Applied Biopharmaceutics & Pharmacokinetics Sixth Edition Hill Leon Shargel, PHD, RPh Applied Biopharmaceutics, LLC Raleigh, North Carolina Affiliate Associate Professor, School of Pharmacy Virginia Commonwealth University, Richmond, Virginia Adjunct Associate Professor, School of Pharmacy University of Maryland, Baltimore, Maryland Susanna Wu-Pong, PHD, RPh Associate Professor Director, Pharmaceutical Sciences Graduate Program Department of Pharmaceutics Medical College of Virginia Virginia Commonwealth University Richmond, Virginia Andrew B.C. Yu, PHD, RPh Registered Pharmacist Gaithersburg, Maryland Formerly Associate Professor of Pharmaceutics Albany College of Pharmacy Albany, New York Present Affiliation: CDER, Silver Spring, Maryland *The content of this book represents the personal views of the authors and not that of the FDA. Medical New York Chicago San Francisco Lisbon London Madrid Mexico City Milan New Delhi Juan Seoul Singapore Sydney Toronto
Contents Preface xiii Glossary xv 1. Introduction to Biopharmaceutics and 3. One-Compartment Open Model: Pharmacokinetics 1 Intravenous Bolus Administration 43 Drug Product Performance 1 Elimination Rate Constant 44 Biopharmaceutics 1 Apparent Volume of Distribution 45 Pharmacokinetics 3 Clearance 48 Clinical Pharmacokinetics 4 Practical Focus 50 Practical Focus 4 Clinical Application 53 Pharmacodynamics 5 Calculation k from Urinary Excretion Data 53 Drug Exposure and Drug Response 5 Practice Problem 54 Toxicokinetics and Clinical Toxicology 5 Clinical Application 56 Measurement of Drug Concentrations 6 Chapter Summary 57 Basic Pharmacokinetics and Learning Questions 57 Pharmacokinetic Models 10 Reference 59 Chapter Summary 15 Bibliography 59 Learning Questions Multicompartment Models: Bibliography 18 Intravenous Bolus Administration 61 2. Mathematical Fundamentals in Two-Compartment Open Model 63 Pharmacokinetics 19 Clinical Application 68 Practice Problem 68 Math Self-Exam 19 Practical Focus 69 Estimation and the Use of Calculators and Three-Compartment Open Model 77 Computers 20 Determination of Compartment Models 79 Practice Problems 22 Practical Application 84 Calculus 24 Chapter Summary 86 Graphs 26 Learning Questions 87 Units in Pharmacokinetics 31 References 88 Measurement and Use of Significant Figures 32 Bibliography 89 Units for Expressing Blood Concentrations 33 statistics 33 intravenous Infusion 91 Practical Focus 34 Rates and Orders of Reactions 35 One-Compartment Model Drugs 91 Chapter Summary 40 Infusion Method for Calculating Patient Learning Questions 40 Elimination Half-Life 95 References 42 Bibliography 42 vii
CONTENTS Loading Dose Plus IV Dosage Regimen Schedules 169 Compartment Model 96 Practice Problems 171 Practice Problems 98 Chapter Summary 173 Estimation of Drug Clearance and from Learning Questions 174 Infusion Data 100 References 175 Intravenous Infusion of Two-Compartment Bibliography 175 Model Drugs Focus Pharmacokinetics 177 Chapter Summary Learning Questions 104 Saturable Enzymatic Elimination Processes 179 Reference 106 Practice Problem 180 Bibliography Drug Elimination by Capacity-Limited Pharmacokinetics: One-Compartment 6. Drug Elimination and Clearance 107 IV Bolus 181 fe Clinical Focus 191 Drug Elimination 107 Drugs Distributed as One-Compartment The Kidney 108 Model and Eliminated by Nonlinear Renal Drug Excretion Pharmacokinetics 191 Clinical Application and Time-Dependent Practice Problems 114 Pharmacokinetics 193 Drug Clearance Bioavailability of Drugs that Follow Nonlinear Clearance Models 116 Pharmacokinetics 196 Renal Clearance Nonlinear Pharmacokinetics Due to Determination of Renal Clearance 121 Drug-Protein Binding 196 Relationship of Clearance to Elimination Potential Reasons for Unsuspected and Volume of Distribution 125 Nonlinearity 200 Chapter Summary 127 Chapter Summary 200 Learning Questions 127 Learning Questions 200 References 129 References 202 Bibliography 129 Bibliography 203 7. Pharmacokinetics of Oral 10. Physiologic Drug Distribution and Absorption 131 Protein Binding 205 Pharmacokinetics of Drug Absorption 131 Physiologic Factors of Distribution 205 Significance of Absorption Rate Constants 133 Clinical Focus 213 Zero-Order Absorption Model 133 Apparent Volume Distribution 213 Clinical Practice Problem 216 Drug Delivery 134 Protein Binding of Drugs 219 First-Order Absorption Model 134 Clinical Examples 221 Practice Problem 142 Effect of Protein Binding on the Apparent Chapter Summary 149 Volume of Distribution 222 Learning Questions 149 Relationship of Plasma Drug-Protein Binding References 150 to Distribution and Elimination 227 Bibliography 151 Determinants of Protein Binding 231 Kinetics of Protein Binding 232 8. Multiple-Dosage Regimens 153 Practical Focus 233 Determination of Binding Constants and Drug Accumulation 153 Binding Sites by Graphic Methods 233 Clinical Example 157 Clinical Significance of Drug-Protein Repetitive Injections 158 Binding 236 Intermittent Intravenous Infusion 163 Modeling Drug Distribution 247 Estimation of k and of Aminoglycosides Chapter Summary 248 in Clinical Situations 165 Learning Questions 249 Multiple-Oral-Dose Regimen 166 References 250 Loading Dose 168 Bibliography 251
CONTENTS ix 11. Drug Elimination and Hepatic 13. Physiologic Factors Related to Drug Clearance 253 Absorption 321 Route of Drug Administration and Extrahepatic Drug Absorption and Design of a Drug Drug Metabolism 253 Product 321 Practical Focus 255 Route of Drug Administration 321 Hepatic Clearance 255 Nature of Cell Membranes 324 Enzyme Kinetics 257 Passage of Drugs Across Cell Membranes 326 Clinical Example 261 Oral Drug Absorption During Drug Product Practice Problem 263 Development 333 Anatomy and Physiology of the Liver 265 Drug Interactions in the Gastrointestinal Hepatic Enzymes Involved in the Tract 334 Biotransformation of Drugs 267 Oral Drug Absorption 336 Drug Biotransformation Reactions 269 Methods for Studying Factors that Affect Pathways of Drug Biotransformation 270 Drug Absorption 348 First-Pass Effects 282 Clinical Examples 351 Hepatic Clearance of a Protein-Bound Drug: Effect of Disease States on Drug Absorption Restrictive and Nonrestrictive Clearance Miscellaneous Routes of Drug from Binding 287 Administration 353 Effect of Changing Intrinsic Clearance Chapter Summary 355 Blood Flow on Hepatic Extraction and Learning Questions 356 Elimination Half-Life after IV and Oral References 357 Dosing 288 Bibliography 359 Biliary Excretion of Drugs 289 Role of in Clearance Considerations in and Bioavailability 292. Chapter Summary 293 Product Design In Vitro Learning Questions 294 Drug Product Performance 361 Biblioeranhv 298 Biopharmaceutic Factors Affecting Drug Bioavailability 361 Rate-Limiting Steps in Drug Absorption 363 12. Pharmacogenetics 301 Drug 366,. Formulation Factors Affecting Drug Polymorphism 303 Product Performance 368 Drug Product Performance, Vitro: Dissolution Adverse Drug Reactions Attributed and Drug Release Testing 370 to Genetic Differences 308.. Compendial Methods of Dissolution 374 Genetic Polymorphism Drug Metabolism: Alternative Methods of Dissolution Testing 376 Cytochrome P-450 Isozymes 310. Genetic Polymorphism in Drug Transport: MDR1 (/-Glycoprotein) and Multidrug Dissolution Vivo Genetic Polymorphism Drug Targets 312 Drug Product Considerations 389... Clinical Correlation Example 380394 Abbreviations 317 Relationship of Pharmacokinetics/ Chapter,. Summary 398 References 317. ft. Learning Dissolution Questions Profile Compansons 399 386 Bibliography Pharmacodynamics 318 and Pharmacogenetics/ References 399 Bibliography Drug Product Stability 401 386 313...., Considerations the Design of a Drug Clinical Example 315
X CONTENTS 15. Drug Product Performance, 17. Modified-Release Drug Products 469 In Vivo: Bioavailability and Conventional (Immediate-Release) and Bioequivalence 403 Modified-Release Drug Products 469 Biopharmaceutic Factors 473 Dosage form Selection 475 Purpose of Bioavailability Studies Advantages and Disadvantages of Relative and Availability 406 Extended-Release Products 475 Practice Problem 407 Kinetics of Extended-Release Dosage Forms 476 Methods for Assessing 407 Pharmacokinetic Simulation of Extended-Release Bioequivalence Studies 413 Products 478 Design and Evaluation of Bioequivalence 480 414 Types of Extended-Release Products 480 Study Considerations in the Evaluation of Study 418 Modified-Release Products 495 Clinical 422 Evaluation of Modified-Release Products 497 Evaluation Data Evaluation Data 499 Example 424 Chapter Summary 501 Study Submission Drug Review Learning Questions 501 Process 427 References 502 The Biopharmaceutics Classification System 431 503 Generic Drug Products) 433 Clinical Significance of Bioequivalence 18. Targeted Drug Delivery Systems and Studies 435 Biotechnological Products 505 Special Concerns in Bioavailability and Bioequivalence Studies 436 Biotechnology 506 Generic Substitution 437 Drug Carriers and Targeting 514 Glossary 440 Targeted Drug Delivery 519 Chapter Summary 443 Pharmacokinetics 521 Learning Questions 443 Bioequivalence and Comparability of References 448 Biotechnology-Derived Drug Products 522 Bibliography 449 Chapter Summary 523 Learning Questions 524 16. Impact of Drug Product Quality fisaphy 5 and Biopharmaceutics on Clinical Efficacy 451 Relationship Between Risks From Medicines 451 Pharmacokinetics and Drug Product Quality Product Pharmacodynamics 527 Performance 452 Pharmaceutical Development 453 Pharmacodynamics and Pharmacokinetics 527 Excipient Affect on Drug Product Relationship of Dose to Pharmacologic Performance 455 Effect 534 Practical Focus 456 Relationship Between Dose and Duration of Quality Control and Quality Assurance 457 Activity Single IV Bolus Injection 536 Risk Management 459 Practice Problem 536 Scale-Up and Postapproval Changes (SUPAC) Effect of Both Dose and Elimination Half-Life Product Quality Problems 464 on the Duration of Activity 537 Postmarketing Surveillance 465 Effect of Elimination Half-Life on Duration Glossary 465 of Activity 537 Chapter Summary 466 Clinical Examples 539 Learning Questions 466 Rate of Drug Absorption and Pharmacodynamic References 466 Response 541 Drug Tolerance and Physical Dependency 542 Hypersensitivity and Adverse Response 543
CONTENTS Xi Drug Distribution and Pharmacologic General Approaches for Dose Adjustment Response 544 in Renal Disease 618 Pharmacodynamic Models 545 Measurement of Glomerular Filtration Rate 621 Drug Exposure-Pharmacologic Response Serum Creatinine Concentration and Creatinine Relationships 558 Clearance 622 Chapter Summary 559 Practice Problems 624 Learning Questions 560 Dose Adjustment for Uremic Patients 627 References 561 Extracorporeal Removal of Drugs 638 Bibliography 563 Clinical Examples 642 Effect of Hepatic Disease on Application of Pharmacokinetics to 645 Chapter Summary 651 Clinical Situations 565 Learning Questions 652 Medication Therapy Management 565 Individualization Drug Dosage Regimens 566 Bibliography 655 Therapeutic Drug Monitoring 567 Clinical Example 574 22. Physiologic Pharmacokinetic Models, Design of Dosage Regimens 576 Statistical Conversion from Intravenous Infusion Oral Dosing 578 Moment Theory 657 Determination Dose 579 Physiologic Pharmacokinetic Models 658 Problems 580 Mean Residence Time 670 Effect of Changing Dose and Dosing Statistical Moment Theory 674 on 580 Selection of Pharmacokinetic Models 687 Determination of Frequency of Drug Chapter Summary 689 Administration 581 Learning Questions 689 Determination of Both Dose and Dosage References 690 Interval 582 Bibliography 691 Determination of Route of Administration 583 Dosing of Drugs in Infants and Children 584 Dosing of Drugs the Elderly 585 Appendix A Statistics 693 Dosing of Drugs in the Obese Patient 588 Pharmacokinetics of Drug Interactions 590 of Drug Metabolism 594 Appendix B Applications of Computers in of Monoamine Oxidase (MAO) 595 Pharmacokinetics 707 Induction of Drug Metabolism 596 Inhibition of Drug Absorption 596. _ of Excretion 596 Appendix C Solutions to Frequently Altered Renal Reabsorption Due to Asked Questions (FAQs) and Changing Urinary ph 596 Practical Focus 597 Learning Questions 717 Effect of Food on Drug Disposition 597,., Adverse Drug 597 Appendix D Guiding Principles for Population Pharmacokinetics 597 Human and Animal Regional Pharmacokinetics 608 Research 761 Chapter Summary 609 Learning Questions 610 References 613 Appendix E Popular Drugs and Bibliography 614 Pharmacokinetic 21. Dose Adjustment in Renal and Hepatic Disease 617 Renal Impairment 617 Pharmacokinetic Considerations 617 Parameters 767