Handbook of Pharmacokinetics and Toxicokinetics

Cover
Half Title
Title Page
Copyright Page
Dedication
Table of Contents
Preface
Chapter 1 Pharmacokinetics and Toxicokinetics
1.1 Introduction
1.2 Pharmacokinetics and Pharmacodynamics
1.2.1 Clinical Pharmacokinetics/Pharmacodynamics
1.2.2 PK/PD Modeling and Pharmacometrics
1.2.3 Population PK and PK/PD Modeling
1.2.3.1 Influences of Genetics and Genomics on PK/PD and TK/TD
1.2.3.2 Biomarkers
1.3 Toxicokinetics and Toxicodynamics
1.3.1 TK/TD Modeling, Population Toxicokinetics, and Toxicogenetics
1.4 Basic Concepts and Assumptions of PK and TK
1.5 Introduction to the Routes of Administration
References
Chapter 2 PK/TK Considerations of Auricular (Otic) – Buccal/Sublingual, and Ocular/Ophthalmic Routes of Administration
2.1 Auricular or OTIC Route of Administration
2.1.1 Overview
2.1.2 Blood-Labyrinth-Barrier and Auricular Absorption, Distribution, Metabolism, and Excretion
2.1.2.1 Syndromes and the Sites of Absorption
2.1.2.2 Auricular Distribution, Metabolism, and Excretion
2.1.3 Auricular Rate Equations and PK/TK Models
2.2 Buccal and Sublingual Routes of Administration
2.2.1 Overview
2.2.2 Buccal and Sublingual ADME and Related Rate Equations
2.2.3 Saliva
2.3 Ocular/Ophthalmic Routes of Administration
2.3.1 Overview
2.3.2 The Blood Aqueous Barrier
2.3.3 The Blood-Retinal Barrier
2.3.3.1 BRB Efflux Transporters
2.3.3.2 BRB Influx Transporters
2.3.4 Kinetics of BRB Influx Permeability Clearance – Small Water-Soluble Compounds Given Systemically
2.3.5 Recommended Ocular Routes for Drug Administration
2.3.5.1 Conjunctival Route of Administration
2.3.5.2 Subconjunctival Route of Administration
2.3.5.3 Intracameral Route of Administration
2.3.5.4 Intravitreal Route of Administration
2.3.5.5 Intracorneal Route of Administration
2.3.5.6 Retrobulbar, Peribulbar, and Sub-Tenon Routes of Administration
References
Chapter 3 PK-TK Considerations of Nasal, Pulmonary and Oral Routes of Administration
3.1 Nasal Route of Administration/Exposure
3.1.1 Vestibule, Atrium, Valves, and Turbines
3.1.2 Mucosal Epithelium
3.1.3 Olfactory Epithelium
3.1.4 Nasal ADME of Xenobiotics
3.1.5 Nasal Rate Equations – PK/TK Models
3.1.5.1 A Nose-to-Systemic Circulation PK/TK Model
3.1.5.2 An Inclusive Nose-to-Brain PK/TK Model
3.2 Pulmonary Route of Administration/Exposure
3.2.1 Overview
3.2.2 Morphological Differences of Airways Among Species
3.2.3 Pulmonary Microbiome
3.2.4 ADME of Xenobiotics in the Pulmonary Tract
3.2.4.1 Pulmonary Absorption, Deposition, and Clearance
3.2.4.2 Transport Proteins of Pulmonary Tract
3.2.4.3 Respiratory Tract Metabolic Enzymes – Lung Metabolism of Xenobiotics
3.2.4.4 Pulmonary Deposition and Disposition of Particles
3.2.4.5 Pulmonary Absorption of Gases and Vapors
3.2.4.6 Relevant Pulmonary Kinetic Parameters
3.2.4.7 Role of the Lungs in PK/TK of Xenobiotics: Pulmonary First-Pass Metabolism
3.2.4.8 Pulmonary Rate Equations
3.3 Gastrointestinal (Oral) Route of Administration or Exposure
3.3.1 Overview
3.3.2 Physiologic and Dynamic Attributes of the GI Tract Influencing Xenobiotic Absorption
3.3.2.1 Regional pH of GI Tract and pH-Partition Theory
3.3.2.2 Absorptive Surface Area
3.3.2.3 Gastric Emptying and Gastric Accommodation
3.3.2.4 Intestinal Motility: Small Intestinal Transit Time
3.3.2.5 Role of Bile Salts
3.3.2.6 Hepatic First-Pass Metabolism (Pre-systemic Hepatic Extraction)
3.3.2.7 Gastrointestinal Metabolism – Role of CYP450 Isozymes
3.3.2.8 GI Tract Influx and Efflux Transport Proteins
3.3.2.9 Role of Intestinal Microbiotas
References
Chapter 4 PK/TK Considerations of Intra-Arterial, Intramuscular, Intraperitoneal, Intravenous, and Subcutaneous Routes of Administration
4.1 Intra-Arterial Route of Administration
4.1.1 Overview
4.1.2 Intra-Arterial PK/TK Remarks
4.2 Intramuscular Route of Administration
4.2.1 Overview
4.2.2 ADME of Intramuscular Route of Administration
4.2.2.1 Rate Equations of Intramuscularly Injected Xenobiotics
4.3 Intraperitoneal Route of Administration
4.3.1 Overview
4.3.1.1 Applications of the IP Route of Administration
4.3.2 Kinetics of Intraperitoneal Transport of Xenobiotics
4.4 Intravenous Route of Administration
4.4.1 Overview
4.4.1.1 Intravenous Injection Drawbacks
4.4.1.2 Bolus Injection, Continuous Infusion, Intermittent Infusion
4.4.2 Intravenous PK/TK Analysis
4.5 Subcutaneous Route of Administration
4.5.1 Overview
4.5.2 Rate Equations of Subcutaneously Injected Xenobiotics
4.5.2.1 Subcutaneous Diffusion Rate-Limited Model
4.5.2.2 Subcutaneous Dissolution Rate-Limited Model
4.5.2.3 Subcutaneous Capacity-Limited Model
4.5.2.4 Subcutaneous Models Based on Diffusion Equations
4.5.2.5 Other PK Models for Subcutaneous Insulin
References
Chapter 5 PK/TK Considerations of Transdermal, Intradermal, and Intraepidermal Routes of Administration
5.1 Transdermal Route of Administration
5.1.1 Overview
5.1.2 Stratum Corneum
5.1.3 Epidermis
5.1.4 Dermis
5.1.4.1 Dermis Cells
5.1.4.2 Dermis Appendages
5.1.5 Transdermal Absorption, Metabolism, and Disposition
5.1.5.1 Transdermal Absorption
5.1.5.2 Cutaneous Metabolism of Xenobiotics
5.1.5.3 Skin Transport Proteins
5.1.6 Mathematical Interpretations of Transdermal Absorption of Xenobiotics
5.1.6.1 Diffusion Models
5.1.6.2 Skin-Perm Model
5.1.6.3 One-Layered Diffusion Model
5.1.6.4 Two-Layered Diffusion Model
5.1.6.5 Compartmental Analysis
5.1.6.6 Diffusion–Diffusion Model and Statistical Moments for Percutaneous Absorption
5.1.6.7 Physiological Modeling of Percutaneous Absorption of Xenobiotics
5.1.6.8 Six-Compartment Intradermal Disposition Kinetics of Xenobiotics with Contralateral Compartments
5.2 Intradermal Route of Administration
5.2.1 Overview
5.2.2 PK/TK Parameters and Constants of Drug Absorption from Intradermal Space to Blood
5.3 Intraepidermal Route of Administration
5.3.1 Overview
References
Chapter 6 PK/TK Considerations of Rectal, Vaginal, and Intraovarian Routes of Administration
6.1 Rectal Route of Administration
6.1.1 Overview
6.1.2 Pharmacokinetic Considerations of the Rectal Route of Administration
6.2 Vaginal Route of Administration
6.2.1 Overview
6.2.2 Vaginal Microbiota
6.2.3 Pharmacokinetic Considerations of the Vaginal Route of Administration
6.3 Intraovarian Route of Administration
6.3.1 Overview
References
Chapter 7 PK/TK Considerations of Absorption Mechanisms and Rate Equations
7.1 Introduction
7.2 Passive Diffusion
7.2.1 Transcellular and Paracellular Diffusion
7.2.1.1 Transcellular and Paracellular Transport Rate Equations
7.2.2 Partition Coefficient
7.2.2.1 CLOGPcoeff
7.2.2.2 MLOGPcoeff
7.2.3 Distribution Coefficient
7.2.4 Diffusion Coefficient
7.2.5 Permeation and Permeability Constant
7.2.5.1 Estimation of Apparent Permeability Constant Using Caco-2 Cells
7.3 Carrier-Mediated Transcellular Diffusion
7.4 Transcellular Diffusion Subjected to P-Glycoprotein Efflux
7.4.1 Overview
7.4.2 Pgp Structure and Function
7.4.3 Pgp Computational Equations
7.5 Active Transport
7.6 Endocytosis and Pinocytosis
7.7 Solvent Drag, Osmosis, and Two-Pore Theory
7.8 Ion-Pair Absorption
References
Chapter 8 PK – TK Considerations of Distribution Mechanisms and Rate Equations
8.1 Introduction
8.2 Factors Influencing the Distribution of Xenobiotics in the Body
8.2.1 Influence of Total Body Water on Xenobiotic Distribution
8.2.2 Effect of Blood Flow and Organ/Tissue Perfusion on Xenobiotic Distribution
8.2.2.1 Perfusion-Limited Distribution and Permeability-Limited Distribution (Transcapillary Exchange of Xenobiotics)
8.2.3 Effect of Binding to Plasma Proteins on Xenobiotic Distribution
8.2.3.1 Estimation of Protein-Binding Parameters
8.2.4 Influence of Physicochemical Characteristics of Xenobiotics on Their Distribution
8.2.5 Influence of Extent of Penetration Through the Physiological Barriers, and Parallel Removal Processes on Xenobiotic Distribution
8.2.6 Physiological Barriers
8.2.6.1 Blood–Brain Barrier
8.2.6.2 Blood–Lymph Barrier
8.2.6.3 Placental Barrier
8.2.6.4 Blood–Testis Barrier
8.2.6.5 Blood–Aqueous Humor Barrier (BAB) – also Read Chapter 2, Section 2.3.2
8.2.7 Effect of Body Weight and Composition on Xenobiotic Distribution
8.2.7.1 Ideal Body Weight (IBW in kg)
8.2.7.2 Body Surface Area (BSA in m2)
8.2.7.3 Body Mass Index (BMI in kg/m2)
8.2.7.4 Lean Body Mass (LBM in kg)
8.2.8 Impact of Disease States on Xenobiotic Distribution
8.2.8.1 Congestive Heart Failure (CHF)
8.2.8.2 Chronic Renal Failure (CRF)
8.2.8.3 Hepatic Diseases
8.2.8.4 Cystic Fibrosis (CF)
8.2.8.5 Other Conditions
8.3 Applications and Case Studies
References
Chapter 9 PK/TK Considerations of Xenobiotic Metabolism Mechanisms and Rate Equations
9.1 Introduction
9.2 Liver
9.3 Metabolic Pathways
9.3.1 Phase I Metabolism
9.3.1.1 Flavin-Containing Monooxygenases
9.3.1.2 Flavin-Containing Amine Oxidoreductases
9.3.1.3 Epoxide Hydrolases
9.3.1.4 Cytochrome P450
9.3.1.5 Alcohol Dehydrogenase
9.3.1.6 Diamine Oxidase (Histaminase)
9.3.1.7 Aldehyde Dehydrogenases
9.3.1.8 Xanthine Oxidase
9.3.1.9 Carboxylesterases
9.3.1.10 Peptidase (Protease/Proteinase)
9.3.2 Phase II Metabolism: Conjugation
9.3.2.1 Glucuronidation
9.3.2.2 Sulfation
9.3.2.3 Methylation
9.3.2.4 Acetylation (Acylation)
9.3.2.5 Glutathione Conjugation
9.3.2.6 Amino Acid Conjugation
9.3.3 In Vitro Systems for Xenobiotics Metabolism Study
9.3.3.1 Subcellular Fractions
9.3.3.2 Cellular Fractions – Hepatocytes
9.3.3.3 Organ Fractions (Precision Cut Liver Slices)
9.3.3.4 In-Situ and Ex-Vivo Liver Perfusion Techniques
9.3.3.5 Antibodies Against CYP Proteins
9.3.3.6 bDNA Probes
9.3.3.7 Pure and Recombinant Enzymes
9.3.3.8 Cell Lines
9.3.4 In Vivo Samples for Xenobiotic Metabolism Study
9.3.4.1 Serum and Plasma Samples
9.3.4.2 Urine Samples
9.3.4.3 Bile Samples
9.3.4.4 Portal Vein Cannulation
9.4 Kinetics of In Vitro Metabolism
9.4.1 Michaelis–Menten Kinetics
9.4.2 In Vitro Intrinsic Metabolic Clearance
9.4.3 The Catalytic Efficiency and Turnover Number
9.4.4 Estimation of the Michaelis–Menten Parameters
9.4.4.1 Lineweaver–Burk Plot or Double Reciprocal Plot
9.4.4.2 Hanes–Woolfe Plot
9.4.4.3 Eadie–Hofstee Plot
9.4.4.4 Direct Linear Plot
9.4.4.5 Hill Plot
9.4.5 Assimilation of Intrinsic Clearance in Hepatic Clearance Using Liver Models
9.4.5.1 The Well-Stirred Model (Venous Equilibration Model)
9.4.5.2 The Parallel-Tube Model (Undistributed Sinusoidal Model)
9.4.5.3 The Dispersion Model
9.4.5.4 Physiological PK/TK Organ Model for the Liver
9.4.5.5 Zonal Liver Model
9.4.6 Inhibition of Xenobiotic Metabolism
9.4.6.1 Classifications of Metabolic Inhibition
9.4.7 Induction of Xenobiotic Metabolism
9.5 Applications and Case Studies
References
Chapter 10 PK – TK Considerations of Renal Function and Elimination of Xenobiotics - Estimation of Parameters and Constants
10.1 Introduction
10.2 Glomerular Filtration
10.3 Tubular Reabsorption and Secretion
10.4 Loop of Henle, Distal Tubule, and Collecting Ducts
10.5 Estimation of GFR
10.5.1 Exogenous Markers of GFR
10.5.1.1 Radioisotope-Labeled Compounds
10.5.1.2 Inulin
10.5.1.3 Iohexol
10.5.2 Endogenous Markers of GFR (GFR Biomarkers)
10.5.2.1 Creatinine Clearance
10.5.2.2 Cystatin C
10.6 PK/TK Analysis of Urinary Data
10.6.1 PK/TK Analysis of Urinary Excretion of Unchanged Xenobiotic – Intravenous Bolus Injection
10.6.1.1 Rate Plot – Intravenous Bolus Dose
10.6.1.2 ARE Plot aka Sigma-Minus Plot – Intravenous Bolus Dose
10.6.2 PK/TK Analysis of Urinary Elimination of Xenobiotic Metabolites Following Intravenous Bolus Injection
10.6.2.1 Amount of Metabolite Remaining to be Eliminated from the Body Following IV Bolus Dose Administration
10.6.2.2 Urinary Elimination Rate of Metabolite and Estimation of Metabolic Rate Constant
10.6.3 PK/TK Analysis of Urinary Excretion of Unchanged Xenobiotic Following Zero-Order Intravenous Infusion
10.6.3.1 Urinary Excretion Rate of Unchanged Xenobiotic During Zero-Order Intravenous Infusion and After Attaining the Steady-State Level
10.6.3.2 Cumulative Amount of Urinary Excretion of Unchanged Xenobiotic During Zero-Order Intravenous Infusion
10.6.4 PK/TK Analysis of Urinary Excretion of Unchanged Xenobiotic Following First-Order Absorption from an Extravascular Route of Administration
10.6.4.1 Urinary Excretion Rate of Unchanged Xenobiotic Following First-Order Absorption into the Systemic Circulation and Estimation of Absorption Rate Constant
10.6.4.2 Amount of Xenobiotic Remaining to be Excreted Unchanged in the Urine Following the First-Order Absorption into the Systemic Circulation from an Extravascular Route of Administration
10.6.5 PK/TK Analysis of Urinary Excretion of Unchanged Xenobiotics that Follow the Two-Compartment Model Subsequent to Intravenous Bolus Injection
10.6.5.1 Urinary Excretion Rate of Unchanged Xenobiotic Following Intravenous Bolus Injection – Two-Compartment Model
10.6.5.2 Amount of Xenobiotic Remaining to be Excreted Unchanged in the Urine Following an Intravenous Bolus Injection – Two-Compartment Model
10.6.6 General Equations of PK/TK Multicompartment Analysis of Urinary Excretion Data – First-Order Absorption and Intravenous Infusion
10.6.7 PK/TK Analysis of Urinary Excretion Data Using Principles of Non-Compartmental Analysis
10.7 Renal Metabolism
10.8 Renal Mechanistic Models
10.9 Estimation of PK/TK Parameters and Constants of Xenobiotics Elimination When Using Renal Replacement Therapy – Dialysis
10.9.1 Overview
10.9.2 Hemodialysis
10.9.3 Peritoneal Dialysis
10.9.4 Composition of Dialysate
10.9.5 Dialysis Clearance
10.9.6 Effects of Dialysis on PK/TK Parameters and Constants
10.10 Applications and Case Studies
References
Chapter 11 Elimination Rates and Clearances (Excretion + Metabolism)
11.1 Introduction
11.2 Rates of Elimination
11.3 Extraction Ratio
11.4 Clearances
11.4.1 Estimation of Clearance Using Theoretical Models
11.4.1.1 Well-Stirred Model
11.4.1.2 Parallel Model
11.4.1.3 Dispersion Model
11.4.2 Clearance Scale-Up in Mammalian Species
11.4.2.1 Extrapolation of Clearance from Animal to Human
11.4.2.2 Body-Weight Dependent Extrapolation of Clearance in Humans
11.4.3 Clearance Estimation in Linear PK/TK
11.4.4 Clearance Estimation in Nonlinear PK/TK
11.4.4.1 Nonlinear Clearance in Target-Mediated Drug Disposition
References
Chapter 12 Approaches in PK/PD and TK/TD Mathematical Modeling
12.1 Introduction
12.2 Physiologically Based PK/TK Models
12.2.1 Description
12.2.2 Model Development
12.2.2.1 Flow-Limited (Perfusion-Limited) Models
12.2.2.2 Permeability-Limited (Membrane-Limited) Models
12.2.2.3 Variability of Physiological/Biochemical Key Parameters
12.2.3 Predictive Capability and Sensitivity Analysis
12.3 Linear PK/TK Compartmental Analysis
12.3.1 Linear Dose-Independent Compartmental Analysis
12.3.1.1 Mathematical Descriptions of a Xenobiotic Administered via an Extravascular Route of Administration: Time Course of the Amount Change at the Site of Absorption in the Body and the Eliminated Amount from the Body
12.3.1.2 Mathematical Description of a Xenobiotic Administered Intravenously – Time Course of the Amount Change in the Body, Formation of Metabolite(s), and Elimination from the Body
12.3.1.3 Mathematical Relationships of the Central Compartment for an Intravenously Administered Xenobiotic that Follows Multicompartment Model: Use of Input-Disposition Function and General Partial Fraction Theorem
12.3.1.4 Mathematical Relationships of the Peripheral Compartment for an Intravenously Administered Xenobiotic that Follows Multicompartment Model: Use of Input-Disposition Function and General Partial Fraction Theorem
12.3.1.5 Mathematical Relationships When a Xenobiotic and Its Metabolite(s) Follow Multicompartmental Model – Intravenous Bolus Dose
12.3.2 Dose-Dependent Compartmental Analysis
12.3.2.1 Compartmental Models with Michaelis–Menten Kinetics
12.4 Non-Compartmental Analysis Based on Statistical Moment Theory
12.4.1 Overview
12.4.2 Mean Residence Time and Mean Input Time
12.4.3 Total Body Clearance and Apparent Volume of Distribution
12.5 PK-PD and TK-TD Modeling
12.5.1 Overview
12.5.2 Xenobiotic–Receptor Interaction and the Law of Mass Action
12.5.3 Pharmacodynamic Models of Plasma Concentration and Response
12.5.3.1 Linear Pharmacodynamic Model
12.5.3.2 Log-Linear Pharmacodynamic Model
12.5.3.3 Nonlinear Hyperbolic Emax Model
12.5.3.4 Non-Hyperbolic Sigmoidal Model
12.5.4 PK/PD and TK/TD Models
12.5.4.1 Linking the Nonlinear Hyperbolic Emax Concept to Compartmental Models
12.5.4.2 Linking Non-Hyperbolic Sigmoidal Model to PK/TK Models with Different Inputs
12.5.5 The Effect Compartment
12.5.5.1 PK/TK Models Connected to the Effect Compartment
12.6 Physiologically Based PK/TK Models with Effect Compartment
12.7 Hysteresis Loops in PK/PD or TK/TD Relationships
12.8 Target-Mediated Drug Disposition Models
12.8.1 One-Compartment TMDD Models
12.8.2 Two-Compartment TMDD Models
References
Chapter 13 Practical Applications of PK/TK Models: Instantaneous Exposure to Xenobiotics - Single Intravenous Bolus Injection
13.1 Introduction
13.2 Linear One-Compartment Open Model – Intravenous Bolus Injection
13.2.1 Half-Life of Elimination
13.2.2 Time Constant
13.2.3 Apparent Volume of Distribution
13.2.4 Total Body Clearance
13.2.5 Duration of Action
13.2.6 Estimation of Fraction of Dose in the Body at a Given Time
13.2.7 Estimation of Fraction of Dose Eliminated by All Routes of Elimination at a Given Time
13.2.8 Determination of the Area Under Plasma Concentration–Time Curve after Intravenous Bolus Injection
13.3 Linear Two-Compartment Open Model with Bolus Injection in the Central Compartment and Elimination from the Central Compartment
13.3.1 Equations of the Two-Compartment Model
13.3.2 Estimation of the Initial Plasma Concentration and Volumes of Distribution, Two-Compartment Model
13.3.3 Estimation of the Rate Constants of Distribution and Elimination
13.3.4 Half-Lives of the Two-Compartment Model
13.3.4.1 Biological Half-Life – Two-Compartment Model
13.3.4.2 Elimination Half-Life – Two-Compartment Model
13.3.4.3 Half-Life of – Two-Compartment Model
13.3.4.4 Half-Life of
13.3.4.5 Half-Life of
13.3.5 Determination of the Area Under the Plasma Concentration–Time Curve, Volumes of Distribution, and Clearances – Two-Compartment Model
13.3.6 Assessment of the Time Course of Xenobiotics in the Peripheral Compartment – Two-Compartment Model
13.4 Linear Two-Compartment Open Model with Bolus Injection in the Central Compartment and Elimination from the Peripheral Compartment
13.5 Linear Three-Compartment Open Model with Intravenous Bolus Injection and Elimination from the Central Compartment
13.6 Linear Three-Compartment Open Model with Intravenous Bolus Injection in the Central Compartment and Elimination from a Peripheral Compartment
13.7 Model Selection
13.8 Applications and Case Studies
References
Chapter 14 Practical Applications of PK/TK Models: Continuous Zero‑Order Exposure to Xenobiotics - Intravenous Infusion
14.1 Introduction
14.2 Compartmental Analysis
14.2.1 Linear One-Compartment Model with Zero-Order Input and First-Order Elimination
14.2.1.1 Estimation of the Time Required to Achieve Steady-State Plasma Concentration Using a Single Long-Term Infusion
14.2.1.2 Administration of Loading Dose with Intravenous Infusion to Achieve the Steady-State Level Without a Long Delay
14.2.1.3 Estimation of Plasma Concentration after Termination of Infusion
14.2.1.4 Estimation of Duration of Action in Infusion Therapy
14.2.2 Linear Two-Compartment Model with Zero-Order Input and First-Order Disposition
14.2.2.1 PK/TK Equations of Zero-Order Input into the Central Compartment with First-Order Elimination from the Central Compartment
14.2.3 Simultaneous Intravenous Bolus and Infusions Administration into the Central Compartment of a Two-Compartment Open Model with First-Order Elimination from the Central Compartment
14.2.4 Linear Two-Compartment Model with Two Consecutive Zero-Order Inputs, as Loading and Maintenance Doses, with First-Order Elimination from the Central Compartment
14.2.5 Three-Compartment Model with Zero-Order Input into the Central Compartment and First-Order Elimination from the Central Compartment
14.2.6 Three-Compartment Model with Zero-Order Input into the Central Compartment and First-Order Elimination from a Peripheral Compartment
14.3 Applications and Case Studies
References
Chapter 15 Practical Applications of PK/TK Model: First-Order Absorption via Extravascular Route - Oral Administration
15.1 Introduction
15.2 Compartmental Analysis
15.2.1 Linear One-Compartment Model with First-Order Input and First-Order Elimination
15.2.1.1 Initial Estimates of the Overall Elimination Rate Constant, and Absorption Rate Constant,
15.2.1.2 Estimation of Time to Peak Xenobiotic Concentration –
15.2.1.3 Estimation of Peak Concentration (Cpmax)
15.2.1.4 Estimation of the Area Under Plasma Concentration–Time Curve
15.2.1.5 Estimation of Total Body Clearance and Apparent Volume of Distribution
15.2.1.6 Fraction of Dose Absorbed (F) – Absolute Bioavailability
15.2.1.7 Duration of Action
15.2.2 Linear Two-Compartment Model with First-Order Input in the Central Compartment and First-Order Elimination from the Central Compartment
15.2.2.1 Equations of the Model
15.2.2.2 Interpretation of , , and
15.2.2.3 Parameters and Constants of the Two-Compartment Model with First-Order Input
15.2.2.4 Estimation of First-Order Absorption Rate Constant of a Two-Compartment Model – Loo–Riegelman Method
15.2.3 Linear Two-Compartment Model with First-Order Input in the Peripheral Compartment and First-Order Elimination from the Peripheral Compartment
15.2.4 Linear Three-Compartment Model with First-Order Input in the Central Compartment and First-Order Elimination from the Central Compartment
15.3 Applications and Case Studies
References
Chapter 16 Practical Application of PK/TK Models: Multiple Dosing Kinetics
16.1 Introduction
16.2 Kinetics of Multiple Intravenous Bolus Injections – One-Compartment Model
16.2.1 Equations of Plasma Peak and Trough Levels
16.2.2 Estimation of Time Required to Achieve Steady-State Plasma Levels
16.2.3 Average Steady-State Plasma Concentration
16.2.4 Loading Dose vs Maintenance Dose
16.2.5 Extent of Accumulation of Xenobiotics Multiple Dosing in the Body
16.2.6 Estimation of Plasma Concentration After the Last Dose
16.2.7 Design of a Dosing Regimen
16.2.7.1 Dosing Regimen Based on a Target Concentration
16.2.7.2 Dosing Regimen Based on Steady-State Peak and Trough Levels
16.2.7.3 Dosing Regimen Based on Minimum Steady-State Plasma Concentration
16.3 Kinetics of Multiple Oral Dose Administration
16.3.1 Peak, Trough, and Average Plasma Concentrations Before and After Achieving Steady-State Levels
16.3.2 Extent of Accumulation in Multiple Oral Dosing
16.3.3 Oral Administration of Loading Dose, Maintenance Dose and Designing a Dosing Regimen
16.4 Effect of Changing Dose, Dosing Interval, and Half-Life on the Accumulation in the Body and Fluctuation of Plasma Concentration
16.5 Effect of Irregular Dosing Interval on Plasma Concentrations of Multiple Dosing Regimen
16.6 Multiple Dosing Kinetics – Two-Compartment Model
16.6.1 Peak, Trough, and Average Plasma Concentrations Before and After Achieving the Steady-State Levels for Two-Compartment Model Xenobiotics Given Intravenously
16.6.2 Estimation of the Time Required to Achieve Steady-State Plasma Levels of Two-Compartment Model Xenobiotics Given Intravenously
16.6.3 Estimation of Fraction of Steady State, Accumulation Index, and Relationship Between Loading Dose vs Maintenance Dose
16.6.4 Evaluation of Plasma Level after the Last Dose
16.6.5 The Concept of Half-Life in Multiple Dosing Kinetics of Multicompartmental Models
16.7 Multiple Intravenous Infusions
16.8 Applications and Case Studies
References
Chapter 17 Biopharmaceutics Provisions, Classifications and Mechanistic Models
17.1 Introduction
17.2 Influence of Physicochemical Properties on Absorption of Xenobiotics
17.2.1 Polymorphism
17.2.2 Partition Coefficient
17.2.2.1 Rule of Five
17.2.3 Influence of Particle Size, Porosity, and Wettability on Dissolution Rate at the Site of Absorption
17.2.3.1 Absorption of Particles
17.2.3.2 Influence of the Particle Size on the Solubility/Dissolution at the Site of Absorption
17.2.3.3 Influence of Wettability and Porosity on the Dissolution Profile
17.3 Formulation Factors
17.3.1 Solutions and Syrups
17.3.2 Suspensions
17.3.3 Emulsions
17.3.4 Soft and Hard Gelatin Capsules
17.3.5 Compressed Tablets (Uncoated and Coated)
17.3.6 Dosage Form Tactics for Poorly Soluble Compounds
17.4 Disintegration and Dissolution
17.4.1 Mathematical Models of Dissolution
17.4.1.1 Noyes–Whitney Model
17.4.1.2 Hixson–Crowell “Cube Root” Model
17.4.1.3 First-Order Kinetics Model
17.4.1.4 Kitazawa Model
17.4.1.5 Higuchi “Square Root of Time Plot” Model
17.4.1.6 Weibull–Langenbucher Model
17.4.1.7 Korsmeyer–Peppas Model
17.4.1.8 Nernst–Brunner Model
17.4.1.9 Baker–Lonsdale Model
17.4.1.10 Hopfendberg Model
17.4.2 In Vitro–In Vivo Correlation (IVIVC) of Dissolution Data
17.4.2.1 Level A Correlation
17.4.2.2 Level B Correlation
17.4.2.3 Level C Correlation
17.4.2.4 Multiple-Level C Correlation
17.5 Biopharmaceutics Classification System
17.5.1 Absorption Number
17.5.2 Dissolution Number
17.5.3 Dose Number
17.5.4 Classes of Biopharmaceutics Classification System
17.5.4.1 Class I: Compounds with High Permeability and High Solubility
17.5.4.2 Class II: Drugs with High Permeability and Low Solubility
17.5.4.3 Class III: Drugs with Low Permeability and High Solubility
17.5.4.4 Class IV: Drugs with Low Permeability and Low Solubility
17.5.5 Biowaivers
17.5.6 Biopharmaceutics Drug Disposition Classification System
17.6 Other Factors Influencing Absorption of Xenobiotics
17.6.1 Chirality and Enantiomers
17.6.2 Effects of Food and Drink on Absorption of Xenobiotics
17.6.3 Effects of Disease States
17.6.4 Influence of Genetic Polymorphism
17.6.5 Effects of Release Mechanisms from the Solid Dosage Forms
17.6.6 Influence of Drug Administration Scheduling
17.6.7 Presence of Other Substances
17.6.8 Other Factors
17.7 Mechanistic Absorption Models
17.7.1 Absorption Potential Models
17.7.2 Dispersion Models
17.7.3 Compartmental Absorption and Transit Model
17.7.4 Gastrointestinal Transit Absorption Model
17.7.5 Advanced Compartmental Absorption and Transit Model
17.7.6 Advanced Dissolution, Absorption, and Transit Model
17.7.7 Grass Model
References
Chapter 18 Bioavailability, Bioequivalence, and Biosimilarity
18.1 Introduction
18.2 Definitions
18.2.1 Bioavailability
18.2.2 Pharmaceutical Equivalents
18.2.3 Pharmceutical Alternatives
18.2.4 Bioequivalent Drug Products (Bioequivalence)
18.2.5 Therapeutic Equivalents
18.2.6 Generic Drug Products
18.2.7 Absolute and Relative Bioavailability
18.3 Peak Exposure, Total Exposure, and Early Exposure
18.3.1 Estimation of Absolute Bioavailability from Plasma Data – Single Dose
18.3.2 Estimation of Absolute Bioavailability from Amount Eliminated from the Body – Single Dose
18.3.3 Estimation of Relative Bioavailability from Plasma Data – Single Dose
18.3.4 Estimation of Relative Bioavailability from Total Amount Eliminated from the Body – Single Dose
18.4 Bioavailability and First-Pass Metabolism
18.5 Linearity Validation of Relative or Absolute Bioavailability During Multiple Dosing Regimen
18.6 Bioequivalence Evaluation
18.6.1 Required PK/TK Parameters and Other Provisions in Bioequivalence Study
18.6.2 Overview of Statistical Analysis of PK/TK Data for Bioequivalence Study
18.6.3 Required PD/TD Data
18.7 Biosimilar (Biosimilarity and Interchabgeability)
18.7.1 Introduction
18.7.2 Comparability of Biosimilar and Application of PK/PD Parameters
References
Chapter 19 Quantitative Cross-Species Extrapolation and Low-Dose Extrapolation
19.1 Cross-Species Extrapolation
19.1.1 Introduction: Interspecies Scaling in Mammals
19.1.2 Allometric Approach
19.1.2.1 Allometric Approach and Chronological Time
19.1.2.2 Application of Allometric in Converting Animal Dose to Human Dose
19.1.3 Application of PBPK or PBTK in Cross Species Extrapolation
19.1.3.1 Toxicogenomics
19.2 Low-Dose Extrapolation
19.2.1 Introduction
19.2.2 Threshold and Non-Threshold Models
19.2.2.1 The Probit Model
19.2.2.2 The Logit Model
19.2.2.3 The One-Hit Model
19.2.2.4 The Gamma Multi-Hit Model
19.2.2.5 The Armitage-Doll Multi-Stage Model
19.2.2.6 Statistico-Pharmacokinetic Model
References
Chapter 20 Practical Application of PK/TK Models: Population Pharmacokinetics/Toxicokinetics
20.1 Introduction
20.2 Fixed Effect and Random Effect Parameters
20.2.1 Fixed Effect Parameters
20.2.2 Random Effect Parameters
20.2.3 Linear and Nonlinear Mixed-Effect Models
20.2.3.1 Linear Mixed-Effects Model
20.2.3.2 Nonlinear Mixed-Effects Model
20.2.3.3 Partially Linear Mixed-Effect Model
20.2.3.4 Naïve-Pooled Data Approach
20.2.3.5 Naïve Average Data Approach
20.2.3.6 Standard Two-Stage Approach
20.2.3.7 Global Two-Stage Approach
20.2.3.8 Iterative Two-Stage Approach
20.2.3.9 Bayesian Approach
20.3 Computational Tools for popPK/TK
References
Chapter 21 Practical Application of Pk/TK Models: Preclinical PK/TK and Clinical Trial
21.1 Introduction
21.2 Preclinical PK/TK
21.2.1 Estimation of the First Dose in Humans
21.2.2 PK/TK Preclinical Requirements
21.2.2.1 Safety Pharmacology and Toxicity Testing
21.2.2.2 Metabolic Evaluations in Preclinical Phase
21.3 PK/TK and Clinical Trials
21.3.1 Phase I-a Clinical Trial
21.3.2 Phase I-b Clinical Trial
21.3.3 Phase II-a Clinical Trial
21.3.4 Phase II-b Clinical Trial
21.3.5 Phase III Clinical Trial
21.3.6 Phase IV Clinical Trial
References
Chapter 22 Adjustment of Dosage Regimen in: Renal Impairment, Liver disease and Pregnancy
22.1 Renal Impairment
22.1.1 Introduction
22.1.2 Dosage Adjustment for Patients with Renal Impairments
22.1.2.1 Estimation of the Overall Elimination Rate Constant or Half-Life of a Therapeutic Agent Based on the Estimated GFR
22.1.2.2 Adjustment of Multiple Dosing Regimen Using the Adjusted Elimination Rate Constant,
22.1.2.3 Dosage Adjustment Based on the Steady-State Peak and Trough Levels
22.1.3 Applications and Case Studies
22.2 Liver Diseases
22.2.1 Introduction
22.2.2 Dosage Adjustment in Liver Cirrhosis
22.2.2.1 Child-Turcotte-Pugh Score
22.3 Pregnancy
22.3.1 Introduction
22.3.2 Changes Impacting Oral Absorption during Pregnancy
22.3.3 Changes Influencing Drug Distribution during Pregnancy
22.3.4 Changes in Drug Metabolism during Pregnancy
22.3.5 Changes in Renal Excretion during Pregnancy
22.3.5.1 Estimation of GFR during Pregnancy
22.3.6 Role of the Placenta
22.3.7 PK/TK Models
References
Addendum I – Part 1: Standard Terminologies for Routes of Administration
Addendum I – Part 2: Relevant Mathematical Concepts
Addendum I – Part 3: Abbreviation – Glossary – PK/TK Constants and Variables
Addendum II – Part 1
Addendum II – Part 1
Addendum II – Part 1
Addendum II – Part 2
Addendum II – Part 2
Addendum II – Part 2
Addendum II – Part 2
Addendum II – Part 2
Addendum II – Part 2
Addendum II – Part 2
Addendum II – Part 2
Addendum II – Part 2
Addendum II – Part 3
Addendum II – Part 3
Addendum II – Part 3
Addendum II – Part 3
Addendum II – Part 3
Addendum II – Part 3
Addendum II – Part 3
Addendum II – Part 3
Addendum II – Part 4
Addendum II – Part 4
Addendum II – Part 4
Addendum II – Part 4
Addendum II – Part 4
Addendum II – Part 4
Addendum II – Part 4
Addendum II – Part 4
Addendum II – Part 4
Addendum II – Part 5
Addendum II – Part 5
Addendum II – Part 5
Addendum II – Part 5
Addendum II – Part 5
Addendum II – Part 5
Addendum II – Part 5
Addendum II – Part 5
Addendum II – Part 5
Addendum II – Part 6
Addendum II – Part 6
Addendum II – Part 6
Addendum II – Part 6
Addendum II – Part 6
Addendum II – Part 6
Addendum II – Part 7
Addendum II – Part 7
Addendum II – Part 7
Addendum II – Part 7
Addendum II – Part 7
Addendum II – Part 7
Addendum II – Part 7
Addendum II – Part 7
Addendum II – Part 7
Addendum II – Part 8
Addendum II – Part 8
Addendum II – Part 8
Addendum II – Part 8
Addendum II – Part 8
Addendum II – Part 8
Addendum II – Part 8
Addendum II – Part 8
Addendum II – Part 8
Addendum II – Part 9
Addendum II – Part 9
Addendum II – Part 9
Addendum II – Part 9
Addendum II – Part 9
Addendum II – Part 9
Index