PHARMACOKINETIC ANALYSIS

Transcription

1 PHARMACOKINETIC ANALYSIS A PRACTICAL APPROACH Peter I. D. Lee, Ph.D. janssen Research Foundation Titusville, New Jersey Gordon L. Amidon, Ph.D. College of Pharmacy University of Michigan Ann Arbor, Michigan TECHNOMIC ^PUBLISHING CO.. INC J T.ANCASTER BASEl,

2 TABLE OF CONTENTS Preface xi SECTION I: BASICS AND METHODS Chapter 1. Introduction 3 Solving the Pharmacokinetic Puzzle 7 Characterizing Concentration Profiles by the Time Constant Approach 10 Chapter 2. Time Constant Approach 15 Time Constants and Mean Residence Times 15 Physiological Meanings and Clinical Applications of Time Constants 22 Mathematical Definitions of Time Constants and Mean Residence Time 24 Derivation of Mean Residence Time from Input and Output Times 28 A Simple Example 33 Time Constant Plot 34 The Relationship of Rate Limiting Time Constants to the Concentration Profile 36 Model Building in Time Constant Approach 39 An Example Comparing Time Constant Approach and Compartmental Modeling 44 Compartmental Modeling 47 Drug-Defined Models 51 Model-Independent Estimation of Time Constants 53 References 57

3 VI Table of Contents Chapter 3. Evaluation of Time Constants by Visual Inspection of Concentration-Time Profiles 61 Not All the Time Constants Can Be Observed 61 Time Constants Appear on the Concentration-Time Profile According to the Order of Magnitude 63 Flip-Flop and Dominant Time Constant of Terminal Phase 64 Indistinguishable Time Constants with Overlapping Time Windows 66 Time Constant Windows Interrupted by Peak Concentration 67 Observation Time Scale and Identification of Time Constant 69 Superposition Principle and Time Shifting 69 Pharmacokinetic and Pharmacodynamic Links Isolated Multi-Compartment Model 73 Chapter 4. Scaling of Time Constants among Different Animal Species 77 Pharmacokinetic Time Constants and Physiological Time Scales 77 Interspecies Scaling of Time Constants 80 References 87 SECTION II: FORMULATION FACTORS Chapter 5. Influence of Administration Route on Pharmacokinetics Bioavailability 93 Introduction 93 Pharmacokinetic Models 95 Case Studies 104 Examples 112 References 118 Chapter 6. Influence of Formulation on Pharmacokinetics Bioequivalence 121 Introduction 121 Pharmacokinetic Models 123 Case Studies 128 Examples 137 References 140

4 Table of Contents vii Chapter 7. Influence of Dosage on Pharmacokinetics Dose Proportionality 143 Introduction 143 Pharmacokinetic Models 144 Case Studies 147 Examples 157 References 164 Chapter 8. Pharmacokinetics of Sustained Release and Immediate Release Formulations 167 Introduction 167 Pharmacokinetic Models 168 Case Studies 172 Examples 181 References 187 SECTION III: ABSORPTION, DISTRIBUTION, METABOLISM, AND PHARMACODYNAMICS Chapter 9. Absorption of Drugs in the Gastrointestinal Tract 191 Introduction 191 Pharmacokinetic Models 192 Case Studies 196 Examples 206 References 211 Chapter 10. Drug Distribution into Tissue- Tissue Penetration 213 Introduction 213 Pharmacokinetic Models 214 Case Studies 219 Examples 228 References 235 Chapter 11. Pharmacokinetics of Metabolites 237 Introduction 237 Pharmacokinetic Models 239 Case Studies 247 Examples 262 References 271

5 Vi Table of Contents Chapter 3. Evaluation of Time Constants by Visual Inspection of Concentration-Time Profiles 61 Not All the Time Constants Can Be Observed 61 Time Constants Appear on the Concentration-Time Profile According to the Order of Magnitude 63 Flip-Flop and Dominant Time Constant of Terminal Phase 64 Indistinguishable Time Constants with Overlapping Time Windows 66 Time Constant Windows Interrupted by Peak Concentration 67 Observation Time Scale and Identification of Time Constant 69 Superposition Principle and Time Shifting 69 Pharmacokinetic and Pharmacodynamic Links Isolated Multi-Compartment Model 73 Chapter 4. Scaling of Time Constants among Different Animal Species 77 Pharmacokinetic Time Constants and Physiological Time Scales 77 Interspecies Scaling of Time Constants 80 References 87 SECTION II: FORMULATION FACTORS Chapter 5. Influence of Administration Route on Pharmacokinetics Bioavailability 93 Introduction 93 Pharmacokinetic Models 95 Case Studies 104 Examples 112 References 118 Chapter 6. Influence of Formulation on Pharmacokinetics Bioequivalence 121 Introduction 121 Pharmacokinetic Models 123 Case Studies 128 Examples 137 References 140

6 Table of Contents VIi Chapter 7. Influence of Dosage on Pharmacokinetics Dose Proportionality 143 Introduction 143 Pharmacokinetic Models 144 Case Studies 147 Examples 157 References 164 Chapter 8. Pharmacokinetics of Sustained Release and Immediate Release Formulations 167 Introduction 167 Pharmacokinetic Models 168 Case Studies 172 Examples 181 References 187 SECTION III: ABSORPTION, DISTRIBUTION, METABOLISM, AND PHARMACODYNAMICS Chapter 9. Absorption of Drugs in the Gastrointestinal Tract 191 Introduction 191 Pharmacokinetic Models 192 Case Studies 196 Examples 206 References 211 Chapter 10. Drug Distribution into Tissue- Tissue Penetration 213 Introduction 213 Pharmacokinetic Models 214 Case Studies 219 Examples 228 References 235 Chapter 11. Pharmacokinetics of Metabolites 237 Introduction 237 Pharmacokinetic Models 239 Case Studies 247 Examples 262 References 271

7 Viii Table of Contents Chapter 12. Relationship between Pharmacokinetics and Pharmacodynamics Introduction 273 Pharmacokinetic Models 274 Case Studies 283 Examples 298 References SECTION IV: INTERACTIONS Chapter 13. Influence of Food on Pharmacokinetics 315 Introduction 315 Pharmacokinetic Models 316 Case Studies 322 Examples 331 References 342 Chapter 14. Effects of Drug Interactions on Pharmacokinetics 345 Introduction 345 Pharmacokinetic Models 346 Case Studies 350 Examples 356 References 365 SECTION V: SPECIAL POPULATIONS Chapter 15. Influence of Age on Pharmacokinetics 369 Introduction 369 Pharmacokinetic Models 371 Case Studies 376 Examples 383 References 389 Chapter 16. Difference in Pharmacokinetics between Genders 393 Introduction 393 Pharmacokinetic Model 394 Case Study 397 Examples 400 References 405

8 Table of Contents ix Chapter 17. Special Pharmacokinetic Considerations in Renal Impairment 407 Introduction 407 Pharmacokinetic Models 408 Case Studies 413 Examples 425 References 436 Chapter 18. Special Pharmacokinetic Considerations in Hepatic Impairment 439 Introduction 439 Pharmacokinetic Models 440 Case Studies 447 Examples 456 References 464 Chapter 19. Special Pharmacokinetic Considerations in Other Diseases 467 Introduction 467 Pharmacokinetic Models 468 Case Studies 474 Examples 484 References 497 Appendix 1: Evaluation of Mean Residence Times from Input and Output Times 499 Appendix 2: Derivation of AUC and AUMC Using Laplace Transformation 505 Appendix 3: Derivation of AUC and AUMC 509 Index 543