Holdings: Principles of clinical pharmacology

Principles of clinical pharmacology:

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Bibliographic Details
Format:	Book
Language:	English
Published:	Amsterdam [u.a.] Acad. Press 2007
Edition:	2. ed.
Subjects:	Farmacologie Pharmacologie clinique Clinical pharmacology Pharmacology, Clinical Pharmakologie Lehrbuch
Online Access:	Inhaltsverzeichnis
Physical Description:	XIX, 545 S. Ill., graph. Darst.
ISBN:	0123694175 9780123694171

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adam_text	Contents Preface Contributors CHAPTER Introduction to Clinical Pharmacology ARTHUR J. ATKINSON, JR. Background Optimizing Use of Existing Medicines Evaluation and Development of Medicines Pharmacokinetics Concept of Clearance Clinical Assessment of Renal Function Dose-Related Renal Function is Unrecognized Concepts Underlying Clinical Pharmacokinetics Initiation of Drug Therapy (Concept of Apparent Distribution Volume) Continuation of Drug Therapy (Concepts of Elimination Half-Life and Clearance) Drugs Not Eliminated by First-Order Kinetics Mathematical Basis of Clinical Pharmacokinetics 18 First-Order Elimination Kinetics Concept of Elimination Half-Life Relationship of Cumulation Factor Plateau Principle Application of Laplace Transforms to Pharmacokinetics CHAPTER PART I PHARMACOKINETICS CHAPTER Clinical Pharmacokinetics ARTHUR J. ATKINSON, JR. The Target Concentration Strategy Monitoring Serum Concentrations of Digoxin as an Example General Indications for Drug Concentration Monitoring Compartmental Analysis of Drug Distribution ARTHUR J. ATKINSON, JR. Physiological Significance of Drug Distribution Volumes Physiological Basis of Multicompartmental Models of Drug Distribution Basis of Multicompartmental Structure Mechanisms of Transcapillary Exchange Clinical Consequences of Different Drug Distribution Patterns Analysis of Experimental Data Derivation of Equations for a Two-Compartment Model Calculation of Rate Constants and Compartment Volumes from Data Contents Different Estimates of Apparent Volume Distribution CHAPTER Drug Absorption and Bioavailability ARTHUR J. ATKINSON, JR. Drug Absorption Bioavailability Absolute Bioavailability Relative Bioavailability In Vitro Prediction of Bioavailability Kinetics of Drug Absorption after Oral Administration Time to Peak Level Value of Peak Level Use of Convolution/Deconvolution to Assess in Vitro-in Vivo Correlations CHAPTER Effects of Renal Disease on Pharmacokinetics ARTHUR J. ATKINSON, JR. AND MARCUS M. REIDENBERG Effects of Renal Disease on Drug Elimination Mechanisms of Renal Handling of Drugs Effects of Impaired Renal Function on Nonrenal Metabolism Effects of Renal Disease on Drug Distribution Plasma Protein Binding of Acidic Drugs Plasma Protein Binding of Basic and Neutral Drugs Tissue Binding of Drugs Effects of Renal Disease on Drug Absorption Kinetics of Continuous Renal Replacement Therapy Clearance by Continuous Hemofiltration Clearance by Continuous Hemodialysis Extracorporeal Clearance during Continuous Renal Replacement Therapy Clinical Considerations Drug Dosing Guidelines for Patients Requiring Renal Replacement Therapy Extracorporeal Therapy of Patients with Drug Toxicity CHAPTER Effect of Liver Disease on Pharmacokinetics GREGORY M. SUSLA AND ARTHUR J. ATKINSON, JR. Hepatic Elimination of Drugs Restrictively Metabolized Drugs Drugs with an Intermediate Extraction Ratio (0.3 < ER < 0.7) 75 Nonrestrictively Metabolized Drugs Biliary Excretion of Drugs Effects of Liver Disease on Pharmacokinetics Acute Hepatitis Chronic Liver Disease and Cirrhosis Pharmacokinetic Consequences of Liver Cirrhosis Use of Therapeutic Drugs in Patients with Liver Disease Effects of Liver Disease on the Hepatic Elimination of Drugs Effects of Liver Disease on the Renal Elimination of Drugs Effects of Liver Disease on Patient Response Modification of Drug Therapy in Patients with Liver Disease CHAPTER CHAPTER 6 Pharmacokinetics in Patients Requiring Renal Replacement Therapy ARTHUR J. ATKINSON, JR. AND GREGORY ]yi. SUSLA Kinetics Of Intermittent Hemodialysis Solute Transfer across Dialyzing Membranes Calculation of Dialysis Clearance Patient Factors Affecting Hemodialysis of Drugs 59 8 Noncompartmental versus Compartmental Approaches to Pharmacokinetic Analysis DAVID M. FOSTER Introduction Kinetics, Pharmacokinetics, and Pharmacokinetic Parameters Kinetics and the Link to Mathematics Pharmacokinetic Parameters Contents Vil Noncompartmental Noncompartmental Model 92 Kinetic Model 93 Estimating the Kinetic Parameters of the Noncompartmental Model Comp Definitions and Assumptions Linear, Constant-Coefficient Compartmental Models Parameters Estimated from Compartmental Models Noncompartmental versus Compartmental Models Models of Data vs Models of System Equivalent Sink and Source Constraints Recovering Pharmacokinetic Parameters from Compartmental Models Conclusion CHAPTER 9 Distributed Models of Drug Kinetics PAUL F. MORRISON Introduction Central Issues Drug Modality I: Delivery across a Planar-Tissue Interface General Principles Differences between the Delivery of Small Molecules and Macromolecules across a Planar Interface 114 Drug Modality II: Delivery from a Point Source Direct Interstitial Infusion General Principles Low-Flow High-Flow Summary CHAPTER 10 Population Pharmacokinetics RAYMOND MILLER Introduction Analysis of Pharmacokinetic Data Structure of Pharmacokinetic Models Fitting Individual Data Population Pharmacokinetics Population Analysis Methods Model Applications 129 Mixture Models Exposure-Response Models Conclusions PART II DRUG METABOLISM AND TRANSPORT CHAPTER 11 Pathways of Drug Metabolism SANFORD P. MARKEY Introduction Phase I Liver Microsomal Cytochrome P450 Monooxygenases CYP-Mediated Chemical Transformations Non-CYP Phase II Glucuronidation Sulfation 157 Acetylation Additional Effects on Drug Metabolism Enzyme Induction and Inhibition Species Sex Age CHAPTER 12 Methods of Analysis of Drugs and Drug Metabolites SANFORD P. MARKEY Introduction Choice of Analytical Methodology Chromatographie Absorption and Emission Spectroscopy Immunoaffmity Assays Mass Spectrometry Examples of Current Assay Methods HPLC/UV and HPLC/MS Assay of New Chemical Entities HPLC/MS/MS Quantitative Assays of Cytochrome P450 Enzyme Activity HPLC/UV and Immunoassays of Cyclosporine: Assays for Therapeutic Drug Monitoring Vlil Contents Summary of F-ddA, CYP2B6, and Cyclosporine Analyses CHAPTER 13 Clinical Pharmacogenetics DAVID A. Introduction Hierarchy of Pharmacogenetic Information Identification and Selection of Outliers in a Population Examples of Important Genetic Polymorphisms Drug Absorption Drag Distribution Drug Elimination Mutations That Influence Drug Receptors Combined Variants in Drug Metabolism and Receptor Genes: Value of Drug Pathway Analysis Conclusions and Future Directions CHAPTER 14 Equilibrative and Concentrative Transport Mechanisms PETER Introduction Mechanisms of Transport Across Biological Membranes Thermodynamics of Membrane Transport Passive Diffusion Carrier-Mediated Transport: Facilitated Diffusion and Active Transport Uptake Mechanisms Dependent on Membrane Trafficking Paracellular Transport and Permeation Enhancers 204 Description of Selected Membrane Protein Transporters ATP-Binding Cassette Superfamily Multifacilitator Superfamily Transporters Role of Transporters in Pharmacokinetics and Drag Action Role of Transporters in Drug Absorption Role of Transporters in Drug Distribution Role of Transporters in Drug Elimination Role of Transporters in Drug Interactions P-gp Inhibition as an Adjunct to Treating Chemotherapy-Resistant Cancers Role of Transporters in Microbial Drug Resistance 215 Pharmacogenetics and Pharmacogenomics of Transporters Pharmacogenomics of Drug Transport Pharmacogenetics of Drug Transport Future Directions Structural Biology of Membrane Transport Proteins 220 In Silico Prediction of Drug Absorption, Distribution, Metabolism, and Elimination CHAPTER 15 Drug Interactions SARAH ROBERTSON AND SCOTT PENZAK Introduction Epidemiology Classifications Mechanisms of Drug Interactions Interactions Affecting Drug Absorption Interactions Affecting Drug Distribution Interactions Affecting Drug Metabolism Interactions Involving Drug Transport Proteins 237 Interactions Affecting Renal Excretion Prediction and Clinical Management of Drug Interactions In Vitro Screening Methods Genetic Variation Clinical Management of Drug Interactions CHAPTER 16 Biochemical Mechanisms of Drug ARTHUR J. ATKINSON, JR. AND SANFORD P. MARKEY Introduction Drug-Induced Methemoglobinemia Role of Covalent Binding in Drug Drug-Induced Liver Hepatotoxic Reactions Resulting from Covalent Binding of Reactive Metabolites Contents їх Immunologically Mediated 255 Mechanisms of Other Drug Toxicities Systemic Reactions Resulting from Drug Allergy 259 Carcinogenic Reactions to Drugs Teratogenic Reactions to Drugs PART Linear and Log-Linear Model Conclusion III ASSESSMENT OF DRUG EFFECTS CHAPTER 17 Physiological and Laboratory Markers of Drug Effect ARTHUR J. ATKINSON, JR. AND PAUL Biological Markers of Drug Effect Identification and Evaluation of Biomarkers Uses of Biomarkers and Surrogate Use of Serum Cholesterol as a Biomarker and Surrogate Endpoint Application of Serial Biomarker Measurements 282 Future Development of Biomarkers CHAPTER 18 Dose-Effect and Concentration-Effect Analysis ELIZABETH S. LOWE AND FRANK M. BALIS Background Drug-Receptor Interactions Receptor Occupation Theory Receptor-Mediated Effects Graded Dose-Effect Relationship Dose-Effect Parameters Dose Effect and Site of Drag Action Quantal Dose-Effect Relationship Therapeutic Indices Dose Effect and Defining Optimal Dose Pharmacodynamic Models Fixed-Effect Model Maximum-Effect (Emax and Sigmoid Emax) Models CHAPTER 19 Time Course of Drug Response NICHOLAS H. G. HOLFORD AND ARTHUR J. ATKINSON, JR. Pharmacokinetics and Delayed Effects The Incorporation of Pharmacodynamic Models Physicokinetics Physiological Turnover Processes Therapeutic Response, Cumulative Drug Effects, and Schedule Dependence CHAPTER 20 Disease Progress Models NICHOLAS H. G. HOLFORD, DIANE R. MOULD, AND CARL Clinical Pharmacology and Disease Progress Disease Progress Models No Progress Model Linear Progress Model Asymptotic Progress Model Nonzero Asymptote Physiological Turnover Models Growth Models Conclusion PART IV OPTIMIZING AND EVALUATING PATIENT THERAPHY CHAPTER 21 Pharmacological Differences between Men and Women MAYLEE CHEN, JOSEPH S. BERG, AND ANNE Pharmacokinetics Absorption Contents Distribution 326 Renal Excretion Sex Drug Drug Metabolism Interactions of Particular Importance to Women Chronopharmacology, Menstrual Cycle, and Menopause Pharmacodynamics Cardiovascular Effects Analgesic Effects Sex Differences in Immunology and Immunosuppression Summary CHAPTER 22 Drug Therapy in Pregnant and Nursing Women CATHERINE S. STIKA AND MARILYNN FREDERIKSEN Pregnancy Physiology and its Effects On Pharmacokinetics Gastrointestinal Changes Cardiovascular Effects Blood Composition Changes Renal Changes Hepatic Drug-Metabolizing Changes Peripartum Changes Postpartum Changes Pharmacokinetic Studies During Pregnancy Results of Selected Pharmacokinetic Studies in Pregnant Women Guidelines for the Conduct of Drug Studies in Pregnant Women Placental Transfer of Drugs Teratogenesis Principles of Teratology Measures to Minimize Teratogenic Risk Drug Therapy in Nursing Mothers CHAPTER 23 Drug Therapy in Neonates and Patients ELIZABETH FOX AND FRANK M. BALIS Background Chloramphenicol Therapy in Newborns Zidovudine Therapy in Newborns, Infants, and Children Development of Federal Regulations Ontogeny and Pharmacology Drug Absorption Drug Distribution Drug Metabolism Renal Excretion Therapeutic Implications of Growth and Development Effect on Pharmacokinetics Effect on Pharmacodynamics Effect of Childhood Diseases Conclusions CHAPTER 24 Drug Therapy in the Elderly DARRELL R. ABERNETHY Introduction Pathophysiology of Aging Age-Related Changes in Pharmacokinetics Age-Related Changes in Renal Clearance Age-Related Changes in Hepatic and Extrahepatic Drug Age-Related Changes in Effector System Function 379 Central Nervous System Autonomie Cardiovascular Function Renal Function Hematopoietic System and the Treatment of Cancer 383 Drug Groups for Which Age Confers Increased Risk for Conclusions CHAPTER 25 Clinical Analysis of Adverse Drug Reactions KARIM ANTON R. YOUNG Introduction Epidemiology Definitions Contents Xl Classification Clinical Detection Risk Factors Detection Methods Clinical Evaluation Causality Assessment Reporting Requirements ADR Detection in Clinical Trials Methodology Limitations Reporting Requirements Information Sources CHAPTER 26 Quality Assessment of Drug Therapy CHARLES E. DANIELS Introduction Adverse Drug Events Medication Use Process Improving the Quality of Medication Use Organizational Influences On Medication Use Quality Medication Policy Issues Formulary Management Analysis and Prevention of Medication Errors Medication Use Evaluation Summary What Is Project Planning and Management? Portfolio Design, Planning, and Management Maximizing Portfolio Value Portfolio Design Portfolio Planning Portfolio Management Portfolio Optimization Using Sensitivity Analysis 428 Project Planning and Management Project Planning The Project Management Triangle The Project Cycle Project Planning and Management Tools Decision Trees Milestone Charts PERT/CPM Charts Gantt Charts Work Breakdown Structures Financial Tracking Project Scheduling Project Team Management and Decision-Making Core Project Teams Project Team Leadership and Project Support FDA Project Teams Effective Project Meetings Resource Allocation Effective Project Decision-Making Process Leadership and Benchmarking CHAPTER PART V DRUG DISCOVERY AND DEVELOPMENT CHAPTER 27 Portfolio and Project Planning and Management in the Drug Discovery, Development, and Review Process CHARLES GRUDZINSKAS Introduction What Is a Portfolio? 423 28 Drug Discovery SHANNON DECKER AND EDWARD A. SAUSVILLE Introduction Definition of Drug Targets Empirical Drug Discovery Rational Drug Discovery Generating Diversity Natural Products Chemical Compound Libraries Definition of Lead Structures Biochemical Screens Cell-Based Screens Structure-Based Drug Design Qualifying Leads for Transition to Early Trials Xli Contents CHAPTER 29 Preclinical CHRIS INTRODUCTION Components of In Vitro Drug Supply and Formulation In Vivo Studies Models In Vivo Studies Pharmacodynamic Testing In Vivo Studies Drug Development Programs at the NCI History The 3-Cell-Line Prescreen and 60-Cell-Line Screen 456 NCI Drug Development Process The Challenge Therapies and New Paradigms for Clinical Trials CHAPTER 30 Animal Scale-Up ROBERT L. DEDRICK AND ARTHUR J. ATKINSON, JR. Introduction Allometry Use of Allometry to Predict Human Pharmacokinetic Parameters Use of Allometry in Designing Intraperitoneal Dose Regimens Physiological Pharmacokinetics In Vitro-in Vivo Correlation of Hepatic Metabolism 469 CHAPTER 31 Phase I Clinical Studies JERRY M. COLLINS Introduction Disease-Specific Considerations Starting Dose and Dose Escalation Modified Fibonacci Escalation Scheme Pharmacologically Guided Dose Escalation Interspecies Active Metabolites Beyond 475 CHAPTER 32 Pharmacokinetic and Pharmacodynamic Considerations in the Development of Biotechnology Products and Large Molecules PAMELA D. Introduction Monoclonal Antibodies Assay of Macromolecules Interspecies in Humans Pharmacokinetic Characteristics of Macromolecules 483 Endogenous Concentrations Absorption Distribution Metabolism Renal Excretion Application of Sparse Sampling and Population Kinetic Methods Pharmacodynamics Models Regimen Dependency CHAPTER 33 Design of Clinical Development Programs CHARLES GRUDZINSKAS Introduction Phases, Size, and Scope of Clinical Development Programs Global Development Clinical Drug Development Phases Drug Development Time and Cost Picture Impact of Regulation on Clinical Development Programs Goal and Objectives of Clinical Drug Development 505 Objective cometrics Objective Contents ХНІ Objective Objective Objective Objective NDA/BLA Submission Objective Postmarketing Critical Drug Development Paradigms Label-Driven Question-Based Clinical Development Plan Paradigm Differentiation Paradigm Drug Action Paradigm Learning vs Confirming Paradigm Decision-Making Paradigm Fail Early/Fail Cheaply Paradigm Critical Clinical Drug Development Decision Points Which Disease State? What Are the Differentiation Targets? Is the Drug Reasonably Safe for FIH Trials? Starting Dose for the FIH Trial Have Clinical Proof of Mechanism and Proof of Concept Been Obtained? Have the Dose, Dose Regimen, and Patient Population Been Characterized? Will the Product Grow in the Environment? Will the Clinical Development Program Be Adequate for Regulatory Approval? Learning Contemporary Clinical Drug Development Courses and Other Educational Opportunities Failed Clinical Drug Development Programs as Teaching Examples CHAPTER 34 Role of the FDA in Guiding Drug Development LAWRENCE J. SAHAJWALLA Why does the FDA Get Involved in Drug Development? When does the FDA Get Involved in Drug Development? How does the FDA Guide Drug Development? What Are FDA Guidances? Appendix I Abbreviated Tables of Laplace Transforms Appendix II ARTHUR J. ATKINSON, JR. Answers to Study Problems Index
adam_txt	Contents Preface Contributors CHAPTER Introduction to Clinical Pharmacology ARTHUR J. ATKINSON, JR. Background Optimizing Use of Existing Medicines Evaluation and Development of Medicines Pharmacokinetics Concept of Clearance Clinical Assessment of Renal Function Dose-Related Renal Function is Unrecognized Concepts Underlying Clinical Pharmacokinetics Initiation of Drug Therapy (Concept of Apparent Distribution Volume) Continuation of Drug Therapy (Concepts of Elimination Half-Life and Clearance) Drugs Not Eliminated by First-Order Kinetics Mathematical Basis of Clinical Pharmacokinetics 18 First-Order Elimination Kinetics Concept of Elimination Half-Life Relationship of Cumulation Factor Plateau Principle Application of Laplace Transforms to Pharmacokinetics CHAPTER PART I PHARMACOKINETICS CHAPTER Clinical Pharmacokinetics ARTHUR J. ATKINSON, JR. The Target Concentration Strategy Monitoring Serum Concentrations of Digoxin as an Example General Indications for Drug Concentration Monitoring Compartmental Analysis of Drug Distribution ARTHUR J. ATKINSON, JR. Physiological Significance of Drug Distribution Volumes Physiological Basis of Multicompartmental Models of Drug Distribution Basis of Multicompartmental Structure Mechanisms of Transcapillary Exchange Clinical Consequences of Different Drug Distribution Patterns Analysis of Experimental Data Derivation of Equations for a Two-Compartment Model Calculation of Rate Constants and Compartment Volumes from Data Contents Different Estimates of Apparent Volume Distribution CHAPTER Drug Absorption and Bioavailability ARTHUR J. ATKINSON, JR. Drug Absorption Bioavailability Absolute Bioavailability Relative Bioavailability In Vitro Prediction of Bioavailability Kinetics of Drug Absorption after Oral Administration Time to Peak Level Value of Peak Level Use of Convolution/Deconvolution to Assess in Vitro-in Vivo Correlations CHAPTER Effects of Renal Disease on Pharmacokinetics ARTHUR J. ATKINSON, JR. AND MARCUS M. REIDENBERG Effects of Renal Disease on Drug Elimination Mechanisms of Renal Handling of Drugs Effects of Impaired Renal Function on Nonrenal Metabolism Effects of Renal Disease on Drug Distribution Plasma Protein Binding of Acidic Drugs Plasma Protein Binding of Basic and Neutral Drugs Tissue Binding of Drugs Effects of Renal Disease on Drug Absorption Kinetics of Continuous Renal Replacement Therapy Clearance by Continuous Hemofiltration Clearance by Continuous Hemodialysis Extracorporeal Clearance during Continuous Renal Replacement Therapy Clinical Considerations Drug Dosing Guidelines for Patients Requiring Renal Replacement Therapy Extracorporeal Therapy of Patients with Drug Toxicity CHAPTER Effect of Liver Disease on Pharmacokinetics GREGORY M. SUSLA AND ARTHUR J. ATKINSON, JR. Hepatic Elimination of Drugs Restrictively Metabolized Drugs Drugs with an Intermediate Extraction Ratio (0.3 < ER < 0.7) 75 Nonrestrictively Metabolized Drugs Biliary Excretion of Drugs Effects of Liver Disease on Pharmacokinetics Acute Hepatitis Chronic Liver Disease and Cirrhosis Pharmacokinetic Consequences of Liver Cirrhosis Use of Therapeutic Drugs in Patients with Liver Disease Effects of Liver Disease on the Hepatic Elimination of Drugs Effects of Liver Disease on the Renal Elimination of Drugs Effects of Liver Disease on Patient Response Modification of Drug Therapy in Patients with Liver Disease CHAPTER CHAPTER 6 Pharmacokinetics in Patients Requiring Renal Replacement Therapy ARTHUR J. ATKINSON, JR. AND GREGORY ]yi. SUSLA Kinetics Of Intermittent Hemodialysis Solute Transfer across Dialyzing Membranes Calculation of Dialysis Clearance Patient Factors Affecting Hemodialysis of Drugs 59 8 Noncompartmental versus Compartmental Approaches to Pharmacokinetic Analysis DAVID M. FOSTER Introduction Kinetics, Pharmacokinetics, and Pharmacokinetic Parameters Kinetics and the Link to Mathematics Pharmacokinetic Parameters Contents Vil Noncompartmental Noncompartmental Model 92 Kinetic Model 93 Estimating the Kinetic Parameters of the Noncompartmental Model Comp Definitions and Assumptions Linear, Constant-Coefficient Compartmental Models Parameters Estimated from Compartmental Models Noncompartmental versus Compartmental Models Models of Data vs Models of System Equivalent Sink and Source Constraints Recovering Pharmacokinetic Parameters from Compartmental Models Conclusion CHAPTER 9 Distributed Models of Drug Kinetics PAUL F. MORRISON Introduction Central Issues Drug Modality I: Delivery across a Planar-Tissue Interface General Principles Differences between the Delivery of Small Molecules and Macromolecules across a Planar Interface 114 Drug Modality II: Delivery from a Point Source Direct Interstitial Infusion General Principles Low-Flow High-Flow Summary CHAPTER 10 Population Pharmacokinetics RAYMOND MILLER Introduction Analysis of Pharmacokinetic Data Structure of Pharmacokinetic Models Fitting Individual Data Population Pharmacokinetics Population Analysis Methods Model Applications 129 Mixture Models Exposure-Response Models Conclusions PART II DRUG METABOLISM AND TRANSPORT CHAPTER 11 Pathways of Drug Metabolism SANFORD P. MARKEY Introduction Phase I Liver Microsomal Cytochrome P450 Monooxygenases CYP-Mediated Chemical Transformations Non-CYP Phase II Glucuronidation Sulfation 157 Acetylation Additional Effects on Drug Metabolism Enzyme Induction and Inhibition Species Sex Age CHAPTER 12 Methods of Analysis of Drugs and Drug Metabolites SANFORD P. MARKEY Introduction Choice of Analytical Methodology Chromatographie Absorption and Emission Spectroscopy Immunoaffmity Assays Mass Spectrometry Examples of Current Assay Methods HPLC/UV and HPLC/MS Assay of New Chemical Entities HPLC/MS/MS Quantitative Assays of Cytochrome P450 Enzyme Activity HPLC/UV and Immunoassays of Cyclosporine: Assays for Therapeutic Drug Monitoring Vlil Contents Summary of F-ddA, CYP2B6, and Cyclosporine Analyses CHAPTER 13 Clinical Pharmacogenetics DAVID A. Introduction Hierarchy of Pharmacogenetic Information Identification and Selection of Outliers in a Population Examples of Important Genetic Polymorphisms Drug Absorption Drag Distribution Drug Elimination Mutations That Influence Drug Receptors Combined Variants in Drug Metabolism and Receptor Genes: Value of Drug Pathway Analysis Conclusions and Future Directions CHAPTER 14 Equilibrative and Concentrative Transport Mechanisms PETER Introduction Mechanisms of Transport Across Biological Membranes Thermodynamics of Membrane Transport Passive Diffusion Carrier-Mediated Transport: Facilitated Diffusion and Active Transport Uptake Mechanisms Dependent on Membrane Trafficking Paracellular Transport and Permeation Enhancers 204 Description of Selected Membrane Protein Transporters ATP-Binding Cassette Superfamily Multifacilitator Superfamily Transporters Role of Transporters in Pharmacokinetics and Drag Action Role of Transporters in Drug Absorption Role of Transporters in Drug Distribution Role of Transporters in Drug Elimination Role of Transporters in Drug Interactions P-gp Inhibition as an Adjunct to Treating Chemotherapy-Resistant Cancers Role of Transporters in Microbial Drug Resistance 215 Pharmacogenetics and Pharmacogenomics of Transporters Pharmacogenomics of Drug Transport Pharmacogenetics of Drug Transport Future Directions Structural Biology of Membrane Transport Proteins 220 In Silico Prediction of Drug Absorption, Distribution, Metabolism, and Elimination CHAPTER 15 Drug Interactions SARAH ROBERTSON AND SCOTT PENZAK Introduction Epidemiology Classifications Mechanisms of Drug Interactions Interactions Affecting Drug Absorption Interactions Affecting Drug Distribution Interactions Affecting Drug Metabolism Interactions Involving Drug Transport Proteins 237 Interactions Affecting Renal Excretion Prediction and Clinical Management of Drug Interactions In Vitro Screening Methods Genetic Variation Clinical Management of Drug Interactions CHAPTER 16 Biochemical Mechanisms of Drug ARTHUR J. ATKINSON, JR. AND SANFORD P. MARKEY Introduction Drug-Induced Methemoglobinemia Role of Covalent Binding in Drug Drug-Induced Liver Hepatotoxic Reactions Resulting from Covalent Binding of Reactive Metabolites Contents їх Immunologically Mediated 255 Mechanisms of Other Drug Toxicities Systemic Reactions Resulting from Drug Allergy 259 Carcinogenic Reactions to Drugs Teratogenic Reactions to Drugs PART Linear and Log-Linear Model Conclusion III ASSESSMENT OF DRUG EFFECTS CHAPTER 17 Physiological and Laboratory Markers of Drug Effect ARTHUR J. ATKINSON, JR. AND PAUL Biological Markers of Drug Effect Identification and Evaluation of Biomarkers Uses of Biomarkers and Surrogate Use of Serum Cholesterol as a Biomarker and Surrogate Endpoint Application of Serial Biomarker Measurements 282 Future Development of Biomarkers CHAPTER 18 Dose-Effect and Concentration-Effect Analysis ELIZABETH S. LOWE AND FRANK M. BALIS Background Drug-Receptor Interactions Receptor Occupation Theory Receptor-Mediated Effects Graded Dose-Effect Relationship Dose-Effect Parameters Dose Effect and Site of Drag Action Quantal Dose-Effect Relationship Therapeutic Indices Dose Effect and Defining Optimal Dose Pharmacodynamic Models Fixed-Effect Model Maximum-Effect (Emax and Sigmoid Emax) Models CHAPTER 19 Time Course of Drug Response NICHOLAS H. G. HOLFORD AND ARTHUR J. ATKINSON, JR. Pharmacokinetics and Delayed Effects The Incorporation of Pharmacodynamic Models Physicokinetics Physiological Turnover Processes Therapeutic Response, Cumulative Drug Effects, and Schedule Dependence CHAPTER 20 Disease Progress Models NICHOLAS H. G. HOLFORD, DIANE R. MOULD, AND CARL Clinical Pharmacology and Disease Progress Disease Progress Models "No Progress" Model Linear Progress Model Asymptotic Progress Model Nonzero Asymptote Physiological Turnover Models Growth Models Conclusion PART IV OPTIMIZING AND EVALUATING PATIENT THERAPHY CHAPTER 21 Pharmacological Differences between Men and Women MAYLEE CHEN, JOSEPH S. BERG, AND ANNE Pharmacokinetics Absorption Contents Distribution 326 Renal Excretion Sex Drug Drug Metabolism Interactions of Particular Importance to Women Chronopharmacology, Menstrual Cycle, and Menopause Pharmacodynamics Cardiovascular Effects Analgesic Effects Sex Differences in Immunology and Immunosuppression Summary CHAPTER 22 Drug Therapy in Pregnant and Nursing Women CATHERINE S. STIKA AND MARILYNN FREDERIKSEN Pregnancy Physiology and its Effects On Pharmacokinetics Gastrointestinal Changes Cardiovascular Effects Blood Composition Changes Renal Changes Hepatic Drug-Metabolizing Changes Peripartum Changes Postpartum Changes Pharmacokinetic Studies During Pregnancy Results of Selected Pharmacokinetic Studies in Pregnant Women Guidelines for the Conduct of Drug Studies in Pregnant Women Placental Transfer of Drugs Teratogenesis Principles of Teratology Measures to Minimize Teratogenic Risk Drug Therapy in Nursing Mothers CHAPTER 23 Drug Therapy in Neonates and Patients ELIZABETH FOX AND FRANK M. BALIS Background Chloramphenicol Therapy in Newborns Zidovudine Therapy in Newborns, Infants, and Children Development of Federal Regulations Ontogeny and Pharmacology Drug Absorption Drug Distribution Drug Metabolism Renal Excretion Therapeutic Implications of Growth and Development Effect on Pharmacokinetics Effect on Pharmacodynamics Effect of Childhood Diseases Conclusions CHAPTER 24 Drug Therapy in the Elderly DARRELL R. ABERNETHY Introduction Pathophysiology of Aging Age-Related Changes in Pharmacokinetics Age-Related Changes in Renal Clearance Age-Related Changes in Hepatic and Extrahepatic Drug Age-Related Changes in Effector System Function 379 Central Nervous System Autonomie Cardiovascular Function Renal Function Hematopoietic System and the Treatment of Cancer 383 Drug Groups for Which Age Confers Increased Risk for Conclusions CHAPTER 25 Clinical Analysis of Adverse Drug Reactions KARIM ANTON R. YOUNG Introduction Epidemiology Definitions Contents Xl Classification Clinical Detection Risk Factors Detection Methods Clinical Evaluation Causality Assessment Reporting Requirements ADR Detection in Clinical Trials Methodology Limitations Reporting Requirements Information Sources CHAPTER 26 Quality Assessment of Drug Therapy CHARLES E. DANIELS Introduction Adverse Drug Events Medication Use Process Improving the Quality of Medication Use Organizational Influences On Medication Use Quality Medication Policy Issues Formulary Management Analysis and Prevention of Medication Errors Medication Use Evaluation Summary What Is Project Planning and Management? Portfolio Design, Planning, and Management Maximizing Portfolio Value Portfolio Design Portfolio Planning Portfolio Management Portfolio Optimization Using Sensitivity Analysis 428 Project Planning and Management Project Planning The Project Management Triangle The Project Cycle Project Planning and Management Tools Decision Trees Milestone Charts PERT/CPM Charts Gantt Charts Work Breakdown Structures Financial Tracking Project Scheduling Project Team Management and Decision-Making Core Project Teams Project Team Leadership and Project Support FDA Project Teams Effective Project Meetings Resource Allocation Effective Project Decision-Making Process Leadership and Benchmarking CHAPTER PART V DRUG DISCOVERY AND DEVELOPMENT CHAPTER 27 Portfolio and Project Planning and Management in the Drug Discovery, Development, and Review Process CHARLES GRUDZINSKAS Introduction What Is a Portfolio? 423 28 Drug Discovery SHANNON DECKER AND EDWARD A. SAUSVILLE Introduction Definition of Drug Targets Empirical Drug Discovery Rational Drug Discovery Generating Diversity Natural Products Chemical Compound Libraries Definition of Lead Structures Biochemical Screens Cell-Based Screens Structure-Based Drug Design Qualifying Leads for Transition to Early Trials Xli Contents CHAPTER 29 Preclinical CHRIS INTRODUCTION Components of In Vitro Drug Supply and Formulation In Vivo Studies Models In Vivo Studies Pharmacodynamic Testing In Vivo Studies Drug Development Programs at the NCI History The 3-Cell-Line Prescreen and 60-Cell-Line Screen 456 NCI Drug Development Process The Challenge Therapies and New Paradigms for Clinical Trials CHAPTER 30 Animal Scale-Up ROBERT L. DEDRICK AND ARTHUR J. ATKINSON, JR. Introduction Allometry Use of Allometry to Predict Human Pharmacokinetic Parameters Use of Allometry in Designing Intraperitoneal Dose Regimens Physiological Pharmacokinetics In Vitro-in Vivo Correlation of Hepatic Metabolism 469 CHAPTER 31 Phase I Clinical Studies JERRY M. COLLINS Introduction Disease-Specific Considerations Starting Dose and Dose Escalation Modified Fibonacci Escalation Scheme Pharmacologically Guided Dose Escalation Interspecies Active Metabolites Beyond 475 CHAPTER 32 Pharmacokinetic and Pharmacodynamic Considerations in the Development of Biotechnology Products and Large Molecules PAMELA D. Introduction Monoclonal Antibodies Assay of Macromolecules Interspecies in Humans Pharmacokinetic Characteristics of Macromolecules 483 Endogenous Concentrations Absorption Distribution Metabolism Renal Excretion Application of Sparse Sampling and Population Kinetic Methods Pharmacodynamics Models Regimen Dependency CHAPTER 33 Design of Clinical Development Programs CHARLES GRUDZINSKAS Introduction Phases, Size, and Scope of Clinical Development Programs Global Development Clinical Drug Development Phases Drug Development Time and Cost Picture Impact of Regulation on Clinical Development Programs Goal and Objectives of Clinical Drug Development 505 Objective cometrics Objective Contents ХНІ Objective Objective Objective Objective NDA/BLA Submission Objective Postmarketing Critical Drug Development Paradigms Label-Driven Question-Based Clinical Development Plan Paradigm Differentiation Paradigm Drug Action Paradigm Learning vs Confirming Paradigm Decision-Making Paradigm Fail Early/Fail Cheaply Paradigm Critical Clinical Drug Development Decision Points Which Disease State? What Are the Differentiation Targets? Is the Drug "Reasonably Safe" for FIH Trials? Starting Dose for the FIH Trial Have Clinical Proof of Mechanism and Proof of Concept Been Obtained? Have the Dose, Dose Regimen, and Patient Population Been Characterized? Will the Product Grow in the Environment? Will the Clinical Development Program Be Adequate for Regulatory Approval? Learning Contemporary Clinical Drug Development Courses and Other Educational Opportunities Failed Clinical Drug Development Programs as Teaching Examples CHAPTER 34 Role of the FDA in Guiding Drug Development LAWRENCE J. SAHAJWALLA Why does the FDA Get Involved in Drug Development? When does the FDA Get Involved in Drug Development? How does the FDA Guide Drug Development? What Are FDA Guidances? Appendix I Abbreviated Tables of Laplace Transforms Appendix II ARTHUR J. ATKINSON, JR. Answers to Study Problems Index
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discipline	Chemie / Pharmazie Medizin
discipline_str_mv	Chemie / Pharmazie Medizin
edition	2. ed.
format	Book
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genre_facet	Lehrbuch
id	DE-604.BV021814577
illustrated	Illustrated
index_date	2024-07-02T15:52:01Z
indexdate	2024-07-09T20:45:15Z
institution	BVB
isbn	0123694175 9780123694171
language	English
oai_aleph_id	oai:aleph.bib-bvb.de:BVB01-015026808
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physical	XIX, 545 S. Ill., graph. Darst.
publishDate	2007
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publisher	Acad. Press
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spelling	Principles of clinical pharmacology Arthur J. Atkinson ... 2. ed. Amsterdam [u.a.] Acad. Press 2007 XIX, 545 S. Ill., graph. Darst. txt rdacontent n rdamedia nc rdacarrier Farmacologie gtt Pharmacologie clinique Clinical pharmacology Pharmacology, Clinical Pharmakologie (DE-588)4045687-0 gnd rswk-swf (DE-588)4123623-3 Lehrbuch gnd-content Pharmakologie (DE-588)4045687-0 s DE-604 Atkinson, Arthur J. Sonstige oth Digitalisierung UB Regensburg application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=015026808&sequence=000002&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis
spellingShingle	Principles of clinical pharmacology Farmacologie gtt Pharmacologie clinique Clinical pharmacology Pharmacology, Clinical Pharmakologie (DE-588)4045687-0 gnd
subject_GND	(DE-588)4045687-0 (DE-588)4123623-3
title	Principles of clinical pharmacology
title_auth	Principles of clinical pharmacology
title_exact_search	Principles of clinical pharmacology
title_exact_search_txtP	Principles of clinical pharmacology
title_full	Principles of clinical pharmacology Arthur J. Atkinson ...
title_fullStr	Principles of clinical pharmacology Arthur J. Atkinson ...
title_full_unstemmed	Principles of clinical pharmacology Arthur J. Atkinson ...
title_short	Principles of clinical pharmacology
title_sort	principles of clinical pharmacology
topic	Farmacologie gtt Pharmacologie clinique Clinical pharmacology Pharmacology, Clinical Pharmakologie (DE-588)4045687-0 gnd
topic_facet	Farmacologie Pharmacologie clinique Clinical pharmacology Pharmacology, Clinical Pharmakologie Lehrbuch
url	http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=015026808&sequence=000002&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA
work_keys_str_mv	AT atkinsonarthurj principlesofclinicalpharmacology

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