Pharmacokinetics: Basics to Applications

Preface
Acknowledgment
Contents
About the Author
List of Figures
List of Tables
1: Fundamentals of Pharmacokinetics
1.1 Fundamentals of Pharmacokinetics
1.1.1 Pharmacokinetic Parameters and Blood Drug Profile
1.1.2 Multiple-Dose Regimen
1.1.3 Apparent Volume of Distribution or Volume of Distribution (vd)
1.1.4 Steady-State Plasma Concentration of Drug
1.1.5 Drug Accumulation Factor
1.1.6 Krüger-Thiemer´s ``Pharmacokinetic Factor´´
1.1.7 Krüger-Thiemer Dose Ratio
1.1.8 Concept of a Loading Dose
1.1.9 Relationship Between Elimination Rate Constant (KE) and Steady-State Drug Plasma Concentration (css) from Krüger-Thiemer...
References
2: Drug Absorption
2.1 Drug Absorption and Determination of Drug Absorption Rate Constant ``Ka´´
2.1.1 Dominguez Equation and Its Importance
2.1.2 Wagner-Nelson Equation and Method of Determination of Drug Absorption Rate Constant
2.1.3 Determination of Absorption Rate Constant (Ka) from Urinary Excretion Data
2.1.4 Nelson Equation
2.1.5 Wagner and Nelson Equation
2.1.6 Loo-Riegelman Method for Determination of Drug Absorption Rate (Ka)
2.1.7 Method of Residual for Determination of Drug Absorption Rate
2.1.8 Flip-Flop Phenomenon
References
3: Extent of Drug Absorption: Bioavailability, Clearance, Bioequivalence, and Protein Binding
3.1 Extent of Drug Absorption: Bioavailability
3.1.1 Renal Clearance
3.1.2 Determination of Absolute Bioavailability
3.1.3 Determination of Absolute Bioavailability by Urinary Excretion Data
3.1.4 Bioequivalence
3.1.4.1 Chemical Equivalents
3.1.4.2 Pharmaceutical Equivalents
3.1.4.3 Bioequivalents
3.1.4.4 Therapeutic Equivalence
3.1.4.5 Experimental Study Design in Bioequivalence
3.1.5 Drug-Protein Binding
3.1.6 Reciprocal Plot or Klotz Reciprocal Plot
3.1.7 Scatchard Plot
3.1.8 Sandberg Plot
References
4: Pharmacokinetic Models and Drug Distribution
4.1 Various Pharmacokinetic Models and Drug Distribution
4.1.1 Physiological Pharmacokinetic Model (Flow Model)
4.1.2 Blood Flow-Limited Physiological Pharmacokinetic Model or Perfusion Model
4.1.3 Physiological Pharmacokinetic Model with Drug-Protein Binding
4.1.4 Membrane-Limited Model or Diffusion-Limited Model
4.1.5 Statistical Moment Theory
4.1.6 Compartment Models
4.1.6.1 One-Compartment Closed Model
4.1.6.2 One-Compartment Open Model
4.1.6.3 Catenary Model
4.1.6.4 Cyclic Model
4.1.6.5 Mammillary Model
4.1.7 Some Mathematical Approaches for Easy Computation of Compartmental Equations and Their Applications
4.1.7.1 Matrix and Determinant
4.1.7.1.1 Cramer´s Rule
4.1.7.2 Laplace Transform
4.1.7.3 Use of Logarithm and Antilogarithm Tables
4.1.7.4 Relationship Between Common and Natural Logarithms
4.1.8 Details About Compartment Models
4.1.9 Drug Distribution Study Through Compartmental Models
4.1.9.1 One-Compartment Open Model
4.1.9.1.1 Intravenously Bolus Dose
4.1.9.1.2 Intravenous Infusion
4.1.9.1.3 Following One-Compartment Model, Determination of Overall Elimination Rate During the Time t′ Elapsed After the Stop...
4.1.9.1.4 Following One-Compartment Model, Determination of the Overall Elimination Rate While an Infusion of a Drug to a Pati...
4.1.9.2 Two-Compartment Open Model
4.1.9.2.1 Method 1 (Simple Algebraic Method, Simultaneous Quadratic Equation)
4.1.9.2.2 By Matrix and Determinant Method
4.1.9.2.3 Drug Level in the Peripheral (Tissue) Compartment
4.1.9.3 Three-Compartment Open Model
References
5: Drug Metabolism
5.1 Drug Metabolism
5.1.1 Hepatic Drug Metabolism
5.1.1.1 Phase I
5.1.1.2 Phase II Reaction
5.1.2 Pharmacokinetic Compartmental Models and Equations for Assessing Hepatic ``First-Pass´´ Effect of a Drug
5.1.2.1 Model I
5.1.2.2 Model II
5.1.2.3 Model III
5.1.2.4 Model IV
5.1.3 Hepatic First-Pass Effect Invariably Reduces Total Bioavailability of a Drug More When Administered Orally than By Its I...
5.1.4 Determination of Drug Metabolite Levels in Plasma Using Compartmental Model
References
6: Drug Elimination and Nonlinear Kinetics
6.1 Drug Elimination
6.1.1 Nonlinear Kinetics and Capacity-Limited Process
6.1.2 Michaelis-Menten Equation
6.1.3 Capacity-Limited Process/Nonlinear Kinetics
6.1.4 Dose-Plasma Drug Concentration Relationship with Michaelis-Menten Constant Km for Drugs That Undergo Elimination Followi...
6.1.5 Drug Elimination by More Than One Capacity-Limited Process
6.1.6 Sigma-Minus Method to Determine Elimination Rate Constant
6.1.7 Bi-Exponential Absorption-Elimination Equation for Orally Administered Drugs Excreted Unchanged Through Urine
6.1.8 Excretion Rate Method
References
7: Pharmacokinetic Drug-Drug Interactions
7.1 Pharmacokinetic Drug-Drug Interactions
7.1.1 Importance of Drug-Drug Interactions
7.1.1.1 Alteration of Plasma Drug Level
7.1.1.2 Drug-Related Side Effects or Toxic Effects
7.1.1.3 Deteriorative Existing Medical Conditions
7.1.2 Categories
7.1.3 Drug-Drug Interactions: Pharmacokinetic Type
7.1.3.1 Absorption
7.1.3.2 Distribution
7.1.3.3 Metabolism
7.1.3.4 Elimination
7.1.4 Drug-Drug Interactions: Pharmacodynamic Type
7.1.4.1 Involving Receptor Activities
7.1.4.2 Modulating Biological or Physiological Regulatory Function
7.1.4.3 Pharmacological Agonistic/Antagonistic Action
7.1.5 Data Collection
References
8: Pharmacokinetic Applications
8.1 Therapeutic Drug Monitoring and Dose Formula
8.1.1 Therapeutic Drug Monitoring
8.1.1.1 Plasma
8.1.1.2 Serum
8.1.1.3 Required Sectors of Therapeutic Drug Monitoring
8.1.2 Physiological Effects on the Pharmacokinetic Drug Parameters and Available Dose Formula in Neonates, Infants, Children, ...
8.1.2.1 Pediatric Patients
8.1.2.2 Absorption
8.1.2.3 Distribution
8.1.2.4 Metabolism
8.1.2.5 Elimination
8.1.2.6 Mosteller´s Equation
8.1.2.7 Clark´s Formula
8.1.2.8 Fried´s Rule for Infants
8.1.2.9 Cowling´s Formula
8.1.3 Physiological Effects on the Pharmacokinetic Parameters of Drugs and Available Dose Formula in Elderly or Geriatric Pati...
8.1.3.1 Absorption
8.1.3.2 Distribution
8.1.3.3 Metabolism
8.1.3.4 Elimination
8.1.3.5 Dose Calculation of Elderly Patients
8.1.4 Physiological Effects on the Pharmacokinetic Parameters of Drugs in Obese Patients
8.1.5 Physiological Effects on the Pharmacokinetic Parameters of Drugs and Available Dose Formula in Patients with Renal Insuf...
8.1.6 Chronological Pharmacokinetic Guidance for Preclinical and Clinical Studies and Research
8.1.6.1 Study Design
8.1.6.1.1 Group Design
For Preclinical Investigation
For Clinical Investigation
Controlled TrialControlled Trial
RandomizationRandomization
Blinding (Masking) ProcessBlinding (Masking) Process
Cohort StudyCohort Study
8.1.6.1.2 Sample Type
8.1.6.1.3 Sample Size
8.1.6.1.4 Route of Administration
8.1.6.1.5 Mode of Drug Administration
8.1.6.1.6 Scheduling of Drug Administration
8.1.6.1.7 Time Points of Sampling
8.1.6.1.8 Endpoints
8.1.6.1.9 Parameters to Be Analyzed
8.1.6.1.10 Method of Analysis
8.1.6.1.11 Statistical Analysis
8.1.7 Analysis of Pharmacokinetic Data
8.1.7.1 Data Handling
8.1.7.2 Data Editing
8.1.7.3 Outliers
8.1.7.4 Analysis of Pharmacokinetic Data
8.1.7.4.1 Noncompartmental Data Analysis
Compartmental Data Analysis
Model Selection
Initial Estimates
Selection of Minimizing Algorithm
Choice of Weight
Assessing Goodness of Fit
Distinction Between the Models
8.1.7.4.2 Physiological Pharmacokinetic Model
8.1.7.4.3 Pharmacokinetic/Pharmacodynamic Model
8.1.7.4.4 Population-Based Pharmacokinetic Data Analysis
8.1.7.4.5 Nonlinear Mixed Effect Modeling Approach
8.1.7.5 Pharmacokinetic Report
References
9: Pharmacokinetic Sample Collection and Processing
9.1 Pharmacokinetic Sample Collection and Processing for Preclinical and Clinical Experiments
9.1.1 Pharmacokinetic Sampling
9.1.2 Blood Sampling and Right Practices in Phlebotomy
9.1.2.1 Processing of Blood Samples
9.1.2.2 Blood Collections from Small Animals
9.1.3 Urine Specimen
9.1.4 Other Tissue Samples
9.1.5 Other Tissue Fluids
9.1.6 Processing of Fecal Samples
9.1.7 Extraction of Drug/Drug Metabolite from Biological Samples
References
10: Important Bioanalytical Instrumental Techniques in Pharmacokinetics
10.1 Important Bioanalytical Instrumental Techniques
10.1.1 Liquid Chromatography with Tandem Mass Spectroscopy (LC-MS/MS)
10.1.1.1 Working Principle
10.1.1.2 Components and Their Applications
10.1.1.2.1 Liquid Chromatography Part
10.1.1.2.2 Sample Injector
10.1.1.2.3 Pump Device
Direct Gas-Pressure System
Syringe Pump
Pneumatic Intensifier
Reciprocating Pump
10.1.1.2.4 Interface
10.1.1.2.5 Atmospheric Pressure Ionization Technique
10.1.1.2.6 Electrospray Ionization Collision-Induced Dissociation
10.1.1.2.7 MS/MS System
Quadrupole Assembly
Mass Spectra Detectors
10.1.1.3 LC-MS/MS Method Optimization
10.1.1.3.1 Standard Solution
10.1.1.3.2 Optimization of MS/MS Operation and Parameters
10.1.1.3.3 Energy Optimization for Parent Ion Ionization
10.1.1.3.4 Collision Energy Optimization for the Fragmented Ions
10.1.1.3.5 Liquid Chromatographic Optimization
10.1.1.4 Method Confirmation
10.1.2 High-Performance Liquid Chromatography (HPLC)
10.1.2.1 Working Principle
10.1.2.2 Types of HPLC
10.1.2.2.1 Normal-Phase HPLC
10.1.2.2.2 Reversed-Phase HPLC
10.1.2.2.3 Size Exclusion Chromatography
10.1.2.2.4 Ion-Exchange HPLC
10.1.2.3 Different Components of an HPLC System
10.1.2.3.1 Column
10.1.2.3.2 Mobile Phase
10.1.2.3.3 Pumps
10.1.2.3.4 Injectors
10.1.2.3.5 Detector
10.1.2.3.6 Waste Collector
10.1.2.3.7 Data Processor and Recorder
10.1.2.4 Tailing Factor
10.1.2.5 HPLC Method Optimization
10.1.2.5.1 Physicochemical Properties of Drugs
10.1.2.5.2 Choosing Chromatographic Conditions
10.1.2.5.3 Selection of HPLC Method Type
10.1.2.5.4 Column
10.1.2.5.5 Mobile Phase Optimization
10.1.2.5.6 Sample Preparation
10.1.2.5.7 Detectors
10.1.2.5.8 Development of an Analytical Method
10.1.2.5.9 Method Validation
References
11: Statistics in Pharmacokinetics
11.1 Statistics and Biometry
11.1.1 Central Tendency
11.1.1.1 Mean
11.1.1.1.1 Simple Arithmetic Mean
Direct Method
Short-Cut Method
11.1.1.1.2 Weighted Arithmetic Mean
Direct Method
Short-Cut Method
Step Derivation Method
11.1.1.1.3 The Arithmetic Mean of the Composite Group
11.1.1.2 Standard Error of the Mean/Measurement (SEM)
11.1.1.3 Median
11.1.1.4 Mode
11.1.2 Measure of Dispersion
11.1.2.1 The Absolute Measure of Dispersion
11.1.2.1.1 Range
11.1.2.1.2 Quartile Deviation (Q)
11.1.2.1.3 Mean Deviation
11.1.2.1.4 Standard Deviation (SD)
11.1.3 Probability
11.1.3.1 Mutually Exclusive Events
11.1.3.2 Impossible Events
11.1.3.3 Equally Likely Event
11.1.3.4 Sure or a Certain Event
11.1.3.5 Complementary Events
11.1.3.6 Exhaustive Events
11.1.3.7 Sample Space or Event Space
11.1.3.8 Sample Points
11.1.4 Some Important Definitions
11.1.4.1 Continuous Data
11.1.4.2 Discontinuous Data
11.1.4.3 Parametric Data
11.1.4.4 Nonparametric Data
11.1.4.5 Normal Distribution
11.1.4.6 Non-normal Distribution
11.1.4.7 Homogeneous Population
11.1.4.8 Heterogeneous Population
11.1.4.9 Skewness
11.1.4.10 Kurtosis
11.1.4.11 Decision Tree in Statistics
11.1.5 The Null Hypothesis, Alternate Hypothesis, and Degree of Freedom
11.1.6 Population and Sample
11.1.7 Selection of Statistical Methods
11.1.8 Different Statistical Methods Used in Pharmacokinetics
11.1.8.1 Bartlett´s Test for Homogeneity
11.1.8.2 Cochran Test
11.1.8.3 F-Test
11.1.8.4 Types of T-Tests (for Comparison of Means)
11.1.8.5 Student´s t-Test
11.1.8.6 Analysis of Variance (ANOVA)
11.1.8.7 Post Hoc Tests
11.1.8.7.1 Scheffe´s Test
11.1.8.7.2 Dunnett´s t-Test
11.1.8.7.3 Tukey's Test or Tukey Test
11.1.8.7.4 Williams´ Test
11.1.8.7.5 Duncan´s Multiple Range Test
11.1.8.8 Fisher´s Exact Test
11.1.8.9 RXC Chi-Square Test
11.1.8.10 Mann-Whitney U Test/Wilcoxon Rank-Sum Test/Mann-Whitney-Wilcoxon/Wilcoxon-Mann-Whitney Test
11.1.8.11 Analysis of Covariance (ANCOVA)
11.1.8.12 Kruskal-Wallis Test
11.1.9 Scattergram, Linear Regression Model, Correlation Coefficient, Nonlinear Regression Model
11.1.9.1 Linear Regression Model
11.1.9.2 Correlation Coefficient (r)
11.1.9.3 Nonlinear Regression Model
References
12: Pharmacokinetic Software and Tools
12.1 Pharmacokinetic Software and Tools
12.1.1 Software and Tools
12.1.2 Types of Software
12.1.2.1 Application Software
12.1.2.2 System Software
12.1.2.3 Programming Software
12.1.2.4 Driver Software
12.1.3 Importance of Pharmacokinetic Software
12.1.4 Open Source and Commercial Pharmacokinetic Software and Tools
12.1.4.1 PKQuest
12.1.4.2 LAPKB
12.1.4.3 Lixoft
12.1.4.4 SwissADME
12.1.4.5 Edsim++
12.1.4.6 GraphPad Prism
12.1.4.7 JGuiB
12.1.4.8 PKSolver 2.0
12.1.4.9 JPKD
12.1.4.10 PCModfit
12.1.4.11 SimBiology
12.1.4.12 acslXtreme
12.1.4.13 ADAPT 5
12.1.4.14 Kinetica
12.1.4.15 Maxsim2
12.1.4.16 Design-Expert
References
13: Pharmacokinetic Laboratory-Based Experiments
13.1 Pharmacokinetic Laboratory-Based Experiments for Undergraduate and Postgraduate Students
13.1.1 Introduction
13.1.2 Helpful Information in Laboratory Work
13.1.2.1 Practical Concept of Molar Concentration (Conversion of Concentration to Molar Concentration)
13.1.2.2 Buffers
13.1.2.3 Preparation of Tissue Homogenate
13.1.2.4 Preparation of Liver Microsomes
13.1.2.5 Revolution per Minute (RMP) and g Relationship
13.1.2.6 Anticoagulants and Their Concentration for the Clinical Blood Sampling Procedure
13.1.2.7 Protein Precipitation
13.1.2.8 MTT Assay
13.1.2.9 Ethical Clearance
13.1.2.10 Relationship Between Common Logarithm and Natural Logarithm
13.1.2.11 Important Equations
13.1.2.12 Important Units
13.1.2.13 Volume of One Drop of Water
13.1.3 Drug-Plasma Protein (Albumin)-Binding Assessment with a Low Plasma Protein Binding Drug or a High Plasma Protein Bindin...
13.1.3.1 Background
13.1.3.2 Equilibrium Dialysis
13.1.3.2.1 The Donnan Effect
13.1.3.3 Ultrafiltration
13.1.3.4 Ultracentrifugation
13.1.3.5 Experiment No. 1
13.1.3.5.1 Equilibrium Dialysis Method Using Tubing Dialysis Membrane and Albumin to Determine Diclofenac-Albumin Binding
13.1.3.5.2 Membrane Pre-treatment
13.1.3.5.3 Preparation of Protein (BSA)
13.1.3.5.4 Stock Diclofenac Sodium Solution
13.1.3.5.5 Preparation of Calibration Curve of the Drug
13.1.3.5.6 Data Analysis
13.1.3.6 Experiment No. 2
13.1.3.6.1 Rapid Equilibrium Dialysis (RED) Method Using Plasma
13.1.3.6.2 Methods
Assay Protocol
Sample Preparation
Calculation
13.1.3.7 Experiment No. 3
13.1.3.7.1 Assessment of Drug-Protein Binding by Ultrafiltration
Methods
13.1.3.8 Experiment No. 4
13.1.3.8.1 Assessment of Paracetamol-Albumin Binding by Ultracentrifugation
Materials and Equipment
Methods
Determine the Protein-Bound Drug Using the Following Formula
13.1.4 Drug Metabolism
13.1.4.1 Background
13.1.4.2 Experiment No. 5
13.1.4.2.1 Objective
13.1.4.2.2 Methods
13.1.5 One-Compartment Model Following an Intravenous Bolus Dose Administration
13.1.5.1 Background
13.1.5.1.1 Experiment No. 6
Objectives
Materials and equipment
Methods
13.1.6 One-Compartment Model Following an Intravenous Infusion Administration
13.1.6.1 Background
13.1.6.1.1 Experiment No. 7
Objectives
Materials and Equipment
Methods
13.1.7 A Two-Compartment Model Following the Administration of an Intravenous Bolus Dose
13.1.7.1 Background
13.1.7.1.1 Experiment No. 8
Objectives
Materials and Equipment
Methods
13.1.8 A Multi(Three)-Compartment Model Following the Administration of an Intravenous Infusion
13.1.8.1 Background
13.1.8.1.1 Experiment No. 9
Objectives
Materials
Methods
13.1.9 Determination of Drug Absorption In Vitro
13.1.9.1 Background
13.1.9.1.1 Experiment No. 10
Objective
Materials
Methods
13.1.10 Cellular Uptake of Drug
13.1.10.1 Background
13.1.10.1.1 Experiment No. 11
Objective
Methods
13.1.10.1.2 Experiment No. 12
Objective
Methods
Note: For Tissue Drug Uptake
13.1.11 In Vitro Drug Skin Permeation from Transdermal Drug Delivery System (Patch)
13.1.11.1 Background
13.1.11.1.1 Experiment No. 13
Objective
Materials
Methods
Prepare the Calibration CurvePrepare the Calibration Curve
Skin PermeationSkin Permeation
13.1.12 Drug Assay from a Tablet Dosage Form Containing Paracetamol by HPLC Method
13.1.12.1 Background
13.1.12.1.1 Experiment No. 14
Objective
Materials
Methods
13.1.13 Estimation of Plasma and Urine Drug Concentrations by Reversed-Phase HPLC
13.1.13.1 Background
13.1.13.1.1 Experiment No. 15
Objective
Methods
Volunteers, Treatment, and Sample Collection Time PointsVolunteers, Treatment, and Sample Collection Time Points
Drug EstimationDrug Estimation
HPLC ConditionHPLC Condition
13.1.14 Compare the Bioavailability of Ranitidine (300 mg) Tablets of Two Different Brands in Human Volunteers (Bioequivalence...
13.1.14.1 Background
13.1.14.1.1 Experiment No. 16
Objectives
Methods
VolunteersVolunteers
HPLC ConditionsHPLC Conditions
13.1.15 Effect of Food Intake on Drug Bioavailability
13.1.15.1 Background
13.1.15.1.1 Experiment No. 17
Objective
Materials
Methods
Ethical ClearanceEthical Clearance
VolunteersVolunteers
HPLC Analysis (Pillai et al. 1998; Amantea and Narang 1988)HPLC Analysis (Pillai et al. 1998; Amantea and Narang 1988)
13.1.16 The Metabolism of Oxybutynin Hydrochloride to Its Metabolite N-Desethyl Oxybutynin Hydrochloride by Rat Liver Microsom...
13.1.16.1 Background
13.1.16.1.1 Experiment No. 18
Objectives
Materials
Methods
Preparation of MicrosomePreparation of Microsome
Incubation of Oxybutynin with Microsome and Cytochrome Isoform-Specific InhibitorsIncubation of Oxybutynin with Microsome and ...
Method of Estimation of Oxybutynin and N-Desethyl OxybutyninMethod of Estimation of Oxybutynin and N-Desethyl Oxybutynin
Liquid Chromatography ConditionsLiquid Chromatography Conditions
Mass Spectrometry ConditionsMass Spectrometry Conditions
QuantificationQuantification
Preparation of Standard SamplesPreparation of Standard Samples
13.1.17 Simultaneous Determination of Drugs Spiked into Plasma from a Single Tablet Dosage, Using LC-MS System
13.1.17.1 Background
13.1.17.1.1 Experiment No. 19
Objective
Materials
Instrumentation
Standard Solutions Preparation
For Tablet Solution Preparations
Application to Spiked Plasma
Analysis Conditions
MS Parameters
13.1.18 Determination of Metformin and Canagliflozin from a Single Tablet Dosage in Human Plasma by LC-MS/MS Method
13.1.18.1 Background
13.1.18.1.1 Experiment No. 20
Objective
Materials
Equipment
Standard Stock Solutions
Internal Standard (IS)
Calibration Standards
Test Sample Collection and Processing
Analysis Conditions
13.1.19 Retrospective Data Collection
13.1.19.1 Background
13.1.19.1.1 Experiment No. 21
Objective
Method of Collection of Patient Data for Retrospective Study
13.1.20 Development of Clinical Trial Protocol
13.1.20.1 Background
13.1.20.1.1 Experiment No. 22
Objective
Methods
Developing a Clinical Trial Protocol as per ICH GuidelinesDeveloping a Clinical Trial Protocol as per ICH Guidelines
Assignment
References
14: Pharmacokinetic Numerical Problems with Solutions
15: Questions, and Questions and Answers for Practice
15.1 The Practice of Questions and Answers on Topics Based on Pharmacokinetics
15.2 Multiple Choice Questions with Answers for Various Competitive Examinations
15.3 Selected Questions from the University Examinations
Index