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1. Introduction to Biopharmaceutics and Pharmacokinetics
Drug Product Performance
Biopharmaceutics
Pharmacokinetics
Pharmacodynamics
Clinical Pharmacokinetics
Practical Focus
Pharmacodynamics
Drug Exposure and Drug Response
Toxicokinetics and Clinical Toxicology
Measurement of Drug Concentrations
Basic Pharmacokinetics and Pharmacokinetic Models
Chapter Summary
Learning Questions
Answers
References
Bibliography
2. Mathematical Fundamentals in Pharmacokinetics
Calculus
Graphs
Practice Problem
Mathematical Expressions and Units
Units for Expressing Blood Concentrations
Measurement and Use of Significant Figures
Practice Problem
Practice Problem
Rates and Orders of Processes
Chapter Summary
Learning Questions
Answers
References
3. Biostatistics
Variables
Types of Data (Nonparametric Versus Parametric)
Distributions
Measures of Central Tendency
Measures of Variability
Hypothesis Testing
Statistically Versus Clinically Significant Differences
Statistical Inference Techniques in Hypothesis Testing for Parametric Data
Goodness of Fit
Statistical Inference Techniques for Hypothesis Testing With Nonparametric Data
Controlled Versus Noncontrolled Studies
Blinding
Confounding
Validity
Bioequivalence Studies
Evaluation of Risk for Clinical Studies
Chapter Summary
Learning Questions
Answers
References
4. One-Compartment Open Model: Intravenous Bolus Administration
Elimination Rate Constant
Apparent Volume of Distribution
Clearance
Clinical Application
Calculation of k From Urinary Excretion Data
Practice Problem
Practice Problem
Clinical Application
Chapter Summary
Learning Questions
Answers
Reference
Bibliography
5. Multicompartment Models: Intravenous Bolus Administration
Two-Compartment Open Model
Clinical Application
Practice Problem
Practical Focus
Practice Problem
Practical Focus
Three-Compartment Open Model
Clinical Application
Clinical Application
Determination of Compartment Models
Practical Focus
Clinical Application
Practical Problem
Clinical Application
Practical Application
Clinical Application
Chapter Summary
Learning Questions
Answers
References
Bibliography
6. Intravenous Infusion
One-Compartment Model Drugs
Infusion Method for Calculating Patient Elimination Half-Life
Loading Dose Plus IV Infusion—One-Compartment Model
Practice Problems
Estimation of Drug Clearance and VD From Infusion Data
Intravenous Infusion of Two-Compartment Model Drugs
Practical Focus
Chapter Summary
Learning Questions
Answers
Reference
Bibliography
7. Drug Elimination, Clearance, and Renal Clearance
Drug Elimination
Drug Clearance
Clearance Models
The Kidney
Clinical Application
Practice Problems
Renal Clearance
Determination of Renal Clearance
Practice Problem
Practice Problem
Relationship of Clearance to Elimination Half-Life and Volume of Distribution
Chapter Summary
Learning Questions
Answers
References
Bibliography
8. Pharmacokinetics of Oral Absorption
Introduction
Basic Principles of Physiologically Based Absorption Kinetics (Bottom-Up Approach)
Absoroption Kinetics (The Top-Down Approach)
Pharmacokinetics of Drug Absorption
Significance of Absorption Rate Constants
Zero-Order Absorption Model
Clinical Application—Transdermal Drug Delivery
First-Order Absorption Model
Practice Problem
Chapter Summary
Answers
Application Questions
References
Bibliography
9. Multiple-Dosage Regimens
Drug Accumulation
Clinical Example
Repetitive Intravenous Injections
Intermittent Intravenous Infusion
Clinical Example
Estimation of k and VD of Aminoglycosides in Clinical Situations
Multiple-Oral-Dose Regimen
Loading Dose
Dosage Regimen Schedules
Clinical Example
Practice Problems
Chapter Summary
Learning Questions
Answers
References
Bibliography
10. Nonlinear Pharmacokinetics
Saturable Enzymatic Elimination Processes
Practice Problem
Practice Problem
Drug Elimination by Capacity-Limited Pharmacokinetics: One-Compartment Model, IV Bolus Injection
Practice Problems
Clinical Focus
Clinical Focus
Drugs Distributed as One-Compartment Model and Eliminated by Nonlinear Pharmacokinetics
Clinical Focus
Chronopharmacokinetics and Time-Dependent Pharmacokinetics
Clinical Focus
Bioavailability of Drugs That Follow Nonlinear Pharmacokinetics
Nonlinear Pharmacokinetics Due to Drug–Protein Binding
Potential Reasons for Unsuspected Nonlinearity
Dose-Dependent Pharmacokinetics
Clinical Example
Chapter Summary
Learning Questions
Answers
References
Bibliography
11. Physiologic Drug Distribution and Protein Binding
Physiologic Factors of Distribution
Clinical Focus
Apparent Volume Distribution
Practice Problem
Protein Binding of Drugs
Clinical Examples
Effect of Protein Binding on the Apparent Volume of Distribution
Practice Problem
Clinical Example
Relationship of Plasma Drug–Protein Binding to Distribution and Elimination
Clinical Examples
Clinical Example
Determinants of Protein Binding
Clinical Example
Kinetics of Protein Binding
Practical Focus
Determination of Binding Constants and Binding Sites by Graphic Methods
Clinical Significance of Drug–Protein Binding
Clinical Example
Clinical Example
Modeling Drug Distribution
Chapter Summary
Learning Questions
Answers
References
Bibliography
12. Drug Elimination and Hepatic Clearance
Route of Drug Administration and Extrahepatic Drug Metabolism
Practical Focus
Hepatic Clearance
Extrahepatic Metabolism
Enzyme Kinetics—Michaelis–Menten Equation
Clinical Example
Practice Problem
Anatomy and Physiology of the Liver
Hepatic Enzymes Involved in the Biotransformation of Drugs
Drug Biotransformation Reactions
Pathways of Drug Biotransformation
Drug Interaction Example
Clinical Example
First-Pass Effects
Hepatic Clearance of a Protein-Bound Drug: Restrictive and Nonrestrictive Clearance From Binding
Biliary Excretion of Drugs
Clinical Example
Role of Transporters on Hepatic Clearance and Bioavailability
Chapter Summary
Learning Questions
Answers
References
Bibliography
13. Pharmacogenetics and Drug Metabolism
Genetic Polymorphisms
Cytochrome P-450 Isozymes
Phase II Enzymes
Transporters
Chapter Summary
Glossary
Abbreviations
References
14. Physiologic Factors Related to Drug Absorption
Drug Absorption and Design of a Drug Product
Route of Drug Administration
Nature of Cell Membranes
Passage of Drugs Across Cell Membranes
Drug Interactions in the Gastrointestinal Tract
Oral Drug Absorption
Oral Drug Absorption During Drug Product Development
Methods for Studying Factors That Affect Drug Absorption
Effect of Disease States on Drug Absorption
Miscellaneous Routes of Drug Administration
Chapter Summary
Learning Questions
Answers to Questions
References
Bibliography
15. Biopharmaceutic Considerations in Drug Product Design and In Vitro Drug Product Performance
Biopharmaceutic Factors and Rationale for Drug Product Design
Rate-Limiting Steps in Drug Absorption
Physicochemical Properties of the Drug
Formulation Factors Affecting Drug Product Performance
Drug Product Performance, In Vitro: Dissolution and Drug Release Testing
Compendial Methods of Dissolution
Alternative Methods of Dissolution Testing
Dissolution Profile Comparisons
Meeting Dissolution Requirements
Problems of Variable Control in Dissolution Testing
Performance of Drug Products: In Vitro–In Vivo Correlation
Approaches to Establish Clinically Relevant Drug Product Specifications
Drug Product Stability
Considerations in the Design of a Drug Product
Drug Product Considerations
Clinical Example
Chapter Summary
Learning Questions
Answers
References
Bibliography
16. Drug Product Performance, In Vivo: Bioavailability and Bioequivalence
Drug Product Performance
Purpose of Bioavailability and Bioequivalence Studies
Relative and Absolute Availability
Practice Problem
Methods for Assessing Bioavailability and Bioequivalence
In Vivo Measurement of Active Moiety or Moieties in Biological Fluids
Bioequivalence Studies Based on Pharmacodynamic Endpoints—In Vivo Pharmacodynamic (PD) Comparison
Bioequivalence Studies Based on Clinical Endpoints—Clinical Endpoint Study
In Vitro Studies
Other Approaches Deemed Acceptable (by the FDA)
Bioequivalence Studies Based on Multiple Endpoints
Bioequivalence Studies
Design and Evaluation of Bioequivalence Studies
Study Designs
Crossover Study Designs
Clinical Example
Clinical Example
Pharmacokinetic Evaluation of the Data
The Partial AUC in Bioequivalence Analysis
Examples of Partial AUC Analyses
Bioequivalence Examples
Study Submission and Drug Review Process
Waivers of In Vivo Bioequivalence Studies (Biowaivers)
The Biopharmaceutics Classification System (BCS)
Generic Biologics (Biosimilar Drug Products)
Clinical Significance of Bioequivalence Studies
Special Concerns in Bioavailability and Bioequivalence Studies
Generic Substitution
Glossary
Chapter Summary
Learning Questions
Answers
References
17. Biopharmaceutical Aspects of the Active Pharmaceutical Ingredient and Pharmaceutical Equivalence
Introduction
Pharmaceutical Alternatives
Practice Problem
Bioequivalence of Drugs With Multiple Indications
Formulation and Manufacturing Process Changes
Size, Shape, and Other Physical Attributes of Generic Tablets and Capsules
Changes to an Approved NDA or ANDA
The Future of Pharmaceutical Equivalence and Therapeutic Equivalence
Biosimilar Drug Products
Historical Perspective
Chapter Summary
Learning Questions
Answers
References
18. Impact of Biopharmaceutics on Drug Product Quality and Clinical Efficacy
Risks From Medicines
Risk Assessment
Drug Product Quality and Drug Product Performance
Pharmaceutical Development
Example of Quality Risk
Excipient Effect on Drug Product Performance
Practical Focus
Quality Control and Quality Assurance
Practical Focus
Risk Management
Scale-Up and Postapproval Changes (SUPAC)
Practical Focus
Product Quality Problems
Postmarketing Surveillance
Glossary
Chapter Summary
Learning Questions
Answers
References
Bibliography
19. Modified-Release Drug Products and Drug Devices
Modified-Release (MR) Drug Products and Conventional (Immediate-Release, IR) Drug Products
Biopharmaceutic Factors
Dosage Form Selection
Advantages and Disadvantages of Extended-Release Products
Kinetics of Extended-Release Dosage Forms
Pharmacokinetic Simulation of Extended-Release Products
Clinical Examples
Types of Extended-Release Products
Considerations in the Evaluation of Modified-Release Products
Evaluation of Modified-Release Products
Evaluation of In Vivo Bioavailability Data
Chapter Summary
Learning Questions
References
Bibliography
20. Targeted Drug Delivery Systems and Biotechnological Products
Biotechnology
Drug Carriers and Targeting
Targeted Drug Delivery
Pharmacokinetics of Biopharmaceuticals
Bioequivalence of Biotechnology-Derived Drug Products
Learning Questions
Answers
References
Bibliography
21. Relationship Between Pharmacokinetics and Pharmacodynamics
Pharmacokinetics and Pharmacodynamics
Relationship of Dose to Pharmacologic Effect
Relationship Between Dose and Duration of Activity (teff), Single IV Bolus Injection
Practice Problem
Effect of Both Dose and Elimination Half-Life on the Duration of Activity
Effect of Elimination Half-Life on Duration of Activity
Substance Abuse Potential
Drug Tolerance and Physical Dependency
Hypersensitivity and Adverse Response
Chapter Summary
Learning Questions
Answers
References
22. Application of Pharmacokinetics to Clinical Situations
Medication Therapy Management
Individualization of Drug Dosage Regimens
Therapeutic Drug Monitoring
Clinical Example
Clinical Example
Design of Dosage Regimens
Conversion From Intravenous Infusion to Oral Dosing
Determination of Dose
Practice Problems
Effect of Changing Dose ond Dosing Interval on ... and ...
Determination of Frequency of Drug Administration
Determination of Both Dose and Dosage Interval
Practice Problem
Determination of Route of Administration
Dosing Infants and Children
Practice Problem
Dosing the Elderly
Practice Problems
Clinical Example
Dosing the Obese Patients
Pharmacokinetics of Drug Interactions
Inhibition of Drug Metabolism
Inhibition of Monoamine Oxidase (MAO)
Induction of Drug Metabolism
Inhibition of Drug Absorption
Inhibition of Biliary Excretion
Altered Renal Reabsorption Due to Changing Urinary pH
Practical Focus
Effect of Food on Drug Disposition
Adverse Viral Drug Interactions
Population Pharmacokinetics
Clinical Example
Regional Pharmacokinetics
Chapter Summary
Learning Questions
Answers
References
Bibliography
23. Application of Pharmacokinetics to Specific Populations: Geriatric, Obese, and Pediatric Patients
Specific and Special Populations
Module I: Application of Pharmacokinetics to the Geriatric Patients
Summary
Learning Questions
Answers
References
Further Reading
Module II: Application of Pharmacokinetics to the Obese Patients
Summary
Learning Questions
Answers
References
Module III: Application of Pharmacokinetics to the Pediatric Patients
Summary
Learning Questions
Answers
References
24. Dose Adjustment in Renal and Hepatic Disease
Renal Impairment
Pharmacokinetic Considerations
General Approaches for Dose Adjustment in Renal Disease
Measurement of Glomerular Filtration Rate
Serum Creatinine Concentration and Creatinine Clearance
Practice Problems
Dose Adjustment for Uremic Patients
Practice Problem
Practice Problem
Practice Problems
Practice Problem
Extracorporeal Removal of Drugs
Practice Problem
Clinical Examples
Effect of Hepatic Disease on Pharmacokinetics
Practice Problem
Chapter Summary
Learning Questions
Answers
References
Bibliography
25. Empirical Models, Mechanistic Models, Statistical Moments, and Noncompartmental Analysis
Empirical Models
Mechanistic Models
Noncompartmental Analysis
Comparison of Different Approaches
Selection of Pharmacokinetic Models
Chapter Summary
Learning Questions
Answers
References
Bibliography
Appendix A Applications of Software Packages in Pharmacokinetics
Appendix B Glossary
Index
