basic - gbv · 8.7 formulation factors affecting drug absorption after transdermal drug...
TRANSCRIPT
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BASIC SECOND EDITION
MOHSEN A. HEDAYA Kuwait University, Kuwait
CRC Press Taylor Francis Croup
Boca London York
CRC Press is an imprint of Taylor 6t Francis Group, an informa business
Contents Preface xxxi Author xxxiii
Chapter 1 Introduction to Pharmacokinetics 1
Objectives 1 1.1 Introduction 1 1.2 General 1
1.2.1 1 1.2.2 Pharmacokinetics 2 1.2.3 Clinical Pharmacokinetics 3 1.2.4 4 1.2.5 Population Pharmacokinetics 4 1.2.6 Toxicokinetics 5
Application of the Pharmacokinetic Principles in the Biomedical Fields 5 1.3.1 Design and Evaluation of Dosage 5 1.3.2 Evaluation of Drug Formulation 5 1.3.3 Pharmacological Testing 6 1.3.4 Toxicological Testing 6 1.3.5 Evaluation of Organ Function 6 1.3.6 Dosing Regimen Design 6
1.4 Drug Profile 6 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 Modeling 9 1.6.2 Physiological Modeling 9 1.6.3 Approach 11
1.7 Pharmacokinetic-Pharmacodynamic Modeling 11 1.8 Pharmacokinetic Simulations 12
Chapter 2 Review of Mathematical 13
Objectives 13 2.1 Introduction 13 2.2 Exponents 14 2.3 Logarithms 15 2.4 Graphs 16
2.4.1 Cartesian Scale 16 2.4.2 Scale 17
vii
Contents
2.5 18 2.5.1 Linear Regression Analysis 19
2.5.1.1 Graphical Determination of the Line 19
2.5.1.2 Least Squares Method 20 2.6 Calculus 21
2.6.1 Differential Calculus 21 2.6.2 Integral Calculus 21 2.6.3 Pharmacokinetic Applications 21
Practice Problems 22
Chapter 3 Drug Pharmacokinetics Following a Single IV Bolus Administration: Drug Distribution 23
Objectives 23 3.1 Introduction 23 3.2 Drug Distribution Process 24
3.2.1 Rate of Drug Distribution 24 3.2.2 Extent of Drug Distribution 24 3.2.3 between the Drug in
and Tissues 26 3.3 Drug Protein Binding 26
3.3.1 Effect of Changing the Plasma Protein Binding 28 3.3.2 Determination of Plasma Protein Binding 28
3.3.2.1 Ultrafiltration 28 3.3.2.2 Equilibrium Dialysis 28
3.4 Drug Partitioning to Blood 30 3.5 Volume of Distribution 31
Relationship between the Drug in the Body and the Plasma Drug Concentration 31
3.5.2 Drug Protein Binding and the Volume of Distribution 32
3.5.3 Effect of Changing the Plasma Protein Binding on the Volume of Distribution 33
3.6 Drug Distribution after a Single IV Bolus Drug Administration 34
When Fast Equilibrium Established between the Drug in Blood and Tissues 34
3.6.2 When Slow Equilibrium Is Established between the Drug in Blood and Tissues 34
3.7 Determination of the Volume of Distribution 36 3.8 Clinical of the Volume of Distribution 37 3.9 Summary 37 Practice Problems 38
Contents ix
Chapter 4 Drug Pharmacokinetics Following a Single IV Bolus Administration: Drug Clearance 39
Objectives 39 4.1 Introduction 39 4.2 Eliminating Organs 40
4.2.1 Liver 40 4.2.2 Kidney 41
4.3 Total Body Clearance 43 4.3.1 Physiological Approach to Drug Clearance 43 4.3.2 Total Body Clearance and the Rate of Decline
in the Amount of the Drug the Body 45 4.3.3 Total Body Clearance and Volume
of Distribution Are Independent Pharmacokinetic Parameters 45
4.3.4 Determination of the Total Body Clearance 46 4.4 Clinical Importance of the Total Body Clearance 47 4.5 Summary 47 Practice Problems 48
Chapter 5 Drug Pharmacokinetics Following a Single IV Bolus Administration: The Rate of Drug Elimination 49
Objectives 49 5.1 Introduction 49 5.2 Kinetics of the Drug Elimination Process 50
5.2.1 Order of the Drug Elimination Process 50 5.2.2 Rate of Drug Elimination 51 5.2.3 Rate Constant for the Drug Elimination Process 51
5.3 Drug Elimination by Zero-Order Process 52 5.3.1 Determination of the Zero-Order Elimination
Rate Constant 52 5.3.2 Determination of the for Zero-Order
Drug Elimination 54 5.4 Drug Elimination by First-Order Process 56
5.4.1 Determination of the First-Order Elimination Rate Constant 56
5.4.2 Determination of the Half-Life in First-Order Drug Elimination 61
5.4.3 Mathematical Expressions That Describe the Plasma Drug Concentrations after a Single IV Bolus Dose When the Elimination Process Follows First-Order Kinetics 62
5.4.4 Relationship between the First-Order Elimination Rate Constant, Total Body Clearance, and Volume of Distribution 64
Contents
5.5 Area under the Drug Curve 65 5.6 Calculation of Pharmacokinetic Parameters after a Single
IV Bolus Dose 66 5.7 Clinical Importance of the Elimination Rate Constant
and Half-Life 68 5.8 Factors Affecting the Plasma Drug Concentration-Time
Profile after a Single IV Bolus Dose 69 5.8.1 Pharmacokinetic Simulation Exercise 69
5.8.1.1 Dose 70 5.8.1.2 Volume of Distribution 70 5.8.1.3 Total Body Clearance 70
5.9 Summary 70 Practice Problems 71
Chapter 6 Drug Absorption Following Extravascular Administration: Biological, Physiological, and Pathological Considerations 75
Objectives 75 6.1 Introduction 75 6.2 Cell Membrane 76
6.2.1 Structure the Cell Membrane 77 6.2.2 Epithelia 77
6.3 Mechanism of Drug Absorption 78 6.3.1 Passive Diffusion 78 6.3.2 Carrier-Mediated Transport 80 6.3.3 Paracellular 81 6.3.4 Other Mechanisms 81
6.4 Physiological Factors Affecting Drug Absorption after Parenteral Drug Administration 82 6.4.1 Intramuscular 82 6.4.2 Subcutaneous 82
6.5 Physiological Factors Affecting Drug Absorption after Oral Drug Administration 83 6.5.1 83 6.5.2 Esophagus 83 6.5.3 83 6.5.4 Intestine 85 6.5.5 Large Intestine 86
6.6 Physiological Factors Affecting Drug Absorption after Rectal Drug Administration 87
6.7 Physiological Factors Affecting Drug Absorption after Intranasal Drug Administration 87
6.8 Physiological Factors Affecting Drug Absorption after Pulmonary Drug Administration 88
Contents xi
6.9 Physiological Factors Affecting Drug Absorption after Transdermal Drug Administration 89
6.10 Summary 91 References 92
Chapter 7 Drug Absorption Following Extravascular Administration: Molecular and Physicochemical Considerations 93
Objectives 93 7.1 Introduction 93 7.2 Molecular Structure Features Affecting Drug
Absorption 94 7.2.1 Molecular Weight 94 7.2.2 95 7.2.3 Hydrogen-Bond Donor/Acceptor 95 7.2.4 Polar Surface Area 96 7.2.5 of Rotatable Bonds 96 7.2.6 Chirality 96
7.3 Physicochemical Drug Properties 96 7.3.1 pH-Partition Theory 97 7.3.2 Drug Solubility 98
7.3.2.1 pH Drug Solubility 99 7.3.2.2 99 7.3.2.3 Drug Form 100 7.3.2.4 Drug 100
7.3.3 Drug Dissolution 101 7.3.3.1 Surface Area 101 7.3.3.2 Diffusion Coefficient 102 7.3.3.3 Thickness of the Layer 102 7.3.3.4 Drug Solubility at the Site
of Absorption 102 7.3.4 Drug Stability 102
7.4 Integration of the Physical, Chemical, and Physiological Factors Affecting Drug Absorption 103 7.4.1 Biopharmaceutics Classification System 103 7.4.2 Biopharmaceutics Drug Disposition
Classification System 105 References 107
Chapter 8 Drug Absorption Following Extravascular Administration: Formulation Factors 109
Objectives 109 8.1 Introduction 109 8.2 Formulation Factors Affecting Drug Absorption
after Parenteral Drug Administration
Contents
8.3 Formulation Factors Affecting Drug Absorption after Oral Drug Administration 111 8.3.1 Convention Oral Formulations 111
8.3.1.1 Solutions 112 8.3.1.2 Suspensions 112 8.3.1.3 Capsules 112 8.3.1.4 Tablets 112
8.3.2 Modified-Release Oral Formulations 116 8.3.2.1 Formulations with Site-Specific
Drug Release 117 8.3.2.2 Formulations with Controlled Rate
of Drug Release 118 8.4 Formulation Factors Affecting Drug Absorption
after Rectal Drug Administration 119 8.5 Formulation Factors Affecting Drug Absorption
after Intranasal Drug Administration 120 8.6 Formulation Factors Affecting Drug Absorption
after Pulmonary Drug Administration 121 8.7 Formulation Factors Affecting Drug Absorption
after Transdermal Drug Administration 122 References 123
Chapter 9 Drug Pharmacokinetics Following Single Oral Drug Administration: The Rate of Drug Absorption 125
Objectives 125 9.1 Introduction 125 9.2 Drug Absorption after Oral Administration 127
9.2.1 Zero-Order Drug Absorption 127 9.2.2 First-Order Drug Absorption 127
9.3 Plasma Concentration-Time Profile after a Single Dose 129
9.4 Determination of the Absorption Rate Constant 132 9.4.1 Method of Residuais 132
9.4.1.1 Lag Time 135 9.4.1.2 Flip-Flop of and k 136
9.4.2 Wagner-Nelson Method 138 Application of the Wagner-Nelson
Method 141 9.5 Clinical Importance of the Absorption Rate Constant 145 9.6 Pharmacokinetic Simulation Exercise 145 9.7 Summary Practice Problems 146 References
Contents xiii
Chapter 10 Drug Pharmacokinetics Following Single Oral Drug Administration: The Extent of Drug Absorption 151
Objectives 151 10.1 Introduction 151 10.2 Causes of Incomplete Drug 152
10.2.1 Physiological, Physicochemical, and Formulation Factors 152
10.2.2 First-Pass Effect 153 10.2.3 Drug Transporters 154
10.2.3.1 156 10.2.3.2 Oligopeptide Transporters 156
10.2.4 Intestinal Drug Metabolism 157 10.3 Regulatory Requirement for Bioavailability 157 10.4 Determination of the Drug in Vivo Bioavailability 158
10.4.1 Drug Bioavailability 159 10.4.1.1 Absolute Bioavailability 159 10.4.1.2 Relative Bioavailability 160
10.4.2 Calculation of the Drug Bioavailability 160 Calculation of the Drug
Bioavailability the Drug Urinary Excretion Data 161
10.5 Guidelines for Conducting in Vivo Bioavailability Study 10.5.1 Guiding Principles 162 10.5.2 Basic Study Design 162
For New Active Drug Moieties That Have Never Been Previously Marketed.... 163
10.5.2.2 For New Formulations of an Approved Active Drug Ingredient 163
10.5.2.3 For Extended-Release Formulations 163 10.5.2.4 For Combination Drug Products 163
10.6 Clinical Importance of Bioavailability 164 10.7 Calculation of the AUC (The Linear Trapezoidal 165 10.8 Factors Affecting the Plasma Drug Concentration-Time
Profile after a Single Oral Dose 169 10.8.1 Pharmacokinetic Simulation Exercise 169
10.8.1.1 Dose 169 10.8.1.2 Bioavailability 170 10.8.1.3 Total Body Clearance 170 10.8.1.4 Volume of Distribution 170 10.8.1.5 Absorption Rate Constant 171
10.9 Summary 171 Practice Problems 171 References 174
Contents
Chapter 11 Bioequivalence
Objectives 175 Introduction 175 General Definitions 176 Regulatory Requirement for Bioequivalence 177 Criteria for Waiver of the Bioavailability
or Bioequivalence Determination Requirements 178 Approaches for Demonstrating Product Bioequivalence 179
Acute Effect 180 11.5.2 Clinical Studies 180 11.5.3 In Vitro Dissolution Testing 180
Pharmacokinetic Approach to Demonstrate Product Bioequivalence 181 11.6.1 Study Design 181
11.6.1.1 Basic Principles 181 11.6.1.2 Study Subjects 181 11.6.1.3 of Volunteers 181
Ethical Approval 182 11.6.1.5 Drug Dose and Products 182
Drug Administration Protocol 182 11.6.1.7 Blood 182
Analysis of BE Study Samples 183 Analytical Method Validation 183 Determination of the Drug Concentration in the BE Study Samples 185
Pharmacokinetic Parameter Determination 185 11.6.3.1 Extent of Drug Absorption 185
Rate of Drug Absorption 185 11.6.4 Statistical Analysis 185 11.6.5 In Vitro Testing of Study Products 186
Documentation 186 Special Issues Related to BE Determination 187
11.7.1 BE Studies 187 11.7.2 Food-Effect BE Studies 188
Drugs with Long 188 Determination of BE from the Drug Urinary
Excretion Data 188 Fixed Dose Combination 189 Measuring Drug Metabolites in BE Studies 189 Highly Variable Drugs 190 Drugs Exhibiting Nonlinear Pharmacokinetics 190
11.7.9 Endogenous Substances 191 Enantiomers versus Racemates 192 Narrow Therapeutic Range Drug 192
Contents xv
Oral Products Intended for the Effect of the Drug 192
First 192 Summary 193
References 193
Chapter 12 Drug Pharmacokinetics during Constant Rate IV Infusion: The Steady-State Principle 195
Objectives 195 12.1 Introduction 195 12.2 Steady State 196 12.3 Time Required to Achieve Steady State 198
12.3.1 Changing the Drug Infusion Rate 200 12.4 Loading Dose 200 12.5 Termination of the Constant Rate IV Infusion 202 12.6 Determination of the Pharmacokinetic Parameters 203
12.6.1 Total Body Clearance 203 12.6.2 Elimination Rate Constant 203 12.6.3 Volume of Distribution 203
12.7 Dosage with Zero-Order Rate 205 12.8 Factors Affecting the Steady-State Drug Plasma
Concentration during Constant Rate IV Infusion 206 12.8.1 Pharmacokinetic Simulation Exercise 206
12.8.1.1 Infusion Rate 206 12.8.1.2 Total Body Clearance 206 12.8.1.3 Volume of Distribution 206 12.8.1.4 Loading Dose 207
Practice Problems 207
Chapter 13 Steady State during Multiple Drug Administration 211
Objectives 211 13.1 Introduction 211
Plasma Drug Profi ng Multiple Drug Administration 212
13.3 Time Required to Reach Steady State 215 13.4 Loading Dose 215
13.4.1 IV Loading Dose 217 13.4.2 Oral Loading Dose 217
13.5 Average Plasma Concentration at Steady State 217 13.6 Drug Accumulation 220 13.7 Controlled-Release Formulations 221
Effect of Changing the Pharmacokinetic Parameters on the Steady-State Plasma Drug Concentration during Multiple Drug Administration 222
Contents
13.8.1 Pharmacokinetic Simulation Exercise 223 13.8.1.1 Dosing Rate 223 13.8.1.2 Total Body Clearance 223 13.8.1.3 Distribution 223 13.8.1.4 Absorption Rate Constant 223
13.9 Dosing Regimen Design Based on Drug Pharmacokinetics 224 13.9.1 Factors to Be Considered 224
13.9.1.1 Therapeutic Range of the Drug 224 13.9.1.2 Required Effect 224 13.9.1.3 Drug Product 224
Progression of the Patient's Disease State 225
Estimation of the Patient Pharmacokinetic Parameters 225 13.9.2.1 When No Information Is
Available about the Patient's Medical History 225
13.9.2.2 When Information Is Available about the Patient's Medical History 225
13.9.2.3 When the Patient Has a History of Using the Drug under Consideration 225
13.9.3 Selection of Dose and Dosing Interval 226 13.9.3.1 Oral Formulation 226 Oral Formulations
and IV Administration 226 13.9.4 Selection of the Loading Dose 227
Practice Problems 228
Chapter 14 Renal Drug Excretion 233
Objectives 233 14.1 Introduction 233
Studying Drug Elimination through a Single Pathway 234 14.3 Renal Excretion of Drugs 236
14.3.1 Glomerular Filtration 236 14.3.2 Active Secretion 236 14.3.3 Reabsorption 236
14.4 Determination of the Renal Excretion Rate 237 Determination of the Renal
Excretion Rate 238 14.4.2 Renal Excretion Rate-Time Profile 239
14.5 Renal Clearance 241 Creatinine Clearance as a Measure
of Kidney Function 242
Contents xvii
14.6 Cumulative Amount of the Drug Excreted in Urine 243 Determination of the Drug ity
from the Cumulative Amount Excreted in Urine 245 14.6.2 Determination of the Renal
Clearance from the Cumulative Amount Excreted in Urine 245
14.7 Determination of the Pharmacokinetic Parameters from the Renal Excretion Rate Data 246 14.7.1 Elimination Rate Constant and Half-Life 246 14.7.2 Renal Excretion Rate Constant 246 14.7.3 Volume of Distribution 246 14.7.4 Renal Clearance 246 14.7.5 Fraction of Dose Excreted Unchanged in Urine 246 14.7.6 Bioavailability 247
Effect of Changing the Pharmacokinetic Parameters on the Urinary Excretion of Drugs 249 14.8.1 Pharmacokinetic Simulation Exercise 249
14.8.1.1 Dose 249 14.8.1.2 Total Body Clearance 250 14.8.1.3 Renal Clearance 250
Practice Problems 250 References 252
Chapter 15 Metabolite Pharmacokinetics 253
Objectives 253 15.1 Introduction 253 15.2 Drug Pathways 254
15.2.1 Classification of the Reactions 254 15.2.1.1 Phase I Metabolie Reactions 254 15.2.1.2 Phase II Metabolie Reactions 255
15.2.2 P450 255 15.3 Metabolite Pharmacokinetics 257 15.4 Simple Model for Metabolite Pharmacokinetics 259
15.4.1 Metabolite Concentration-Time Profile 261 15.4.1.1 Elimination Rate Limitation 261 15.4.1.2 Formation Rate Limitation 262
15.4.2 Mathematical Description of the Elimination Rate and Formation Rate Limited Metabolites 262
Time to Achieve the Maximum Metabolite Concentration 263
15.5 General Model for Kinetics 264 15.6 Estimation of the Metabolite Pharmacokinetic Parameters 266
15.6.1 Metabolite Elimination Rate Constant 266 15.6.1.1 Elimination Rate Limited Metabolites 266 15.6.1.2 Formation Rate Limited Metabolites 266
Contents
Fraction of the Parent Drug Converted to a Specific Metabolite 267
15.6.3 Metabolite Clearance, 268 15.6.4 Metabolite Volume of Distribution 268 15.6.5 Metabolite Formation Clearance 268
Steady-State Metabolite Concentration during Repeated Administration of the Parent Drug 271
Metabolite Pharmacokinetics after Extravascular Administration of the Parent Drug 274
15.9 Kinetics of Sequential 275 Effect of Changing the Pharmacokinetic Parameters on the Drug and Metabolite Concentration-Time Profiles after a Single IV Drug Administration and during Multiple Drug Administration 276 15.10.1 Pharmacokinetic Simulation Exercise 277
15.10.1.1 Dose 277 15.10.1.2 Drug Total Body Clearance 278 15.10.1.3 Drug Volume of Distribution 278 15.10.1.4 Fraction of the Drug Dose Converted
to Metabolite 279 15.10.1.5 Metabolite Total Body Clearance 279
Metabolite Volume of Distribution 279 Practice Problems 280 References 283
Chapter 16 Nonlinear Pharmacokinetics 285
Objectives 285 16.1 Introduction 285 16.2 Causes of Nonlinear Pharmacokinetics 286
16.2.1 Dose-Dependent Drug Absorption 287 16.2.2 Dose-Dependent Drug Distribution 288 16.2.3 Dose-Dependent Renal Excretion 289 16.2.4 Dose-Dependent Drug Metabolism 290 16.2.5 Other Conditions That Can Lead
to Nonlinear Pharmacokinetics 291 Pharmacokinetics of Drugs by Dose-
Dependent Metabolism: Michaelis-Menten Pharmacokinetics 292 16.3.1 Michaelis-Menten Enzyme Kinetics 292 16.3.2 Pharmacokinetic Parameters 293 16.3.3 Drug Concentration-Time Profile after
Administration of a Drug That Is Eliminated by a Single Pathway That Follows Michaelis-Menten Kinetics 295
Contents xix
16.3.3.1 After Single IV Bolus Administration 295 16.3.3.2 During Multiple Drug Administration 296
Determination of the Pharmacokinetic Parameters for Drugs with Elimination Process That Follows Michaelis-Menten Kinetics 297 16.3.4.1 Volume of Distribution 297 16.3.4.2 Total Body Clearance 297 16.3.4.3 Half-Life 298
Oral Administration of Drugs That Are Eliminated by Michaelis-Menten Process 298
16.5 Determination of the Michaelis-Menten Parameters and Calculation of the Appropriate Dosage Regimens 299 16.5.1 Mathematical Method 299 16.5.2 Direct Linear 300 16.5.3 Linear Transformation Method 302
16.6 Multiple Elimination Pathways 303 Effect of Changing the Pharmacokinetic Parameters
on Drug Concentration-Time Profile 304 16.7.1 Pharmacokinetic Simulation Exercise 304
16.7.1.1 Dose 304 16.7.1.2 304 16.7.1.3 304
Practice Problems 305 References 306
Chapter 17 Multicompartment Pharmacokinetic 309
Objectives 309 17.1 Introduction 309 17.2 Compartmental Pharmacokinetic 311 17.3 Two-Compartment Pharmacokinetic Model 312 17.4 Parameters of the Two-Compartment
Pharmacokinetic Model 314 17.4.1 Definition of the Pharmacokinetic Parameters 315
Mathematical Equation That Describes the Plasma Concentration-Time Profile 316
Determination of the Two-Compartment Pharmacokinetic Model Parameters 318 17.5.1 Method of Residuais 318 17.5.2 Determination of the Model Parameters 319
17.5.2.1 Volume of the Central 319 Area under the Plasma Concentration-
Time Curve, AUC 320 17.5.2.3 Total Body Clearance, 320
Contents
17.5.2.4 Elimination Rate Constant from the Central
320 17.5.2.5 First-Order Transfer Rate Constant
from the Peripheral Compartment to the Central Compartment, 320
17.5.2.6 First-Order Transfer Rate Constant from the Central Compartment to the Peripheral Compartment, 320
17.5.3 Determination of the Volumes of Distribution for the Two-Compartment Pharmacokinetic Model 321
Volume of Distribution at Steady State, 321
17.5.3.2 Volume of Distribution in the Elimination Phase, 322
17.6 Oral Administration of Drugs That Follow the Two-Compartment Pharmacokinetic Model 324 Method for
Determination of after Oral Administration of Drugs That Follow the Two-Compartment Pharmacokinetic Model 325
Constant Rate IV Administration of Drugs That Follow the Two-Compartment Pharmacokinetic Model 326
17.8 Multiple Drug Administration 326 Renal Excretion of Drugs That Follow the
Two-Compartment Pharmacokinetic Model 327 Effect of Changing the Pharmacokinetic Parameters on the Drug Concentration-Time Profile for Drugs That Follow the Two-Compartment Pharmacokinetic Model...328 17.10.1 Pharmacokinetic Simulation Exercise 328
17.10.1.1 Dose 328 17.10.1.2 Total Body Clearance 328 17.10.1.3 Volume of the Central Compartment 328 17.10.1.4 Hybrid Distribution Rate Constant 329 17.10.1.5 Hybrid Elimination Rate Constant 329
Effect of Changing the Pharmacokinetic Parameters on the Drug Distribution between the Central and Peripheral Compartments 329 17.11.1 Dose 329
First-Order Transfer Rate Constant from the Central to the Peripheral 329 First-Order Transfer Rate Constant from the Peripheral to the Central 329 First-Order Elimination Rate Constant from the Central Compartment 330
17.12 Pharmacokinetic Model 330
Contents xxi
17.13 Compartmental Pharmacokinetic Data Analysis 331 Mathematical Description of the Model and Estimation of the Model Parameters 332
Fitting the Experimental Data to the Model Equation 333
17.13.3 Evaluation of the Pharmacokinetic Model 335 Practice Problems 337 References 339
Chapter 18 Drug Pharmacokinetics Following Administration by Intermittent Intravenous Infusion 341
Objectives 341 18.1 Introduction 341 18.2 Drug Concentration-Time Profile during Intermittent
IV Infusion 343 18.2.1 After the First Dose 343
After Repeated Administration before Reaching Steady State 344
18.2.3 At Steady State 345 Effect of Changing the Pharmacokinetic Parameters
on the Steady-State Plasma Concentration during Repeated Intermittent IV Infusion 346 18.3.1 Pharmacokinetic Simulation Exercise 347
18.3.1.1 Dose 347 18.3.1.2 Infusion Time 347 18.3.1.3 Total Body Clearance 347 18.3.1.4 Volume of Distribution 347
Application of the Pharmacokinetic Principles for Intermittent IV Infusion to the Therapeutic Use of Aminoglycoside 348
Pharmacokinetic Characteristics of Aminoglycosides 348
18.4.2 Guidelines for Aminoglycoside Plasma Concentration 348
18.4.3 Aminoglycoside Dosing Regimen 349
18.5 Individualization of Aminoglycoside Therapy 349 18.5.1 Estimation of the Patient's Pharmacokinetic
Parameters 349 Estimation of the Patient's
Pharmacokinetic Parameters Based on the Patient Information 350
18.5.1.2 Estimation of the Patient's Specific Pharmacokinetic Parameters from Aminoglycoside Blood 351
Contents
Determination of the Dosing Regimen Based on the Patient's Specific Parameters 355 18.5.2.1 Selection of the Dosing Interval (T) 355 18.5.2.2 Dose 355 18.5.2.3 Selection of the Loading Dose 355
Practice Problems 359 References 361
Chapter 19 Pharmacokinetic-Pharmacodynamic Modeling 363
Objectives 363 19.1 Introduction 363 19.2 Components the PK/PD 364
19.2.1 Pharmacokinetic Model 364 19.2.2 Measuring the Response 365
19.2.2.1 365 19.2.2.2 Surrogate Endpoint 366 19.2.2.3 Clinical Endpoint 366
19.2.3 Integrating the Pharmacokinetic and Pharmacodynamic Information 366
Direct Response versus Indirect Response 366
Direct Link versus Indirect Link 367
19.2.3.3 Soft Link versus Hard Link 367 19.2.3.4 Time-Variant versus
368 19.3 368
19.3.1 Fixed Effect Model 369 19.3.2 Linear Model 369 19.3.3 Log-Linear Model 370 19.3.4 Model 371 19.3.5 Model 372
19.4 Indirect Link PK/PD 373 19.4.1 Effect Compartment Approach 375
19.5 Indirect Response 378 19.6 Time-Variant Pharmacodynamic 381 19.7 Other Pharmacodynamic 382
19.7.1 Irreversible Effect 382 19.7.2 Transduction Process Modeling 382 19.7.3 Pharmacokinetic without Drug
Concentrations 383 19.7.4 Disease Progression 383
19.8 PK/PD Modeling Process 384 Stating the Objectives, Proposing
a Tentative Model, and Designing the Study 384
Contents
19.8.2 Initial Data Exploration and Data Transformation 384
19.8.3 Refining and Evaluation of the PK/PD Model 385 19.8.4 the PK/PD Model 386
19.9 Applications of the PK/PD Modeling in Drug Development and Clinical Use of Drugs 386
19.10 PK/PD 387 19.10.1 Direct Link 387 19.10.2 Indirect Link Model Using Effect Compartment 388 19.10.3 Indirect Response 388
References 388
Chapter 20 Noncompartmental Approach in Pharmacokinetic Data Analysis 391
Objectives 391 20.1 Introduction 391 20.2 Noncompartmental Approach in Data Analysis 392 20.3 Mean Residence Time after IV Bolus Administration 393
20.3.1 Calculation of the AUC and AUMC 393 20.3.1.1 Area under the Plasma
Concentration-Time Curve 393 Area under the First Moment-Time
Curve 394 20.3.2 MRT after Different Routes of Administration 396
MRT after Extravascular Administration 396
20.3.2.2 MRT after Constant Rate IV Infusion 398 20.4 Other Pharmacokinetic Parameters That Can Be
Determined Using the Noncompartmental Approach 398 20.5 Determination of the MRT for Compartmental 400 Practice Problems 401 References 402
Chapter 21 Physiological Approach to Hepatic Clearance 403
Objectives 403 21.1 Introduction 403 21.2 Organ Clearance 404 21.3 Hepatic Extraction Ratio 404 21.4 Intrinsic Clearance 405 21.5 Systemic Bioavailability 406 21.6 Effect of Changing Intrinsic Clearance and Hepatic
Blood Flow on the Hepatic Clearance, Systemic Availability, and Drug Concentration-Time Profile 406
Contents
21.6.1 Low Extraction Ratio Drugs 407 21.6.2 High Extraction Ratio Drugs 409
21.7 Protein Binding and Hepatic Extraction 415 21.8 Pharmacokinetic Simulation Exercise 415 Practice Problems 416 References 417
Chapter 22 Physiologically Based Pharmacokinetic 419
Objectives 419 22.1 Introduction 419 22.2 Pharmacokinetic 420
22.2.1 General Model Structure 420 22.2.2 General Principles of Tissue Distribution 421
22.3 Physiologically Based Pharmacokinetic Model Development 423 22.3.1 Model Presentation 423
22.3.1.1 Model Components 423 22.3.1.2 Mathematical Presentation
the Model 425 22.3.2 Model Parameterization 433 22.3.3 Model Simulation and Parameter Estimation 434 22.3.4 Model Validation 435 22.3.5 Model Implementation 435
22.3.5.1 Extrapolation 436 22.3.5.2 Extrapolation 436 22.3.5.3 and
Extrapolation 436 22.4 Interspecies Scaling 436
PBPK Modeling Approach for Interspecies Scaling 437 22.4.2 Allometric Approach for Interspecies Scaling 437
22.5 PBPK 439 22.5.1 Estimating the Starting Dose for Entry
to 439 22.5.2 Applications of PBPK in Therapeutic
Use 440 References 441
Chapter 23 Therapeutic Drug Monitoring 443
Objectives 443 23.1 Introduction 443 23.2 General Principles of Initiation and Management
of Drug Therapy 444 Use of Therapeutic Drug Monitoring
in the Management of Drug Therapy 445
Contents xxv
23.3 Drug Blood Concentration versus Drug Dose 446 23.4 Therapeutic Range 447 23.5 Drug Candidates for Therapeutic Drug Monitoring 449
23.5.1 Drugs with Low Therapeutic Index 449 23.5.2 Drugs with Large Variability
in Their Pharmacokinetic Properties 449 23.5.3 Drugs Commonly Used in High-Risk
Patients or Patients with Multiple Medical Problems 450
23.6 Determination of the Drug Concentration Samples 450
23.6.1 Biological Samples 450 23.6.2 Time of 451 23.6.3 Measured Drug Moiety 451 23.6.4 Analytical Technique 452
23.7 Establishing a Therapeutic Drug Monitoring (Clinical Pharmacokinetic) Service 453 23.7.1 Major 454 23.7.2 Procedures 454
Determination of the Initial Dosing Regimen 454
23.7.2.2 Determination of the Patient's Specific Pharmacokinetic Parameters 454
23.7.2.3 Calculation of the Dosage Requirements Based on the Patient's Specific Pharmacokinetic Parameters of Drug 455
23.7.3 Pharmacoeconomics of Therapeutic Drug Monitoring 455
References 456
Chapter 24 Pharmacokinetics in Special Patient Populations 457
Objectives 457 24.1 Introduction 457 24.2 Regulatory Aspects of Pharmacokinetic Studies
in Special Populations 458 24.3 Patients with Renal Dysfunction 459
24.3.1 Dosing Regimens in Renal Dysfunction Patients Based on Creatinine Clearance 460
24.3.2 General Approach for Calculation of Dosing Regimens in Renal Dysfunction Patients 462
24.4 Patients Receiving Renal Replacement Therapy 465 24.4.1 Principle of Hemodialysis and Hemofiltration 465
XXVI Contents
24.4.2 Factors Affecting Drug Clearance during RRT 466 24.4.3 Dose during RRT 467
24.5 Patients with Hepatic Insufficiency 467 Pharmacokinetic and Pharmacodynamic
Changes in Hepatic Dysfunction 468 24.5.2 Dose Adjustment in Hepatic Dysfunction 470 24.5.3 Additional Considerations for Dose Adjustment
in Liver Dysfunction 471 24.6 Obese Patients 472
Assessment of Body and Body Weight 472
24.6.2 Alteration in Drug Pharmacokinetics in Obese Patients 473
24.7 Pediatric Patients 475 Developmental Changes in Pediatric Patients
That Affect Drug Absorption 476 24.7.2 Developmental Changes in Pediatric Patients
That Affect Drug Distribution 477 24.7.3 Developmental Changes in Pediatric Patients
That Affect Drug Metabolism 478 24.7.4 Developmental Changes in Pediatric Patients
That Affect Renal Drug Excretion 479 24.7.5 Integrating the Differences in all the
Pharmacokinetic Processes in Pediatric Patients 480 24.8 Elderly Patients 480
Physiological Changes in Elderly Patients That Affect Drug Absorption 480
24.8.2 Physiological Changes in Elderly Patients That Affect Drug Distribution 480
24.8.3 Physiological Changes in Elderly Patients That Affect Drug Metabolism 481
24.8.4 Physiological Changes in Elderly Patients That Affect Renal Drug Excretion 481
24.8.5 Integrating the Differences in All the Pharmacokinetic Processes in Elderly Patients
24.9 Pregnant and Nursing Mothers 482 Physiological Changes That Affect
Drug Absorption during Pregnancy 482 24.9.2 Physiological Changes That Affect
Drug Distribution during Pregnancy 482 24.9.3 Physiological Changes That Affect Drug
Metabolism and Excretion during Pregnancy 482 24.9.4 Drug Pharmacokinetics in Nursing Women 483
Factors Related to the Drug Properties 483
Contents xxvii
24.9.4.2 Factors Related to Maternal Pharmacology 483
24.9.4.3 Factors Related to the Infant 484 Practice Problems 484 References 486
Chapter 25 Pharmacokinetic Drug-Drug Interactions 489
Objectives 489 25.1 Introduction 489 25.2 Classification of Drug-Drug Interactions 490
25.2.1 Mechanism of Drug-Drug Interactions 490 25.2.2 Desirable versus Undesirable Drug-Drug
Interactions 491 25.3 Pharmacokinetic Drug-Drug Interactions 491
25.3.1 Pharmacokinetic Drug-Drug Interactions That Affect Drug Absorption 491
25.3.2 Pharmacokinetic Drug-Drug Interactions That Affect Drug Distribution 492
25.3.3 Pharmacokinetic Drug-Drug Interactions That Affect Drug Metabolism 493
25.3.4 Pharmacokinetic Drug-Drug Interactions That Affect Drug Proteins 495
25.3.5 Pharmacokinetic Drug-Drug Interactions That Affect Drug Excretion 496
25.4 Evaluation of Pharmacokinetic Drug-Drug Interactions 497 25.4.1 Time Course of the Interaction 497 25.4.2 Extrapolation from a Drug to Another 497 25.4.3 Therapeutic Index of the Drug 498 25.4.4 Sequence of Administration
of the Interacting Drugs 498 25.4.5 of Drug Dose 498
25.5 Drug-Drug Interaction Studies in Drug Development 499 25.5.1 In Vitro Studies 499 25.5.2 In Vivo Studies 500 25.5.3 Labeling Considerations 502
References 502
Chapter 26 Pharmacogenetics: The Genetic Basis of Pharmacokinetic and Pharmacodynamic Variability 505
Objectives 505 26.1 Introduction 505 26.2 Gene Structure and Gene Variations 506
Contents
26.3 Genetic in Pharmacokinetics 508 26.3.1 P450 508 26.3.2 Thiopurine Methyltransferase 510 26.3.3 511 26.3.4 511 26.3.5 Drug Transporters 512
26.4 Genetic Polymorphism in Pharmacodynamics 513 26.5 Implementation of Pharmacogenetic Testing in Clinical
Practice 513 26.6 Future Directions 514 References 515
Chapter 27 Applications of Computers in Pharmacokinetics 517
Objectives 517 27.1 Introduction 517 27.2 Commonly Used Pharmacokinetic Computer Programs 518
27.2.1 518 27.2.2 518 27.2.3 Boomer and MultiForte 519 27.2.4 CalcuSyn 519 27.2.5 Cyber Patient 519 27.2.6 Datakinetics 520 27.2.7 e-Pharmacokinetics 520 27.2.8 GastroPlus 520 27.2.9 Kinetica 521 27.2.10 Modern Biopharmaceutics 521 27.2.11 MONOLIX 521 522
NCOMP 522 27.2.14 NLMEM Macro 522 27.2.15 NONMEM 522
PCCAL 523 27.2.17 PDx-Pop 523 27.2.18 PK Solutions 523 27.2.19 524 27.2.20 PKSolver 524 27.2.21 RxKinetics 524 27.2.22 Scientist for Windows 524 27.2.23 525 27.2.24 STELLA 525 27.2.25 T.D.M.S.2000 525 27.2.26 Simulator 526 27.2.27 USC PACK Pharmacokinetic Programs 526 27.2.28 WinNonlin 527 27.2.29 WinNonMix 527
Contents xxix
Chapter 28 The CD 529
Objectives 529 28.1 Introduction 529 28.2 Pharmacokinetic Program 529
Basic Pharmacokinetic Concepts 530 28.2.2 Pharmacokinetic Simulations 531 28.2.3 Pharmacokinetic/Pharmacodynamic
28.3 Suggestions for Using the Companion CD 531 References 532
Solutions for the Practice Problems 533
Index 545