Rowland and Tozer's Clinical Pharmacokinetics and Pharmacodynamics: Concepts and Applications

 

Description:

 

Updated with the latest clinical advances, Rowland and Tozer’s Clinical Pharmacokinetics and Pharmacodynamics, Fifth Edition , explains the relationship between drug administration and drug response, taking a conceptual approach that emphasizes clinical application rather than science and mathematics. Bringing a real-life perspective to the topic, the book simplifies concepts and gives readers the knowledge they need to better evaluate drug applications.

 

 

Table of Contents:

 

Nonproprietary and Brand Names of Drugs in Text and Illustrations

Definition of Symbols

SECTION 1 BASIC CONSIDERATIONS

CHAPTER 1 Therapeutic Relevance

CLINICAL SETTING

Input–Response Phases

Variability in Drug Response

Adherence

THE INDUSTRIAL PERSPECTIVE

ORGANIZATION OF THE BOOK

CHAPTER 2 Fundamental Concepts and Terminology

PHARMACOKINETICS

Systemic Exposure

Sites of Measurement

Unbound Drug Concentration

Exposure–Time Profile

Period of Observation

Chemical Purity and Analytic Specificity

Active Metabolites and Prodrugs

Anatomic and Physiologic Considerations

Sites of Administration

Events after Entering Systemically

Models for Drug Absorption and Disposition

Definitions of Pharmacokinetic Terms

Systemic Absorption

Disposition

Distribution

Elimination

Biliary Secretion and Fecal Excretion

PHARMACODYNAMICS

Classification of Response

Assessment of Drug Response

Relating Response to Exposure

Graded Response

Quantal Response

Desirable Characteristics

DOSE–TIME–RESPONSE RELATIONSHIPS

Turnover Concepts in Drug Response

KEY RELATIONSHIPS

STUDY PROBLEMS

SECTION 2 EXPOSURE AND RESPONSE AFTERA SINGLE DOSE

CHAPTER 3 Kinetics Following an Intravenous Bolus Dose

APPRECIATION OF KINETIC CONCEPTS

Volume of Distribution and Clearance

First-order Elimination

Half-life

Fraction of Dose Remaining

Clearance, Area, and Volume of Distribution

Mean Residence Time

A CASE STUDY

Distribution Phase

Terminal Phase

Elimination Half-life

Clearance

Volume of Distribution

Clearance and Elimination

Distribution and Elimination: Competing Processes

PATHWAYS OF ELIMINATION

Renal Clearance

Renal Excretion as a Fraction of Total Elimination

ESTIMATION OF PHARMACOKINETIC PARAMETERS

Plasma Data Alone

Plasma and Urine Data

A Question of Precision

Measurement Fluid

Use of Computers

CHANGE IN DOSE

KEY RELATIONSHIPS

STUDY PROBLEMS

CHAPTER 4 Membranes and Distribution

MEMBRANES

TRANSPORT PROCESSES

Protein Binding

Diffusion

Drug Properties Determining Permeability

Membrane Characteristics

Carrier-Mediated Transport

REVERSIBLE NATURE OF TRANSPORT

RATE OF DISTRIBUTION TO TISSUES

Perfusion Rate Limitation

Permeability Rate Limitation

EXTENT OF DISTRIBUTION

Apparent Volume of Distribution

Binding within Blood

Plasma Protein Binding

Tissue Distribution

Tissue Binding

Transporters

SMALL VOLUME OF DISTRIBUTION

Model

Location in Body

Altered Binding and Loading Dose

KEY RELATIONSHIPS

STUDY PROBLEMS

CHAPTER 5 Elimination

PROCESSES OF ELIMINATION

CLEARANCE IN GENERAL

Description of Clearance by Organ, Process, or Site of Measurement

Plasma or Serum versus Blood Clearance

Additivity of Clearance

HEPATIC CLEARANCE

Perfusion, Protein Binding, and Hepatocellular Activity

Intrinsic Clearance

Perfusion

Plasma Protein Binding

Hepatocellular Eliminating Activity

A Memory Aid

Some Complexities

Permeability

Location of Transporters

Biliary Excretion and Enterohepatic Cycling

RENAL CLEARANCE

The Nephron: Anatomy and Function

Glomerular Filtration

Active Secretion

Protein Binding and Perfusion

Tubular Reabsorption

Renal Metabolism

DEPENDENCE OF ELIMINATION KINETICS ON CLEARANCE AND DISTRIBUTION

Half-life in Plasma

Half-life in Blood and Plasma Water

INTEGRATION OF KINETIC AND PHYSIOLOGIC CONCEPTS

Interrelationships among Pharmacokinetic Parameters and Physiologic Variables

Primary Parameters and Physiologic Variables

Secondary Pharmacokinetic Parameters and Derived Values

Induction of Metabolism

Metabolic Inhibition

Altered Blood Flow

Altered Active Tubular Secretion

Altered Plasma Protein Binding

KEY RELATIONSHIPS

STUDY PROBLEMS

CHAPTER 6 Kinetics Following an Extravascular Dose

ROUTES OF EXTRAVASCULAR ADMINISTRATION

KINETICS OF ABSORPTION

EXPOSURE–TIME AND EXPOSURE–DOSE RELATIONSHIPS

Comparison with Intravenous Administration

CHANGES IN DOSE OR ABSORPTION KINETICS

Changing Dose

Changing Absorption Kinetics

Disposition Is Rate-Limiting

Absorption Is Rate-Limiting

Distinguishing between Absorption and Disposition Rate Limitations

Changing Disposition Kinetics

Predicting Changes in Peak Concentration and Peak Time

ASSESSMENT OF PRODUCT PERFORMANCE

Formulation

Bioequivalence Testing

ASSESSMENT OF PHARMACOKINETIC PARAMETERS

Plasma Data Alone

Bioavailability

Relative Bioavailability

Fraction Eliminated

Other Pharmacokinetic Parameters

Urine Data Alone

Plasma and Urine Data

Virtual Bioequivalence

Local Bioequivalence

KEY RELATIONSHIPS

STUDY PROBLEMS

CHAPTER 7 Absorption

ABSORPTION FROM SOLUTION

Gastrointestinal Absorption

Gastric Emptying

Intestinal Absorption and Permeability

Causes of Loss in Oral Bioavailability

Competing Intestinal Reactions

First-Pass Loss

Separating Gut Wall from Hepatic First-Pass Loss

Hepatic First-Pass Predictions

Saturable First-Pass Metabolism

Absorption from Intramuscular and Subcutaneous Sites

ABSORPTION FROM SOLID DOSAGE FORMS

Dissolution

Gastric Emptying and Intestinal Transit

Gastric Emptying

Rapid Dissolution in Stomach

Rapid Dissolution in Intestine

Intestinal Absorption Windows

Poor Dissolution

Biopharmaceutics Classification System

Modified-Release Products

Changing Rate Control

Precipitation and Redissolution

Absorption from Other Sites

INTEGRATION OF KINETIC AND PHYSIOLOGIC CONCEPTS

Change in the Speed of Absorption

Change in Extent of Absorption

Change in Drug Disposition

Induction, Low Extraction Ratio

Induction, High Extraction Ratio

Impaired Renal Function

Increase in Urine pH

KEY RELATIONSHIPS

STUDY PROBLEMS

CHAPTER 8 Response

TIME DELAYS BETWEEN CONCENTRATION AND RESPONSE

Detecting Time Delays

Causes of Time Delay

Tissue Distribution

Pharmacodynamics

Direct and Indirect Link

Indirect Response Models

Systems in Flux

Revealing the Concentration–Response Relationship

Effect Compartment

Systems in Flux

DECLINE OF RESPONSE WITH TIME

When Pharmacokinetics Rate-Limits Decline

When Pharmacodynamics Rate-Limits Decline

ONSET AND DURATION OF RESPONSE

Onset of Effect

Duration of Effect

Impact of Transporter Polymorphism on Exposure–Response Relationships

KEY RELATIONSHIPS

STUDY PROBLEMS

SECTION 3 THERAPEUTIC REGIMENS

CHAPTER 9 Therapeutic Window

DOSAGE REGIMENS

THERAPEUTIC EXPOSURE

THERAPEUTIC INDEX

ADDITIONAL CONSIDERATIONS

Multiple Active Species

Single-Dose Therapy

Duration versus Intensity of Exposure

Time Delays

ACHIEVING THERAPEUTIC GOALS

STUDY PROBLEMS

CHAPTER 10 Constant-Rate Input

EXPOSURE–TIME RELATIONSHIPS

The Plateau Value

Mean Residence Time

Time to Reach Plateau

Postinfusion

Changing Infusion Rates

Bolus Plus Infusion

SHORT-TERM INFUSIONS

CONSEQUENCE OF SLOW TISSUE DISTRIBUTION

Rapid Induction of Anesthesia

Decrease in Infusion Rate on Chronic Administration

Recovery from Anesthesia

PHARMACODYNAMIC CONSIDERATIONS

The Drug Itself

Onset of Response

Response on Stopping an Infusion

Response Infusion versus Single Dose

Turnover of Affected Systems

Altered Turnover

Establishment of a New Steady State

Interpretation of Non–Steady-State Observations

TOLERANCE

INTEGRATION OF KINETIC AND PHYSIOLOGIC CONCEPTS

Drug A. Inhibition of Hepatic Metabolism, Low Hepatic Extraction Ratio

Drug B. Inhibition of Hepatic Metabolism, High Hepatic Extraction Ratio

Drug C. Induction of Hepatic Metabolism, Low Hepatic Extraction Ratio

Drug D Induction of Hepatic Metabolism, High Hepatic Extraction Ratio

TRANSLATIONAL JUSTIFICATION FOR USING CONTINUOUS INFUSIONS

KEY RELATIONSHIPS

STUDY PROBLEMS

CHAPTER 11 Multiple-Dose Regimens

PRINCIPLES OF DRUG ACCUMULATION

Maxima and Minima on Accumulation to the Plateau

Average Level at Plateau

Rate of Accumulation to Plateau

Accumulation Index

Change in Regimen

RELATIONSHIP BETWEEN INITIAL AND MAINTENANCE DOSES

MAINTENANCE OF DRUG IN THE THERAPEUTIC RANGE

Half-lives Less than 30 Minutes

Half-Lives between 30 min and 8 hr

Half-Lives between 8 and 24 hr

Half-Lives Greater than 24 hr

Reinforcing the Principles

ADDITIONAL CONSIDERATIONS

Extravascular Administration

Plasma Concentration versus Amount in Body

DESIGN OF DOSAGE REGIMENS USING PLASMA CONCENTRATION

When Bioavailability and Volume Are Unknown

MODIFIED-RELEASE PRODUCTS

EVALUATION OF A MULTIPLE-DOSE REGIMEN

Clearance/Bioavailability

Half-life

Degree of Accumulation

Degree of Fluctuation at Plateau

Other Parameters

PHARMACODYNAMIC CONSIDERATIONS

Time to Achieve Therapeutic Effect

Intermittent Administration

Onset, Duration, and Intensity

Development of Tolerance

Modality of Administration

WHEN ABSORPTION OR DISPOSITION IS ALTERED

Sketch of Concentration–Time Profiles

Model of Multiple Intravenous Doses

Extravascular Administration

Inhibition of Hepatic Metabolism (Condition A)

Induction of Metabolism (Condition B)

TRANSLATIONAL JUSTIFICATION FOR USING SINGLE DAILY DOSING OVER MORE FREQUENT ADMINISTRATION

Other Situations

STUDY PROBLEMS

SECTION 4 INDIVIDUALIZATION

CHAPTER 12 Variability

EXPRESSIONS OF INDIVIDUAL DIFFERENCES

Quantifying Variability

Describing Variability

POPULATION ANALYSIS

MAXIMUM LIKELIHOOD APPROACH

WHY PEOPLE DIFFER

DEFINING THE DOSE–RESPONSE RELATIONSHIP

THERAPEUTIC EXPOSURE

KINETIC MANIFESTATIONS

DYNAMIC MANIFESTATIONS

DOSE STRENGTHS

STUDY PROBLEMS

CHAPTER 13 Genetics

INHERITED VARIATION IN PHARMACOKINETICS

Oxidation

S-Methylation

Conjugation

Acetylation

Hydrolysis

Additional Clinical Considerations

INHERITED VARIABILITY IN PHARMACODYNAMICS

METABOLIC PHENOTYPING

PHARMACOGENETICS-BASED THERAPEUTIC RECOMMENDATIONS

STUDY PROBLEMS

CHAPTER 14 Age, Weight, and Gender

THE TYPICAL PATIENT AND USUAL DOSAGE REGIMEN

Who Is the “Typical Patient”?

What Is the “Usual Dosage Regimen”?

PHARMACODYNAMICS

PHARMACOKINETICS

Absorption

Disposition

Body Weight and Composition

Loading Dose

Maintenance Dosing Rate

CHANGE IN PHYSIOLOGIC FUNCTIONS AND DRUG DISPOSITION WITH AGE

Creatinine Clearance and Renal Function

Neonates and Infants

Children

Adults and the Elderly

Metabolism

Neonates and Infants

Children

Adults and the Elderly

Entire Lifespan

GENDER DIFFERENCES

Pharmacokinetics

Pharmacodynamics

ADJUSTMENT OF DOSAGE FOR AGE

Neonates and Infants

Children

Adults

The Elderly

DOSAGES EXPRESSED PER KILOGRAM BODY WEIGHT OR PER 1.73 SQUARE METERS

KEY RELATIONSHIPS

STUDY PROBLEMS

CHAPTER 15 Disease

IMPACT OF DISEASE ON PHARMACOKINETICS

Hepatic Diseases

Cardiovascular Diseases

Renal Diseases

The Pharmacotherapeutic Problem

Decrease in Unbound Clearance

Decrease in Binding to Plasma Proteins

Estimation of Renal Function

Adjustment of Dosage Regimens

General Guidelines and Additional Considerations

HEMODIALYSIS

Dialysis Clearance

Extraction from Blood

Rate of Recovery in Dialysate

Amount Recovered in Dialysate

Extraction Coefficient

Drug Elimination

Effectiveness of Procedure

DRUG ADMINISTRATION TO DIALYSIS PATIENTS

PERITONEAL DIALYSIS

Dialysis Clearance

Route of Administration

DIALYSIS IN DRUG OVERDOSE

Toxic Metabolites

Other Considerations

IMPACT OF DISEASE ON PHARMACODYNAMICS

KEY RELATIONSHIPS

STUDY PROBLEMS

CHAPTER 16 Nonlinearities

DEFINITION OF NONLINEAR KINETIC BEHAVIOR

CAUSES OF NONLINEARITY

SATURABLE PROCESSES

Saturable Metabolism

Saturable Transport

Saturable Binding to Plasma Proteins

Pharmacodynamics

NONLINEAR ABSORPTION

Solubility

Saturable Active Transport

SATURABLE FIRST-PASS METABOLISM

CAPACITY-LIMITED METABOLISM

Alcohol

Phenytoin

Plateau

Time to Plateau

Alterations in Metabolism

CONCENTRATION-DEPENDENT RENAL EXCRETION

SATURABLE TRANSPORT

SATURABILITY OF PLASMA PROTEIN AND TISSUE BINDING

Binding to Plasma Proteins

Tissue Binding

TIME-DEPENDENT DISPOSITION

RECOGNITION OF NONLINEARITIES

Urinary Recovery

Analysis

Concentration–Time Profile

Analysis

Protein-Binding Data

Analysis

KINETICS IN DRUG OVERDOSE

THERAPEUTIC CONSEQUENCES OF NONLINEARITIES

KEY RELATIONSHIPS

STUDY PROBLEMS

CHAPTER 17 Drug Interactions

CLASSIFICATION

ALTERED ABSORPTION

ALTERED DISTRIBUTION

Conditions Favoring Displacement

Therapeutic Implications

Acute Events

Events at Plateau

Kinetic Features

ALTERED CLEARANCE

Inhibition

Competitive Inhibition

Mechanism-Based Inhibition

Induction

Other Causes of Altered Clearance

MULTIFACETED INTERACTIONS

Warfarin–Phenylbutazone Interaction

Digoxin–Quinidine Interaction

Atorvastatin–Rifampicin Interaction

PHARMACODYNAMIC INTERACTIONS

KEY RELATIONSHIPS

STUDY PROBLEMS

CHAPTER 18 Initiating and Managing Therapy

ANTICIPATING SOURCES OF VARIABILITY

Pharmacodynamic Variability

Pharmacokinetic Variability

INITIATING THERAPY

Choosing the Starting Dose

When Is a Loading Dose Needed?

What Should the Loading Dose Be?

Dose Titration

MANAGING THERAPY

Low Therapeutic Index

Use of Biomarkers, Surrogates, and Clinical Endpoints

Tolerance

Dose Strengths and Stratification of Patients

Adherence and Persistence Issues

Missed Dose(s)

“Makeup” Dose(s)

Doubling Up of Doses

DISCONTINUING THERAPY

TARGET CONCENTRATION STRATEGY

Criteria for Monitoring Plasma Drug Concentrations

Good Concentration–Response Relationship

High Probability of Therapeutic Failure

When a Problem Arises

Population Pharmacokinetic Information Available

Reliable Assay

Concentration Monitoring

When Is It Useful?

The Target Concentration

Frequency of Monitoring

Pertinent Information Needed

Evaluation Procedure

Dosing Scenarios

Missed Dose(s)

9-13-17-21 Regimen

Dose and Interval Unequal

Confidence in Estimates

Changes in Therapy

KEY RELATIONSHIPS

STUDY PROBLEMS

SECTION 5 SUPPLEMENTAL TOPICS

CHAPTER 19 Distribution Kinetics

EVIDENCE OF DISTRIBUTION KINETICS

INTRAVENOUS BOLUS DOSE

Presentation of Data

Sum of Exponential Terms

A Compartmental Model

Pharmacokinetic Parameters

Clearance

Volume of Distribution

Distribution Kinetics and Elimination

A Mathematical Aid

AN EXTRAVASCULAR DOSE

CONSTANT-RATE INFUSION

Short-Term Infusion

Long-Term Infusion

Events at Plateau

Turnover of Endogenous Substances

Time to Reach Plateau

Bolus plus Infusion

MULTIPLE DOSING AND REGIMEN DESIGN

Absorption Kinetics

Frequency of Dosing

Utility of Volume Terms

ALTERED CLEARANCE

Changes in Concentration and Half-life

DRUG REDISTRIBUTION

PHARMACODYNAMIC CONSIDERATIONS

Single Bolus Dose

Multiple Dosing

KEY RELATIONSHIPS

STUDY PROBLEMS

CHAPTER 20 Metabolites and Drug Response

CONTRIBUTION OF METABOLITES TO DRUG RESPONSE

SINGLE DOSE OF DRUG

Rate-Limiting Step

Plasma Concentration

Impact of Hepatic Extraction

CONSTANT-RATE DRUG INFUSION

The Plateau

Time to Plateau

Bolus plus Infusion

Infusion Alone

Postinfusion

MULTIPLE-DOSE DRUG REGIMEN

PREDICTION FROM SINGLE-DOSE DATA

VARIABILITY

NONLINEAR METABOLITE FORMATION OR ELIMINATION

ADDITIONAL CONSIDERATIONS

Response

Interconversion

Estimation of Metabolite Formation

From Plasma Metabolite Concentration

From Metabolite Excretion

Detection of Changes in Pharmacokinetics

KEY RELATIONSHIPS

STUDY PROBLEMS

CHAPTER 21 Protein Drugs

PEPTIDE, POLYPEPTIDE, AND PROTEIN DRUGS

COMPARISON OF THE PHARMACOKINETICS OF PROTEIN DRUGS WITH THAT OF CONVENTIONAL NONPROTEIN DRUGS

Absorption

Distribution

Renal Excretion

Metabolism

Fcγ-Mediated Clearance

FcRn-Mediated Clearance

NONLINEARITIES

Target-Mediated Drug Disposition

Immunogenicity-Mediated Clearance

PHARMACODYNAMICS

Pharmacodynamics of Nonantibody Protein Drugs

Pharmacodynamics of Antibody Drugs

Immunotoxicotherapeutic Agents

Agents that Destroy Target Cells

Agents that Alter Cell Function

Antibody-Directed Drug Delivery

Pharmacokinetic and Pharmacodynamic Rate Limitations

INTRAVENOUS ADMINISTRATION

SUBCUTANEOUS AND INTRAMUSCULAR ADMINISTRATION

Large Proteins and Lymphatic Transport

Capillary Permeability

Molecular Size

Rate and Extent of Systemic Absorption

CONCURRENT DISEASE STATES

Renal Disease

Hepatic Disease

IMMUNOGENIC RESPONSES

FUTURE OF THE AREA

STUDY PROBLEMS

CHAPTER 22 Prediction and Refinement of Human Kinetics from In Vitro, Preclinical, and Early Clinical Data

ALLOMETRY AND DISPOSITION KINETICS

Origin

Application to Drugs

Deviation from Expectation

Correcting for Protein Binding

MICRODOSING

PREDICTION OF CLEARANCE

PREDICTION OF DISTRIBUTION

PREDICTION OF ABSORPTION

PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELS

Development and Verification of Physiologically Based Pharmacokinetic Models

PREDICTING PHARMACODYNAMICS

MOVING TO VIRTUAL PATIENT POPULATIONS

APPENDICES

APPENDIX A Assessment of AUC

APPENDIX B Ionization and the pH Partition Hypothesis

APPENDIX C Distribution of Drugs Extensively Bound to Plasma Proteins

APPENDIX D Plasma-to-Blood Concentration Ratio

APPENDIX E Well-Stirred Model of Hepatic Clearance

APPENDIX F Absorption Kinetics

APPENDIX G Wagner-Nelson Method

APPENDIX H Mean Residence Time

APPENDIX I Amount of Drug in Body on Accumulation to Plateau

APPENDIX J Introduction to MS Excel Simulations

APPENDIX K Answers to Study Problems

Index

 

An aparitie	16 Aug. 2019
Autor	Ph.D Schmidt, Dr. Stephan , Hartmut Derendorf (
Dimensiuni	18.54 x 4.32 x 25.65 cm
Editura	LWW
Format	Hardcover
ISBN	9781496385048
Limba	Engleza
Nr pag	864