Basic Pharmacokinetics

by Hedaya, Mohsen A.

• ISBN13: 9781420046717
• ISBN10: 1420046713
• Edition: 1st
• Format: Hardcover
• Copyright: 2007-04-23
• Publisher: CRC Press

Summary

An accessible introduction to foundational concepts, Basic Pharmacokinetics has been carefully designed for students and others who have never studied the subject before. Exploring the use of mathematical models to predict the response of individual patients to drugs, this book features a CD-ROM that complements the material presented in the text. The CD includes computer-based presentations that use graphics and simulations to allow readers to visualize how a change in one or more pharmacokinetic parameter is reflected in the drug profile of the body. Using a self-instructional format, this text serves as a useful reference covering such topics as drug absorption and therapeutic drug monitoring.

Table of Contents

Introduction to Biopharmaceutics and Pharmacokinetics	p. 1
Introduction	p. 1
Application of Biopharmaceutic and Pharmacokinetic Principles in Biomedical Fields	p. 2
Drug Formulation Design	p. 2
Drug Dosage Form Design	p. 2
Pharmacological Testing	p. 3
Toxicological Testing	p. 3
Evaluation of Organ Function	p. 3
Dosing Regimen Design	p. 3
Drug Concentration-Time Profile	p. 3
Linear and Nonlinear Pharmacokinetics	p. 3
Linear Pharmacokinetics	p. 3
Nonlinear Pharmacokinetics	p. 4
Pharmacokinetic Modeling	p. 4
Compartmental Modeling	p. 4
Physiological Modeling	p. 4
Noncompartmental Approach	p. 5
Pharmacokinetic Simulation	p. 5
Questions	p. 5
Drug Pharmacokinetics Following Single Intravenous Administration	p. 7
Introduction	p. 7
Elimination Rate Constant	p. 8
Rate of Drug Elimination	p. 8
Rate Constant for Drug Elimination	p. 8
Order of Drug Elimination	p. 8
Zero-Order Elimination	p. 8
First-Order Elimination	p. 10
Determination of the First-Order Elimination Rate Constant k	p. 13
Mathematical Expressions That Describe the Amount of the Drug in the Body When Elimination Process Follows First-Order Elimination	p. 13
Clinical Importance of the Elimination Rate Constant	p. 15
Summary	p. 16
Volume of Distribution	p. 16
Relationship between the Drug Amount in the Body and Drug Blood Concentration	p. 16
Drug Protein Binding and Volume of Distribution	p. 17
Determination of Volume of Distribution	p. 19
Clinical Importance of Volume of Distribution	p. 19
Summary	p. 21
Half-Life	p. 21
Half-Life during Zero-Order and First-Order Elimination	p. 21
Zero-Order Elimination	p. 21
First-Order Elimination	p. 22
Graphical Determination of Half-Life	p. 22
Clinical Importance of Half-Life	p. 23
Summary	p. 24
Total Body Clearance	p. 24
Relationship between Total Body Clearance, Volume of Distribution, and the Elimination Rate Constant	p. 24
Determination of Total Body Clearance	p. 25
Total Body Clearance and Volume of Distribution Are Independent Pharmacokinetic Parameters	p. 25
Clinical Importance of Total Body Clearance	p. 26
Summary	p. 26
Area Under the Curve	p. 27
Factors Affecting Area Under the Curve after a Single IV Bolus Dose	p. 27
Calculation of Area Under the Curve after a Single IV Bolus Dose	p. 28
Clinical Importance of Area Under the Curve	p. 29
Factors Affecting the Drug Blood Concentration-Time Profile after a Single IV Bolus Dose	p. 30
Dose	p. 30
Volume of Distribution	p. 31
Total Body Clearance	p. 31
Practice Problems	p. 31
Drug Absorption Following Oral Administration: Biopharmaceutical Considerations	p. 37
Introduction	p. 37
Physiological Factors Affecting Oral Drug Absorption	p. 38
Nature of the GIT Membrane	p. 38
Passive Diffusion	p. 38
Carrier-Mediated Transport	p. 39
Paracellular	p. 39
Other Mechanisms	p. 39
Gastrointestinal Physiology	p. 39
Buccal Cavity	p. 40
Esophagus	p. 40
Stomach	p. 40
Small Intestine	p. 40
Large Intestine	p. 41
Rectum	p. 41
Effect of Food on Drug Absorption	p. 41
Pathological Conditions Affecting Drug Absorption	p. 41
Physical Factors Affecting Oral Drug Absorption	p. 42
Drug Physicochemical Properties	p. 42
Drug Lipid Solubility	p. 42
pH Partition Theory	p. 43
Dissolution of the Drug	p. 44
Surface Area	p. 45
Diffusion Coefficient	p. 45
Thickness of the Unstirred Layer	p. 45
Drug Solubility	p. 45
Dosage Form Characteristics	p. 46
Types of Oral Dosage Forms	p. 47
Solutions	p. 47
Suspensions	p. 47
Capsules	p. 47
Tablets	p. 47
Coated Tablets	p. 48
Sustained-Release Tablets	p. 48
In Vitro Disintegration Test	p. 48
In Vitro Dissolution Test	p. 48
Rotating Basket	p. 49
Paddle Method	p. 49
Other Methods	p. 49
Dissolution Requirements	p. 49
Correlation of In Vitro Drug Dissolution with In Vivo Drug Absorption	p. 49
Questions	p. 50
Drug Pharmacokinetics Following Single Oral Drug Administration: Rate of Drug Absorption	p. 51
Introduction	p. 51
Drug Absorption after Oral Administration	p. 52
Plasma Concentration-Time Profile after a Single Oral Dose	p. 54
Determination of Absorption Rate Constant	p. 56
Method of Residuals	p. 56
Lag Time	p. 58
Flip Flop of k[subscript a] and k	p. 58
Wagner-Nelson Method	p. 60
Clinical Importance of Absorption Rate Constant	p. 62
Summary	p. 63
Practice Problems	p. 64
Drug Pharmacokinetics Following Single Oral Drug Administration: Extent of Drug Absorption	p. 67
Introduction	p. 67
General Definitions	p. 68
Purpose of Bioavailability and Bioequivalence Studies	p. 69
Causes for Variation in Drug Bioavailability	p. 69
Factors Related to Drug Formulation and Route of Administration	p. 69
Route of Administration	p. 69
Dosage Form	p. 69
Excipient	p. 70
Factors Related to the Drug	p. 70
Drug Solubility	p. 70
Drug Partition Coefficient	p. 70
Stability and Drug Interaction	p. 70
Factors Related to the Patient	p. 71
Individual Variability	p. 71
Site of Administration	p. 71
Diseases	p. 71
First-Pass Effect	p. 71
Pharmacokinetic Basis of Drug Bioavailability and Bioequivalence	p. 72
Determination of Drug Bioavailability	p. 72
Expected Values for Drug Bioavailability	p. 74
Clinical Importance of Bioavailability and Bioequivalence	p. 74
Calculation of Area under the Curve (Linear Trapezoidal Rule)	p. 75
Regulatory Requirements for Bioavailability and Bioequivalence	p. 79
Design and Evaluation of Bioequivalence Studies	p. 80
Criteria for Waiver of Bioavailability Requirements	p. 81
Factors Affecting the Blood Concentration-Time Profile after a Single Oral Dose	p. 81
Dose	p. 82
Bioavailability	p. 82
Total Body Clearance	p. 82
Volume of Distribution	p. 82
Absorption Rate Constant	p. 82
Practice Problems	p. 82
Steady-State Principle and Drug Pharmacokinetics during Constant-Rate Intravenous Infusion	p. 87
Introduction	p. 87
Plasma Concentration during Continuous Constant-Rate IV Drug Administration	p. 88
Time Required to Reach Steady State	p. 89
Loading Dose	p. 90
Determination of the Pharmacokinetic Parameters	p. 92
Total Body Clearance	p. 92
Elimination Rate Constant	p. 92
Volume of Distribution	p. 92
Effect of Changing the Pharmacokinetic Parameters on Steady-State Plasma Concentration during Constant-Rate IV Infusion	p. 94
Infusion Rate	p. 94
Volume of Distribution	p. 94
Total Body Clearance	p. 94
Practice Problems	p. 95
Steady State during Multiple Drug Administrations	p. 99
Introduction	p. 99
Drug Plasma Concentration-Time Profile during Multiple Drug Administrations	p. 100
Average Plasma Concentration at Steady State	p. 102
Time Required to Reach Steady State	p. 104
Loading Dose	p. 105
Intravenous Drug Administration	p. 105
Extravascular Drug Administration	p. 105
Drug Accumulation	p. 105
Controlled-Release Formulations	p. 106
Effect of Changing the Pharmacokinetic Parameters on Steady-State Plasma Concentration during Repeated Drug Administration	p. 107
Dosing Rate	p. 107
Total Body Clearance	p. 107
Volume of Distribution	p. 107
Absorption Rate Constant	p. 107
Dosage Regimen Design	p. 107
Factors to Be Considered	p. 107
Therapeutic Range of the Drug	p. 107
Required Onset of Effect	p. 108
Drug Formulation	p. 108
Patient Disease State	p. 108
Estimation of Patient Pharmacokinetic Parameters	p. 108
Lack of the Patient's Medical History	p. 108
Information Available about the Patient's Medical History	p. 108
Patient with History of Using the Drug	p. 108
Selection of Dose and Dosing Interval	p. 109
Controlled-Release Oral Formulation	p. 109
Fast-Release Oral Formulations and IV Bolus Administration	p. 109
Selection of Loading Dose	p. 110
Practice Problems	p. 111
Renal Drug Elimination	p. 115
Introduction	p. 115
Mechanisms of Renal Excretion of Drugs	p. 116
Glomerular Filtration	p. 116
Tubular Secretion	p. 116
Tubular Reabsorption	p. 116
Determination of Renal Excretion Rate	p. 117
Experimental Determination of Renal Excretion Rate	p. 117
Renal Excretion Rate-Time Profile	p. 118
Renal Clearance	p. 119
Creatinine Clearance as a Measure of Kidney Function	p. 120
Cumulative Amount of the Drug Excreted in Urine	p. 121
Determination of Renal Clearance from the Cumulative Amount Excreted in Urine	p. 122
Determination of Pharmacokinetic Parameters from Renal Excretion Rate Data	p. 123
Elimination Rate Constant and Half-Life (k and t[subscript fraction12])	p. 123
Renal Excretion Rate Constant k[subscript e]	p. 123
Volume of Distribution Vd	p. 123
Renal Clearance CL[subscript R]	p. 123
Fraction of Dose Excreted Unchanged in Urine	p. 124
Bioavailability	p. 124
Effect of Changing the Pharmacokinetic Parameters on Urinary Excretion of Drugs	p. 127
Dose	p. 127
Total Body Clearance	p. 127
Renal Clearance	p. 127
Practice Problems	p. 128
Metabolite Pharmacokinetics	p. 131
Introduction	p. 131
Simple Model for Metabolite Kinetics	p. 133
Elimination Rate Limitation	p. 135
Formation Rate Limitation	p. 136
Mathematical Description of Elimination Rate-and Formation Rate-Limited Metabolites	p. 137
Time to Achieve Maximum Metabolite Concentration	p. 137
General Model for Metabolite Kinetics	p. 138
Estimation of Metabolite Pharmacokinetic Parameters	p. 140
Metabolite Elimination Rate Constant	p. 140
Elimination Rate-Limited Metabolites	p. 140
Formation Rate-Limited Metabolites	p. 140
Fraction of the Parent Drug Converted to a Specific Metabolite (or Amount of Metabolite Formed)	p. 141
Metabolite Clearance	p. 142
Metabolite Volume of Distribution	p. 142
Metabolite Formation Clearance	p. 142
Effect of Changing the Pharmacokinetic Parameters on Drug and Metabolite Concentration-Time Profiles after a Single IV Drug Administration	p. 145
Drug Dose	p. 145
Drug Total Body Clearance CL[subscript T]	p. 146
Drug Volume of Distribution Vd	p. 146
Fraction of Drug Dose Converted to Metabolite f[subscript m]	p. 146
Metabolite Total Body Clearance CL[subscript T(m)]	p. 147
Metabolite Volume of Distribution Vd[subscript (m)]	p. 147
Steady-State Metabolite Concentration during Repeated Administrations of Parent Drug	p. 147
Effect of Changing the Pharmacokinetic Parameters on the Steady-State Drug and Metabolite Concentrations during Repeated Drug Administrations	p. 150
Drug Dose	p. 150
Drug Total Body Clearance CL[subscript T]	p. 151
Drug Volume of Distribution Vd	p. 151
Fraction of Drug Dose Converted to Metabolite f[subscript m]	p. 151
Metabolite Total Body Clearance CL[subscript T(m)]	p. 151
Metabolite Volume of Distribution Vd[subscript (m)]	p. 151
Metabolite Kinetics after Extravascular Administration of the Parent Drug	p. 151
Kinetics of Sequential Metabolism	p. 152
Practice Problems	p. 153
Disease State and Drug Pharmacokinetics	p. 159
Introduction	p. 159
Patients with Kidney Dysfunction	p. 159
Factors Affecting the Change in Drug Pharmacokinetics in Patients with Kidney Dysfunction	p. 159
Fraction of Dose Excreted Unchanged in Urine	p. 159
Degree of Kidney Dysfunction	p. 160
Dosage Adjustment in Patients with Renal Dysfunction	p. 160
Determination of Kidney Function	p. 160
Determination of the Fraction of Dose Excreted Unchanged in Urine	p. 161
Determination of Dosage Requirements in Patients with Reduced Kidney Function	p. 161
Patients with Liver Diseases	p. 163
Child-Pugh Score	p. 164
Practice Problems	p. 165
Nonlinear Pharmacokinetics	p. 169
Introduction	p. 169
Causes of Nonlinear Pharmacokinetics	p. 169
Saturable Drug Absorption	p. 169
Saturable Protein Binding	p. 169
Saturable Renal Elimination	p. 170
Saturable Drug Metabolism	p. 170
Others	p. 170
Evidence of Nonlinear Pharmacokinetics	p. 170
Michaelis-Menten Enzyme Kinetics	p. 170
Pharmacokinetic Parameters	p. 172
Plasma Concentration-Time Profile after a Single Intravenous Dose of a Drag Eliminated by a Metabolic Pathway That Follows Michaelis-Menten Kinetics	p. 173
After a Single Drug Administration	p. 173
After Multiple Drug Administrations	p. 174
Determination of the Pharmacokinetic Parameters	p. 175
Total Body Clearance	p. 175
Half-Life	p. 176
Effect of Changing the Pharmacokinetic Parameters on Plasma Concentration-Time Profile	p. 176
Dose	p. 176
V[subscript max]	p. 176
K[subscript m]	p. 176
Oral Administration of Drugs Eliminated by a Michaelis-Menten Process	p. 177
Pharmacokinetic Parameter Determination and Dosage Recommendation	p. 177
Mathematical Method	p. 177
Direct Linear Plot	p. 178
Linear Transformation Method	p. 180
Multiple Elimination Pathways	p. 180
Practice Problems	p. 181
Multicompartment Pharmacokinetic Models	p. 185
Introduction	p. 185
Two-Compartment Pharmacokinetic Model	p. 186
Two-Compartment Pharmacokinetic Model Parameters	p. 189
Definition of the Pharmacokinetic Parameters	p. 189
Mathematical Equation That Describes the Plasma Concentration-Time Profile	p. 190
Determination of Two-Compartment Pharmacokinetic Model Parameters	p. 191
Method of Residuals	p. 191
Determination of Model Parameters	p. 192
Volume of Central Compartment V[subscript c]	p. 193
Area under the Curve (AUC)	p. 193
Total Body Clearance CL[subscript T]	p. 193
First-Order Elimination Rate Constant from Central Compartment k[subscript 3]	p. 193
First-Order Transfer Rate Constant from Peripheral Compartment to Central Compartment k[subscript 2]	p. 193
First-Order Transfer Rate Constant from Central Compartment to Peripheral Compartment k[subscript 1]	p. 194
Volume of Distribution at Steady State Vd[subscript ss]	p. 194
Volume of Distribution in Elimination Phase Vd[subscript beta]	p. 194
Effect of Changing the Pharmacokinetic Parameters on Drug Concentration-Time Profile after a Single IV Dose	p. 196
Dose	p. 196
Volume of Distribution	p. 196
Hybrid Distribution Rate Constant [alpha]	p. 197
Hybrid Elimination Rate Constant [beta]	p. 197
Oral Administration of Drugs That Follow the Two-Compartment Pharmacokinetic Model	p. 197
Constant Rate IV Administration of Drugs That Follow the Two-Compartment Pharmacokinetic Model	p. 198
Multiple Drug Administrations	p. 199
Renal Excretion of Drugs That Follow the Two-Compartment Pharmacokinetic Model	p. 199
Effect of Changing the Pharmacokinetic Parameters on Drug Distribution between Central and Peripheral Compartments	p. 200
Dose	p. 200
First-Order Transfer Rate Constant from Central to Peripheral Compartment k[subscript 1]	p. 200
First-Order Transfer Rate Constant from Peripheral to Central Compartment k[subscript 2]	p. 200
First-Order Elimination Rate Constant from Central Compartment k[subscript 3]	p. 201
Three-Compartment Pharmacokinetic Model	p. 201
Practice Problems	p. 202
Drug Pharmacokinetics Following Administration by Intermittent Intravenous Infusion	p. 205
Introduction	p. 205
Drug Concentration-Time Profile during Intermittent IV Infusion	p. 206
After First Dose	p. 206
After Repeated Administration before Reaching Steady State	p. 208
At Steady State	p. 209
Effect of Changing the Pharmacokinetic Parameters on Steady-State Plasma Concentration during Repeated Intermittent IV Infusion	p. 210
Dose	p. 210
Infusion Time	p. 210
Total Body Clearance	p. 210
Volume of Distribution	p. 210
Application of Pharmacokinetic Principles for Intermittent IV Infusion to Therapeutic Use of Aminoglycoside	p. 210
Pharmacokinetic Characteristics	p. 211
Absorption	p. 211
Distribution	p. 211
Excretion	p. 211
Guidelines for Aminoglycoside Plasma Concentration	p. 211
Extended-Interval Aminoglycoside Dosing Regimen	p. 212
Individualization of Aminoglycoside Therapy	p. 212
Determination of Initial Dosing Regimen Based on Population Parameters	p. 212
Determination of Patient-Specific Pharmacokinetic Parameters	p. 213
If the Patient Is to Receive the First Aminoglycoside Dose	p. 213
If the Patient Received Aminoglycosides before but the Steady State Was Not Achieved	p. 215
If the Patient Received Aminoglycosides and Steady State Has Been Achieved	p. 216
Determination of the Dosing Regimen Based on the Patient's Specific Parameters	p. 217
Selection of Dosing Interval [tau]	p. 217
Selection of Dose	p. 217
Selection of Loading Dose	p. 217
Practice Problems	p. 221
Noncompartmental Approach to Pharmacokinetic Data Analysis	p. 225
Introduction	p. 225
Noncompartmental Approach in Data Analysis	p. 226
Mean Residence Time	p. 227
Calculation of AUC and AUMC	p. 228
Area Under the Plasma Concentration-Time Curve	p. 228
Area Under the First Moment-Time Curve	p. 228
Mean Residence Time after Different Routes of Administration	p. 231
Mean Residence Time after Extravascular Administration	p. 231
The Mean Residence Time after Constant-Rate IV Infusion	p. 233
Other Pharmacokinetic Parameters That Can Be Determined Using the Noncompartmental Approach	p. 233
Determination of Mean Residence Time for Compartmental Models	p. 234
Practice Problems	p. 235
Physiological Approach to Hepatic Clearance	p. 237
Introduction	p. 237
Organ Clearance	p. 237
Hepatic Extraction Ratio	p. 238
Intrinsic Clearance (CL[subscript int])	p. 239
Systemic Bioavailability	p. 239
Effect of Change in Intrinsic Clearance and Hepatic Blood Flow on Hepatic Clearance, Systemic Availability, and Drug Concentration-Time Profile	p. 240
Low Extraction Ratio Drugs	p. 240
High Extraction Ratio Drugs	p. 243
Protein Binding and Hepatic Extraction	p. 250
Practice Problems	p. 250
Pharmacokinetic-Pharmacodynamic Relationship	p. 253
Introduction	p. 253
Pharmacodynamic Models	p. 254
Fixed-Effect Model	p. 255
Linear Model	p. 255
Log-Linear Model	p. 256
E[subscript max] Model	p. 257
Sigmoid E[subscript max] Model	p. 259
Link between Pharmacokinetic and Pharmacodynamic Models	p. 260
Application of Pharmacodynamic Models	p. 260
Duration of Drug Effect	p. 260
Dosing Regimen	p. 261
Practice Problems	p. 261
Therapeutic Drug Monitoring	p. 263
Introduction	p. 263
General Principles of Initiation and Management of Drug Therapy	p. 263
Drug Blood Concentration versus Drug Dose	p. 264
Therapeutic Range	p. 265
Variability in Drug Pharmacokinetics and Response	p. 267
Body Weight	p. 267
Age	p. 267
Pediatrics	p. 267
Geriatrics	p. 267
Drug-Drug Interactions	p. 268
Genetic Factors	p. 268
Pregnancy	p. 268
Diseases	p. 268
Other Factors	p. 269
Advantages of Therapeutic Drug Monitoring	p. 269
Facilitate Rapid Achievement of an Appropriate Dosing Regimen	p. 269
Evaluate Existing Dosing Regimen	p. 269
Prophylaxis against Toxicity	p. 269
Distinguish between Pharmacokinetic and Pharmacodynamic Causes of Therapeutic Failure	p. 269
Cost-Effectiveness	p. 269
Candidate Drugs For Therapeutic Drug Monitoring	p. 270
Drugs with Low Therapeutic Index	p. 270
Drugs with Great Variability in Their Pharmacokinetic Properties	p. 270
Drugs Used in Patients Who Are at High Risk of Toxicity	p. 270
Methods for Measuring Drug Blood Concentrations	p. 270
Establishing a Therapeutic Drug Monitoring Service	p. 271
Major Requirements	p. 271
Procedures	p. 271
Determination of Initial Dosing Regimen	p. 271
Determination of the Patient's Specific Pharmacokinetic Parameters	p. 271
Calculation of Dosage Requirements Based on the Patient's Specific Pharmacokinetic Parameters of the Drug	p. 272
Questions	p. 272
Solutions to Practice Problems	p. 273
Index	p. 285
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