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