CS X .'

Pharmacokineticsof Drugs

Contributors

G.L. Amidon, J.P.F. Bai, L.P. Balant, CM. Barksdale, I.A. BlairD.D. Breimer, M. Chiba, J. Delforge, M. EichelbaumB.L. Ferraiolo, A.J. Fischman, M. Gex-Fabry, N. HolfordJ. Kantrowitz, H.K. Kroemer, T.M. Ludden, J.M. MayerB. Maziere, C. McMartin, G. Mikus, M.A. MohlerG.D. Nordblom, R. O'Neill, K.S. Pang, O. PelkonenA. Racine-Poon, R.H. Rubin, J.-L. Steimer, B.H. StewartH.W. Strauss, B. Testa, S. Vozeh, P.G. Welling, R.J. WillsA. Yacobi

Editors

Peter G. Welling and Luc P. Balant

With a Foreword by J.G. Wagner

(52

Springer-VerlagBerlin Heidelberg New York London ParisTokyo Hong Kong Barcelona Budapest

2.T.

Contents

A. Introduction

CHAPTER 1

of Pharmacokinetics in Drug Discovery and DevelopmentP.G. WELLING. With 3 Figures 3

A. Historical Background 3B. Regulatory Submissions 4C. The Process 4D. Discovery 5E. Preclinical Development 6

I. Toxicology and Toxicokinetics 8II. Pharmacokinetic-Pharmacodynamic Relationships 10

III. Interactions 11F. Clinical Development 11

I. Phase 1 : 11II. Phase 2 13

III. Phase 3 15IV. Interactions 16V. Regulatory Submissions 16

G. Postsubmission and Postmarketing Studies 17H. Summary 18References 18

B. Analytical Methods

CHAPTER 2

Contemporary Aspects of Radioimmunoassay Development forDrug AnalysisG.D. NORDBLOM and CM. BARKSDALE. With 2 Figures 23

A. Introduction 23B. Synthesis of Drug Derivatives for Immunogen Preparation 24

XIV Contents

I. Coupling of Hapten Carboxyl Group to Carrier Protein 24II. Addition of Carboxyl to Existing Functional Group 24

III. Addition of a Functional Group for Bridge to CarboxylicAcid 25

IV. Altering the Basic Structure of the Hapten 26C. Immunogen Preparation 26

I. Hapten-Carrier Protein Ratios 26II. Carrier Protein Characteristics 28

D. Immunization Considerations 29I. Species Effects 29

II. Use of Adjuvants 29III. Immunization Sites and Schedules 30

E. Matrix Effects of Biological Fluids 31I. Methods for Sample Matrix Effect Elimination 32

1. Filtration/Precipitation of Protein 322. Solvent Extraction 323. Solid Phase Chromatographic Extraction 334. High-Performance Liquid Chromatographic Sample

Preparation 33II. Elimination of Sample Matrix Effect by Sample Size 34

F. The Suitability of Radioimmunoassay for Drug Analysis 35References 37

CHAPTER 3

Mass Spectrometry in Drug Disposition and PharmacokineticsLA. BLAIR 41

A. Introduction 41B. Ionization Techniques 42

I. Electron Ionization 42II. Positive Chemical Ionization 43

III. Electron Capture Negative Chemical Ionization 43IV. Liquid Secondary Ion/Fast Atom Bombardment 44V. Thermospray 46

VI. Atmospheric Pressure Ionization 47VII. Collision-Induced Dissociation 49

C. Chromatographic Techniques 51I. Gas Chromatography/Mass Spectrometry 51

II. Liquid Chromatography/Mass Spectrometry 54D. Metabolism Studies 57

I. In Vitro Studies 57II. In Vivo Studies in Animal Models 59

III. In Vivo Studies in Humans 62E. Pharmacokinetic Studies 64

Contents XV

I. Introduction 64II. Animal Models 65

III. Humans 65F. Summary 68References 69

CHAPTER 4

Analytical Methods for Biotechnology ProductsB.L. FERRAIOLO and M.A. MOHLER 85.

A. Introduction 85B. Methods 85

I. Radiolabels 851. Selection of Radiolabel 852. Whole-Body Autoradiography 863. Radiolabel Realities 86

II. Immunoassays 881. Enzyme Immunoassays 892. Radiolabel-Based Immunoassays 893. Immunoassay Limitations 894. Immunoassay Interferences 90

III. Bioassays 91IV. Other Immunological Techniques 92V. Chromatography 92

VI. Electrophoretic Techniques 93VII. Mass Spectrometry 93

C. Conclusions 94References 94

C. In Vitro Methods-Protein and Tissue Binding

CHAPTER 5

Metabolism: Scaling-up from In Vitro to Organ and Whole BodyK.S. PANG and M. CHIBA. With 15 Figures 101

A. Introduction 101B. Correlation of In Vitro and In Vivo Data 102

I. Concept of Organ Clearance 1021. Hepatic Clearance Models 1042. In Vitro-Organ Correlations 110

II. Concept of Total Body Clearance I l l1. From In Vitro to In Vivo: Compartmental Modeling 1242. From In Vitro to In Vivo: Physiological Modeling 1253. From Perfused Organs to In Vivo 128

XVI Contents

C. Poor Correlations Between In Vitro and Perfused Organs 132I. Inadequacy of In Vitro Estimates 132

1. Estimation of Enzymatic Parameters 1322. Multiplicity of Enzymes 1363. Membrane-Bound Enzymes 1374. Time-Dependent Kinetics 138

II. Structural Considerations and Physiological Variables 1401. Flow 1442. Protein Binding 1453. Transmembrane Limitation 1504. Cosubstrate 1515. Acinar Heterogeneity 153

D. Reasons for Poor Correlations Between In Vitro, PerfusedOrgans, and In Vivo 160

E. Conclusions 161References 162

CHAPTER 6

Gastrointestinal Transport of Peptide and Protein Drugs and ProdrugsJ.P.F. BAI, B.H. STEWART, and G.L. AMIDON. With 7 Figures 189

A. Introduction 189B. Mucosal Cell Absorption 190

I. Paracellular Absorption 190II. Transcellular Absorption 190

1. Simple Diffusion 1902. Carrier-Mediated Process 1913. Endocytosis 191

C. Mucosal Cell Transport of Peptide Drugs 192I. Characteristics of Small Peptide Transport 192

1. Substrate Structural Requirements 192II. Carrier-Mediated Transport of Peptide Drugs 193

1. y5-Lactam Antibiotics 1932. ACE Inhibitors 195

D. Estimating Extent of Drug Absorption 195I. Fraction of Dose Absorbed-Permeability Correlation 195

II. Comparison of Passive and Carrier-Mediated Transport 196E. Peptide Prodrug Approaches to Improving Intestinal Absorption 198

I. Peptide Prodrugs of a-Methyldopa 198II. Peptide Prodrug Approaches for Acidic Drugs 199

III. Other Peptide Prodrugs 202F. Summary 203References 203

Contents XVII

D. Classical Problems

CHAPTER 7

v Stereoselectivity in Metabolic Reactions of Toxication and DetoxicationJ.M. MAYER and B. TESTA. With 8 Figures 209

A. Introduction 209B. Principles of Stereoselective Xenobiotic Metabolism 210

I. Chiral Recognition and Stereoselective Processes inXenobiotic Metabolism and Disposition 210

II. Substrate Stereoselectivity and Product Stereoselectivity . . . . 211III. Substrate-Product Stereoselectivity 212IV. Relevance to Molecular Toxicology 212

C. Toxicologically Relevant Examplesof Stereoselective Metabolism 213

I. Introduction 213II. Substrate Stereoselectivity in Drug Oxidation: Disopyramide

and Mianserin 213III. Product Stereoselectivity in Drug Oxidation and Reduction:

Phenytoin and Nabilone 219IV. Substrate Stereoselectivity in Xenobiotic Conjugation:

Fenvalerate 220D. The Case of Profens 220

I. Metabolic Chiral Inversion: In Vivo and In Vitro Studies . . . . 220II. Mechanism of Inversion 224

III. Toxicological Consequences of Chiral Inversion 226E. Conclusion 227References 228

CHAPTER 8

y Interethnic Differences in Drug Disposition and Response: Relevancefor Drug Development, Licensing, and RegistrationL.P. BALANT and P.G. WELLING 233

A. Introduction 233B. Case Reports 234

I. Unexpected Behavior 234II. A Biopharmaceutical Dilemma 234

III. The Drug Which Did Not Become a Case 235IV. The Drug Which Is Not a Case 237

C. Basic Concepts and Definitions 237D. Integration of Pharmacokinetic, Pharmacodynamic, and

Toxicokinetic Principles in Drug Development 240

XVIII Contents

I. The Conceptual Framework 240II. Preclinical Studies 241

III. Phase 1 Studies 241IV. Phase 2 Studies 242V. Phase 3 Clinical Studies 242

VI. Regulatory Considerations 244VII. Interethnic Differences in Drug Behavior and Action and

PK/PD Integration 244E. Preclinical Studies 245F. Phase 1 Studies and Interethnic Differences 246

I. Investigational Pharmacokinetics 246II. Investigational Pharmacodynamics 248

III. Bioavailability Investigations 249IV. Bioequivalence Studies 250

G. Phase 2 Studies 250H. Phase 3 Studies 251I. Phase 4 Studies in the Context of Drug Product Licensing 251

I. Pharmacoanthropological Considerations 252II. Studies in Healthy Volunteers 253

III. Studies in Patients 253J. Conclusions 254References 255Appendix. Selected References on Interethnic Differences in Drug

Kinetics . .• 257

CHAPTER 9

Clinical Relevance of PharmacogeneticsH.K. KROEMER, G. MIKUS, and M. EICHELBAUM 265

A. Introduction 265B. The Genetic Polymorphism of the Sparteine/Debrisoquine

Oxidation 269I. Molecular Mechanisms of the Sparteine/Debrisoquine

Polymorphism 270II. Clinical Consequences of the Sparteine/Debrisoquine

Polymorphism and Assignment of Genotype or Phenotype .. . 271C. The Genetic Polymorphism of Mephenytoin Oxidation 273

I. Molecular Mechanisms of the Mephenytoin Polymorphism . . . 274II. Clinical Consequences of Polymorphic Mephenytoin

Oxidation and Assignment of Genotype or Phenotype 275D. The Genetic Polymorphism of N-Acetylation 277

I. Molecular Mechanisms of Polymorphic N-Acetylation 277II. Clinical Consequences of Polymorphic Acetylation and

Assignment of Genotype or Phenotype 278

Contents XIX

E. Genetic Polymorphisms and Drug Development 279F. Genetic Polymorphisms and Drug Interactions 280G. Conclusions 281References 281

CHAPTER 10

Role of Environmental Factors in the Pharmacokinetics of Drugs:Considerations with Respect to Animal Models, P-450 Enzymes, andProbe DrugsO. PELKONEN and D.D. BREIMER. With 2 Figures 289

A. Introduction 289B. Relevant Environmental Factors 290

I. What Are "Relevant" Environmental Factors? 290II. Examples 293

1. Cigarette Smoking 2932. Alcohol Drinking 2943. Drugs 2944. Occupational Chemicals 2945. Other Factors 295

C. Animal Models 295I. Environmental Regulation of P-450 Isoforms in the Rat 298

II. Similarities and Differences Between Species 298III. Reasons for Interspecies Differences 299IV. Model Experiments in Animals 300

D. Important (Iso)enzymes in Man 300I. P-450 Enzymes 300

1. P-450 1A1 3032. P-450 1A2 3043. P-450 2A6 3054. P-450 2B6 3055. P-450 2C 3056. P-450 2D6 3067. P-450 2E1 3068. P-450 3A 307

II. Conjugative Enzymes 308III. Heterologous Expression Systems 308

E. Probe Drugs 309I. The Probe Drug Concept 309

1. The "Ideal" Probe Drug 3092. "General" vs "Specific" Probe Drugs :... 310

II. Importance of Enzyme Specificity 310III. Selected Probe Drugs 311

1. Antipyrine 311

XX Contents

2. Aminopyrine 3123. Caffeine 3124. Theophylline 3135. Nifedipine 3146. Barbiturates 3147. Tolbutamide 3158. Warfarin 3159. Other Potential Probes 316

10. Endogenous Probes 317IV. Cocktail Approach 317

F. Practical Considerations for Human Studies 318G. Final Considerations 319References 320

CHAPTER 11

Time Course of Drug EffectN.H.G. HOLFORD and T.M. LUDDEN 333

A. Introduction 333I. Why Prediction of Effect Over Time Is Important 334

1. Drug Development 3342. Dosage Individualization 335

B. Methodological Considerations Relevant to Measuring Effects . . . 336I. Standardization 336

II. Continuous Scale Versus Discrete Response 337III. Baseline and Placebo Effect 338

C. Pharmacokinetic-Pharmacodynamic Models 338I. Pharmacokinetics 338

II. Kietics of Receptor Binding 338III. Steady-State Pharmacodynamic Models 339IV. Non-Steady-State Pharmacodynamic Models 340

1. Effect Compartment 3402. Physiological Mediator 341

V. Placebo Effect 3431. Pharmacokinetics 3432. Placebo Effect Model 3433. Placebo Efficacy 344

VI. Disease Time Course and Drug Effects 3441. Disease Time Course 3442. Models of Drug Effect on Disease Progression 345

VII. Tolerance 3461. Pharmacokinetics 3462. Pharmacodynamics 348

D. Conclusion 349References 350

Contents XXI

E. Future Trends in Pharmacokinetics

CHAPTER 12

Biotechnology ProductsB.L. FERRAIOLO, R.J. WILLS, and M.A. MOHLER 355

A. Introduction 355B. Pharmacokinetic/Pharmacodynamic Studies 355

I. Oligonucleotides 355II. Proteins 357

1. Insulin 3582. Relaxin 3583. Interferon-a-2A 358

C. Regimen-Dependent Effects 359I. Growth Hormone 359

II. Parathyroid Hormone 359III. Tissue Plasminogen Activator 359

D. Binding Proteins/Inhibitors 360I. Growth Hormone 360

II. Tissue Plasminogen Activator 361III. Insulin-like Growth Factor-I 361IV. Deoxyribonuclease 361

E. Catabolism of Biotechnology Products 362I. Catabolism at Extravascular Sites of Administration 362

F. Drug Interactions 363References 364

CHAPTER 13

Peptide and Protein DrugsC. MCMARTIN. With 2 Figures 371

A. Introduction 371I. Differences Between the Pharmacokinetics of Peptides/

Proteins and Other Drugs 371II. Scope of This Review 374

B. Pharmacokinetic Mechanisms 374I. Distribution in the Body 374

II. Inactivation and Elimination 3751. Glomerular Filtration 3752. Peptidolysis 3753. Receptor-Mediated Clearance 375

III. Uptake from Site of Administration 3751. Subcutaneous or Intramuscular Injection 3762. Intranasal Administration 3763. Oral or Rectal Administration 376

XXII Contents

IV. Pharmacokinetic Behavior Resulting from the Distributionand Elimination Processes 376

C. Experimental Approaches 376I. Analytical Methods 377

1. Ex Vivo Bioassay 3772. Radioimmunoassay 3773. Radiolabeling 3774. High-Performance Liquid Chromatography 3775. Radiosequencing 378

II. Plasma Pharmacokinetics 3781. Intravenous Bolus and Infusion Studies 3782. Methods of Assaying Samples 3783. Information That can Be Derived from Plasma

Pharmacokinetic Studies 3784. Use of Organ Ablation to Locate Clearance Sites 378

III. Distribution, Metabolism, and Elimination 3791. Typical Experiments and Results 3792. Difficulties in Interpreting Results 3793. Problems in Carrying Out Drug Elimination Studies 379

IV. Organ Clearance 380V. Receptor-Mediated Clearance Kinetics 380

VI. Absorption (Bioavailability) Measurement 3801. Oral Route 3802. Nasal Route 381

D. Conclusions 381References 381

CHAPTER 14

ToxicokineticsJ. KANTROWITZ and A. YACOBI. With 7 Figures 383

A. Introduction 383B. Principles of Toxicokinetics 383C. Bioanalytical Procedures to Support Toxicokinetic Studies 385D. Dose-Plasma Concentration Relationship (Linear-Nonlinear

Kinetics) 386E. Changes in Concentrations upon Multiple Dosing 392F. Designing Troubleshooting Studies to Explain Aberrant Data . . . 395

I. Absorption Issues 3951. Dose Proportionality 3952. Effect of Diet 3963. Effect of Vehicles 396

II. Metabolism Issues 3961. Enzyme Induction 396

Contents XXIII

2. Effect of Age 3973. Sex Dependency 399

G. Species Comparisons and Interspecies (Allometric) Scaling 399H. Utilization of Pharmacokinetic/Toxicokinetic Data in the Design

of Early Clinical Trials 402References 403

CHAPTER 15

The Population Approach: Rationale, Methods, and Applications inClinical Pharmacology and Drug DevelopmentJ.-L. STEIMER, S. VOZEH, A. RACINE-POON, N. HOLFORD, andR. O'NEILL. With 8 Figures 405

A. Introduction 405B. Rationale 406

I. "Population Studies" in Large Samples of Subjects 407II. Controlled Experimental Studies in Small Groups 409

III. The Population Approach 412C. An Overview of Statistical Methodology for Model-Based

Population Analysis 414I. Population Model 414

II. Population Methods for Data Analysis 417III. Synthesis 418

D. Current Experience with the Population Approach and ItsApplications to Drug Therapy 419

I. Introduction 419II. Detection of Patient Groups with Altered Kinetics 419

III. Design of Optimum A Priori Dosage Regimen 424IV. Bayesian Estimation of Individual Pharmacokinetic

Parameters 426V. Recent Novel Applications of Nonlinear Mixed Effects

Models to Other Drug-Related Areas 427E. Problems and Issues? 431

I. Misconceptions 431II. Some Practical Problems 432

1. Reliability of Data and Analysis 4322. Methodological Issues 433

III. Validation of the Results 435F. Integration of the Population Approach into Clinical Drug

Development 437I. Introduction 437

II. Early Human Studies (Phase I) 438III. Early Clinical Studies (Phase II) 438IV. Clinical Trials (Late Phase II, Phase III) 439

XXIV Contents

V. Late Clinical Trials (Late Phase III, Phase IV) 441G. Concluding Remarks 441References 443

F. Impact of New Methods on Pharmacokinetics

CHAPTER 16

Contribution of Positron Emission Tomographyto Pharmacokinetic StudiesB. MAZIERE and J. DELFORGE. With 7 Figures 455

A. Introduction 455B. Positron Emitters 456C. Drug Labeling - Radiochemistry 456D. Positron Emission Tomography 457E. Direct Radiolabeled Drug Studies 459

I. Drug Distribution 459II. Drug-Drug and Drug-Nutrient Interactions 460

III. Drug-Receptor Interactions 4611. Tranquilizers 4642. Neuroleptics 464

F. Indirect Radioactive Pharmacokinetic Studies 465G. Kinetic Modeling with PET 467

I. A Two-Compartment Model: the [15O] Water Model 468II. A Three-Compartment Linear Model: the [18F] Fluoro-

deoxyglucose Model 469HI. A Multicompartment Nonlinear Model: the Ligand-

Receptor Model 470IV. Modeling Using Simplified Models 472V. Modeling Using the Multi-injection Approach 474

H. Conclusion 474References 475

CHAPTER 17

In Vivo Imaging in Drug Discovery and DesignA.J . FISCHMAN, R . H . R U B I N , and H . W . STRAUSS. With 8 Figures . . . . 481

A . Introduction 481B. Pharmacokinetics 482

I. Antimicrobial Agents 4851. Erythromycin 4852. Fluconazole 486

II. Antineoplastic Agents 488

Contents XXV

1. Platinum Compounds 4882. 5-Fluorouracil 489

III. Neuroleptics 489IV. Angiotensin-Converting Enzyme Inhibitors 489V. Nuclear Magnetic Resonance 490

C. Pharmacodynamics 491I. Cardiovascular 491

1. Ventricular Function 4912. Blood Volume 4943. Cardiac Output 495

II. Renal Perfusion and Function 495III. Antineoplastic Agents 496IV. Liver Function 497V. Intestinal Function 497

VI. Antimicrobial Agents 498VII. Nuclear Magnetic Resonance 498

D. Summary 499References 501

G. Appendix

CHAPTER 18

Considerations on Data Analysis Using Computer Methods andCurrently Available Software for Personal ComputersM. GEX-FABRY and L.P. BALANT 507

A. Introduction 507B. Program Features and Requirements 508

I. Data Entry 508II. Pharmacokinetic Model Specification 509

1. Compartmental Models 5092. Noncompartmental Approach 5103. Pharmacodynamic Models 5104. Absorption Kinetics and Bioavailability Studies 5115. Urinary Data Analysis 5116. Population Pharmacokinetics 5117. Calculation of Individual Dosage Regimen 512

III. Error Model specification 512IV. Parameter Estimation 513

1. Least-Squares and Maximum Likelihood Estimators . . . 5132. Linear Equations 5143. Nonlinear Equations 514

V. Confidence Limits on Estimated Parameters 517VI. Statistical Measures of Goodness of Fit 517

XXVI Contents

VII. Solving Systems of Differential Equations 518VIII. Graphic Display of Results 519

IX. Printing and Plotting Results 520X. User Interface and Documentation 520

XL Hardware and Software Requirements 521C. Directory of Surveyed Software 521D. Conclusion 526References 526

Subject Index 529