlinear Pharmacokinetics 240
13.3 Pharmacokinetics of Drugs Eliminated by Dose-Dependent
Metabolism, Michaelis-Menten Pharmacokinetics 240
13.3.1 Michaelis-Menten Enzyme Kinetics 240
13.3.2 The Pharmacokinetic Parameters 242
13.3.3 Drug Concentration-Time Profile after Administration
of a Drug Which Is Eliminated by Single Metabolic
Pathway That Follows Michaelis-Menten Kinetics 243
13.3.3.1 After Single IV Bolus Administration 243
13.3.3.2 During Multiple Drug Administration 245
13.4 Determination of the Pharmacokinetic Parameters for Drugs with
Elimination Process that Follows Michaelis-Menten Kinetics 246
13.4.1 The Volume of Distribution 246
13.4.2 The Total Body Clearance 246
13.4.3 The Half-Life 246
13.5 Oral Administration of Drugs that Are Eliminated by a
Process that Follows Michaelis-Menten Kinetics 247
13.6 Determination of the Michaelis-Menten Parameters and
Calculation of the Appropriate Dosage Regimens 247
13.6.1 Mathematical Method 248
13.6.2 The Direct Linear Plot 249
13.6.3 The Linear Transformation Method 251
13.7 Multiple Elimination Pathways 252
13.8 The Effect of Changing the Pharmacokinetic Parameters
on the Drug Concentration-Time Profile 253
13.8.1 The Dose 253
13.8.2 The Vmax 254
13.8.3 The Km 254
13.9 Summary 254
References 256

14 Multicompartment Pharmacokinetic Models258

14.1 Introduction 258
14.2 Compartmental Pharmacokinetic Models 260
14.3 The Two-Compartment Pharmacokinetic Model 260
14.4 The Parameters of the Two-Compartments Pharmacokinetic Model 263
14.4.1 Definition of the Pharmacokinetic Parameters 263
14.4.2 The Mathematical Equation That Describes the Plasma
Concentration-Time Profile for Drugs That Follow
Two-Compartment Pharmacokinetic Models 264
 Contents xvii
14.5 Determination of the Two-Compartment
Pharmacokinetic Model Parameters 266
14.5.1 The Method of Residuals 266
14.5.2 Determination of the Other Model Parameters 268
14.5.2.1 Volume of the Central Compartment, Vc 268
14.5.2.2 The Area under the Plasma
Concentration-Time Curve, AUC 268
14.5.2.3 The Total Body Clearance, CLT 268
14.5.2.4 The First-Order Elimination Rate Constant
from the Central Compartment, k10 268
14.5.2.5 The First-Order Transfer Rate Constant
from the Peripheral Compartment to
the Central Compartment, k 21 268
14.5.2.6 The First-Order Transfer Rate Constant
from the Central Compartment to the
Peripheral Compartment, k12 269
14.5.3 Determination of the Volumes of Distribution
for the Two-Compartment Pharmacokinetic
Model 269
14.5.3.1 The Volume of Distribution
at Steady State, Vdss 269
14.5.3.2 The Volume of Distribution during
the Elimination Phase, Vd β 270
14.6 Pharmacokinetic Behavior of Drugs that Follow
the Two-Compartment Pharmacokinetic Model 272
14.6.1 Oral Administration of Drugs that Follow the
Two-Compartment Pharmacokinetic Model 272
14.6.2 Constant Rate IV Administration of Drugs
That Follow the Two-Compartment
Pharmacokinetic Model 273
14.6.3 Multiple Administration of Drugs That Follow
the Two-Compartment Pharmacokinetic Model 273
14.6.4 Renal Excretion of Drugs That Follow the
Two-Compartment Pharmacokinetic Model 274
14.7 Effect of Changing the Pharmacokinetic Parameters
on the Concentration-Time Profile of Drugs That
Follow Two-Compartment Pharmacokinetic Model 274
14.7.1 Dose 275
14.7.2 Total Body Clearance 275
14.7.3 Volume of the Central Compartment 275
14.7.4 The Hybrid Distribution and Elimination
Rate Constants 275
14.7.5 The Inter-Compartmental Clearance 275