9780071603935

Table of Contents


	Preface	xiii
	Glossary	xv
1	Introduction to Biopharmaceutics and Pharmacokinetics	1
	Drug Product Performance	1
	Biopharmaceutics	1
	Pharmacokinetics	3
	Clinical Pharmacokinetics	4
	Practical Focus	4
	Pharrnacodynamics	5
	Drug Exposure and Drug Response	5
	Toxicokinetics and Clinical Toxicology	5
	Measurement of Drug Concentrations	6
	Basic Pharmacokinetics and Pharmacokinetic Models	10
	Chapter Summary	15
	Learning Questions	17
	References	17
	Bibliography	18
2	Mathematical Fundamentals in Pharmacokinetics	19
	Math Self-Exam	19
	Estimation and the Use of Calculators and Computers	20
	Practice Problems	22
	Calculus	24
	Graphs	26
	Units in Pharmacokinetics	31
	Measurement and Use of Significant Figures	32
	Units for Expressing Blood Concentrations	33
	Statistics	33
	Practical Focus	34
	Rates and Orders of Reactions	35
	Chapter Summary	40
	Learning Questions	40
	References	42
	Bibliography	42
3	One-Compartment Open Model: Intravenous Bolus Administration	43
	Elimination Rate Constant	44
	Apparent Volume of Distribution	45
	Clearance	48
	Practical Focus	50
	Clinical Application	53
	Calculation of k from Urinary Excretion Data	53
	Practice Problem	54
	Clinical Application	56
	Chapter Summary	57
	Learning Questions	57
	Reference	59
	Bibliography	59
4	Multicompartment Models: Intravenous Bolus Administration	61
	Two-Compartment Open Model	63
	Clinical Application	68
	Practice Problem	68
	Practical Focus	69
	Three-Compartment Open Model	77
	Determination of Compartment Models	79
	Practical Application	84
	Chapter Summary	86
	Learning Questions	87
	References	88
	Bibliography	89
5	Intravenous Infusion	91
	One-Compartment Model Drugs	91
	Infusion Method for Calculating Patient Elimination Half-Life	95
	Loading Dose Plus IV Infusion�One- Compartment Model	96
	Practice Problems	98
	Estimation of Drug Clearance and V_n from Infusion Data	100
	Intravenous Infusion of Two-Compartment Model Drugs	100
	Practical Focus	102
	Chapter Summary	104
	Learning Questions	104
	Reference	106
	Bibliography	106
6	Drug Elimination and Clearance	107
	Drug Elimination	107
	The Kidney	108
	Renal Drug Excretion	111
	Clinical Application	114
	Practice Problems	114
	Drug Clearance	114
	Clearance Models	116
	Renal Clearance	118
	Determination of Renal Clearance	121
	Relationship of Clearance to Elimination Half-Life and Volume of Distribution	125
	Chapter Summary	127
	Learning Questions	127
	References	129
	Bibliography	129
7	Pharmacokinetics of Oral Absorption	131
	Pharmacokinetics of Drug Absorption	131
	Significance of Absorption Rate Constants	133
	Zero-Order Absorption Model	133
	Clinical Application� Transdermal Drug Delivery	134
	First-Order Absorption Model	134
	Practice Problem	142
	Chapter Summary	149
	Learning Questions	149
	References	150
	Bibliography	151
8	Multiple-Dosage Regimens	153
	Drug Accumulation	153
	Clinical Example	157
	Repetitive Intravenous Injections	158
	Intermittent Intravenous Infusion	163
	Estimation of k and V_D of Aminoglycosides in Clinical Situations	165
	Multiple-Oral-Dose Regimen	166
	Loading Dose	168
	Dosage Regimen Schedules	169
	Practice Problems	171
	Chapter Summary	173
	Learning Questions	174
	References	175
	Bibliography	175
9	Nonlinear Pharmacokinetics	177
	Saturable Enzymatic Elimination Processes	179
	Practice Problem	180
	Drug Elimination by Capacity-Limited Pharmacokinetics: One-Compartment Model, IV Bolus Injection	181
	Clinical Focus	191
	Drugs Distributed as One-Compartment Model and Eliminated by Nonlinear Pharmacokinetics	191
	Chronopharmacokinetics and Time-Dependent Pharmacokinetics	193
	Bioavailability of Drugs that Follow Nonlinear Pharmacokinetics	196
	Nonlinear Pharmacokinetics Due to Drug-Protein Binding	196
	Potential Reasons for Unsuspected Nonlinearity	200
	Chapter Summary	200
	Learning Questions	200
	References	202
	Bibliography	203
10	Physiologic Drug Distribution and Protein Binding	205
	Physiologic Factors of Distribution	205
	Clinical Focus	213
	Apparent Volume Distribution	213
	Practice Problem	216
	Protein Binding of Drugs	219
	Clinical Examples	221
	Effect of Protein Binding on the Apparent Volume of Distribution	222
	Relationship of Plasma Drug-Protein Binding to Distribution and Elimination	227
	Determinants of Protein Binding	231
	Kinetics of Protein Binding	232
	Practical Focus	233
	Determination of Binding Constants and Binding Sites by Graphic Methods	233
	Clinical Significance of Drug-Protein Binding	236
	Modeling Drug Distribution	247
	Chapter Summary	248
	Learning Questions	249
	References	250
	Bibliography	251
11	Drug Elimination and Hepatic Clearance	253
	Route of Drug Administration and Extrahepatic Drug Metabolism	253
	Practical Focus	255
	Hepatic Clearance	255
	Enzyme Kinetics	257
	Clinical Example	261
	Practice Problem	263
	Anatomy and Physiology of the Liver	265
	Hepatic Enzymes Involved in the Biotransformation of Drugs	267
	Drug Biotransformation Reactions	269
	Pathways of Drug Biotransformation	270
	First-Pass Effects	282
	Hepatic Clearance of a Protein-Bound Drug: Restrictive and Nonrestrictive Clearance from Binding	287
	Effect of Changing Intrinsic Clearance and/or Blood Flow on Hepatic Extraction and Elimination Half-Lite after IV and Oral Dosing	288
	Biliary Excretion of Drugs	289
	Role of Transporters in Hepatic Clearance and Bioavailability	292
	Chapter Summary	293
	Learning Questions	294
	References	296
	Bibliography	298
12	Pharmacogenetics	301
	Polymorphism	303
	Pharmacogenomics	306
	Adverse Drug Reactions Attributed to Genetic Differences	308
	Genetic Polymorphism in Drug Metabolism: Cytochrome P-450 Isozymes	310
	Genetic Polymorphism in Drug Transport: MDR I (P-Glycoprotein) and Multidrug Resistance	311
	Genetic Polymorphism in Drug Targets	312
	Relationship of Pharmacokinetics/ Pharmacodynamics and Pharmacogenetics/ Pharmacogenomics	313
	Clinical Example	315
	Summary	316
	Glossary	316
	Abbreviations	317
	References	317
	Bibliography	318
13	Physiologic Factors Related to Drug Absorption	321
	Drug Absorption and Design of a Drug Product	321
	Route of Drug Administration	321
	Nature of Cell Membranes	324
	Passage of Drugs Across Cell Membranes	326
	Oral Drug Absorption During Drug Product Development	333
	Drug Interactions in the Gastrointestinal Tract	334
	Oral Drug Absorption	336
	Methods for Studying Factors that Affect Drug Absorption	348
	Clinical Examples	351
	Effect of Disease States on Drug Absorption	351
	Miscellaneous Routes of Drug Administration	353
	Chapter Summary	355
	Learning Questions	356
	References	357
	Bibliography	359
14	Biopharmaceutic Considerations in Drug Product Design and In Vitro Drug Product Performance	361
	Biophannaceutie Factors Affecting Drug Bioavailability	361
	Rate-Limiting Steps in Drug Absorption	363
	Physicoehemical Nature of the Drug	366
	Formulation Factors Affecting Drug Product Performance	368
	Drug Product Performance, In Vitro: Dissolution and Drug Release Testing	370
	Compendial Methods of Dissolution	374
	Alternative Methods of Dissolution Testing	376
	Meeting Dissolution Requirements	378
	Problems of Variable Control in Dissolution Testing	379
	Performance of Drug Products: In Vitro-In Vivo Correlation	380
	Dissolution Profile Comparisons	386
	Drug Product Stability	386
	Considerations in the Design of a Drug Product	387
	Drug Product Considerations	389
	Clinical Example	394
	Chapter Summary	398
	Learning Questions	399
	References	399
	Bibliography	401
15	Drug Product Performance, In Vivo: Bioavailability and Bioequivalence	403
	Drug Product Performance	403
	Purpose of Bioavailability Studies	405
	Relative and Absolute Availability	406
	Practice Problem	407
	Methods for Assessing Bioavailability	407
	Bioequivalence Studies	413
	Design and Evaluation of Bioequivalence Studies	414
	Study Designs	417
	Crossover Study Designs	418
	Clinical Example	422
	Evaluation of the Data	423
	Bioequivalence Example	424
	Study Submission and Drug Review Process	427
	The Biopharmaceutics Classification System	431
	Generic Biologics (Biosimilar Drug Products)	433
	Clinical Significance of Bioequivalence Studies	435
	Special Concerns in Bioavailability and Bioequivalence Studies	436
	Generic Substitution	437
	Glossary	440
	Chapter Summary	443
	Learning Questions	443
	References	448
	Bibliography	449
16	Impact of Drug Product Quality and Biopharmaceutics on Clinical Efficacy	451
	Risks From Medicines	451
	Drug Product Quality and Drug Product Performance	452
	Pharmaceutical Development	453
	Excipient Affect on Drug Product Performance	455
	Practical Focus	456
	Quality Control and Quality Assurance	457
	Risk Management	459
	Scale-Up and Postapproval Changes (SUPAC)	461
	Product Quality Problems	464
	Postmarketing Surveillance	465
	Glossary	465
	Chapter Summary	466
	Learning Questions	466
	References	466
17	Modified-Release Drug Products	469
	Conventional (Immediate-Release) and Modified-Release Drug Products	469
	Biopharmaccutic Factors	473
	Dosage form Selection	475
	Advantages and Disadvantages of Extended-Release Products	475
	Kinetics of Extended-Release Dosage Forms	476
	Pharmacokinetic Simulation of Extended-Release Products	478
	Clinical Examples	480
	Types of Extended-Release Products	480
	Considerations in the Evaluation of Modified-Release Products	495
	Evaluation of Modified-Release Products	497
	Evaluation of In Vivo Bioavailability Data	499
	Chapter Summary	501
	Learning Questions	501
	References	502
	Bibliography	503
18	Targeted Drug Delivery Systems and Biotechnological Products	505
	Biotechnology	506
	Drug Carriers and Targeting	514
	Targeted Drug Delivery	519
	Pharmacokinetics of Biopharmaceuticals	521
	Bioequivalence and Comparability of Biotechnology-Derived Drug Products	522
	Chapter Summary	523
	Learning Questions	524
	References	524
	Bibliography	525
19	Relationship Between Pharmacokinetics and Pharmacodynamics	527
	Pharmacodynamics and Pharmacokinetics	527
	Relationship of Dose to Pharmacologic Effect	534
	Relationship Between Dose and Duration of Activity (t _eff), Single IV Bolus Injection	536
	Practice Problem	536
	Effect of Both Dose and Elimination Half-Life on the Duration of Activity	537
	Effect of Elimination Half-Life on Duration of Activity	537
	Clinical Examples	539
	Rate of Drug Absorption and Pharinacodynamic Response	541
	Drug Tolerance and Physical Dependency	542
	Hypersensitivity and Adverse Response	543
	Drug Distribution and Pharmacologic Response	544
	Pharmacodynamic Models	545
	Drug Exposure-Pharmacologic Response Relationships	558
	Chapter Summary	559
	Learning Questions	560
	References	561
	Bibliography	563
20	Application of Pharmacokinetics to Clinical Situations	565
	Medication Therapy Management	565
	Individualization of Drug Dosage Regimens	566
	Therapeutic Drug Monitoring	567
	Clinical Example	574
	Design of Dosage Regimens	576
	Conversion from Intravenous Infusionto Oral Dosing	578
	Determination of Dose	579
	Practice Problems	580
	Effect of Changing Dose and Dosing Interval on C^∞_max, C^∞_min, and C^∞_av	580
	Determination of Frequency of Drug Administration	581
	Determination of Both Dose and Dosage Interval	582
	Determination of Route of Administration	583
	Dosing of Drugs in Infants and Children	584
	Dosing of Drugs in the Elderly	585
	Dosing of Drugs in the Obese Patient	588
	Pharmacokinetics of Drug Interactions	590
	Inhibition of Drug Metabolism	594
	Inhibition of Monoamine Oxidase (MAO)	595
	Induction of Drug Metabolism	596
	Inhibition of Drug Absorption	596
	Inhibition of Biliary Excretion	596
	Altered Renal Reabsorption Due lo Changing Urinary pH	596
	Practical Focus	597
	Effect of Food on Drug Disposition	597
	Adverse Viral Drug Interactions	597
	Population Pharmacokinetics	597
	Regional Pharmacokinetics	608
	Chapter Summary	609
	Learning Questions	610
	References	613
	Bibliography	614
21	Dose Adjustment in Renal and Hepatic Disease	617
	Renal Impairment	617
	Pharmacokinetic Considerations	617
	General Approaches for Dose Adjustment in Renal Disease	618
	Measurement of Glomerular Filtration Rate	621
	Serum Creatinine Concentration and Creatinine Clearance	622
	Practice Problems	624
	Dose Adjustment for Uremic Patients	627
	Extracorporeal Removal of Drugs	638
	Clinical Examples	642
	Effect of Hepatic Disease on Pharmacokinetics	645
	Chapter Summary	651
	Learning Questions	652
	References	653
	Bibliography	655
22	Physiologic Pharmacokinetic Models, Mean Residence Time, and Statistical Moment Theory	657
	Physiologic Pharmacokinetic Models	658
	Mean Residence Time	670
	Statistical Moment Theory	674
	Selection of Pharmacokinetic Models	687
	Chapter Summary	689
	Learning Questions	689
	References	690
	Bibliography	691
Appendix A	Statistics	693
Appendix B	Applications of Computers in Pharmacokinetics	707
Appendix C	Solutions to Frequently Asked Questions (FAQs) and Learning Questions	717
Appendix D	Guiding Principles for Human and Animal Research	761
Appendix E	Popular Drugs and Pharmacokinetic Parameters	767
	Index	773