Biopharmaceutics Modeling and Simulations. Theory, Practice, Methods, and Applications

Description

This book provides pharmaceutical professionals with essential tools for modeling biopharmaceutics. The author uses illustrations and practical problems rather than heavy math to explain the basics of modeling and simulation programs and how to apply them to different biopharmaceutical properties. Readers will find critical guidance on the design of drug formulations for achieving desired medicinal effects, including practical applications examples in drug research such as running and interpreting models, compound and formulation selection, mechanisms, and virtual clinical trials.

Table of Contents

• Preface

1. Introduction
1. An illustrative description of oral drug absorption: the whole story
2. Three regimes of oral drug absorption
3. Stomach-Small intestine-Colon
4. Drug and API form
5. The concept of mechanistic modeling
2. Theoretical framework I: Solubility
1. Definition of concentration
2. Acid-base and bile micelle binding equilibriums
3. Equilibrium solubility
4. Fraction of undissociated species (f0)
3. Theoretical framework II: Dissolution
1. Diffusion coefficient
2. Dissolution and particle growth
3. Nucleation
4. Theoretical framework III: Biological membrane permeation
1. Overall scheme
2. General permeation equation
3. Permeation rate constant, permeation clearance and permeability
4. Intestinal tube flatness and permeation parameters
5. Effective concentration for intestinal membrane permeability
6. Surface area expansion by plicate and villi
7. Unstirred water layer permeability
8. Epithelial membrane permeability (Passive processes)
9. Enteric cell model
10. Gut wall metabolism
11. Hepatic metabolism and excretion
5. Theoretical framework IV: Gastrointestinal transit models and integration
1. GI transit models
2. Time dependent changes of physiological parameters
3. Integration 1: analytical solutions
4. Integration 2: numerical integration
5. In vivo Fa from PK data
6. Absolute bioavailability and Fa
7. Other administration route
8. Skin
6. Physiology of gastrointestinal tract and other administration sites in humans and animals
1. Morphology of gastrointestinal tract
2. Movement of gastrointestinal tract
3. Fluid character of gastrointestinal tract
4. Transporters and drug metabolic enzymes in the intestine
5. Intestinal and liver blood flow
6. Physiology related to enterohepatic recirculation
7. Nasal
8. Pulmonary
9. Skin
7. Drug parameters
1. Dissociation constant (pKa)
2. Octanol water partition coefficient
3. Bile micelle partition coefficient (Kbm)
4. Particle size and shape
5. Solid form
6. Solubility
7. Terminology
8. Dissolution rate/release rate
9. Precipitation
10. Epithelial membrane permeability
11. In vivo experiments
8. Validation of mechanistic models
1. Concerns related to model validation using in vivo data
2. Strategy for transparent and robust validation of biopharmaceutical modeling
3. Prediction steps
4. Validation for permeability limited cases
5. Validation for dissolution rate and solubility permeability limited cases (without the stomach effect)
6. Validation for dissolution rate and solubility permeability limited cases (with the stomach effect)
7. Salts
8. Reliability of biopharmaceutical modelling
9. Bioequivalence and biopharmaceutical classification system
1. Bioequivalence
2. The history of BCS
3. Regulatory biowaiver scheme and BCS
4. Exploratory BCS
5. In vitro in vivo correlation
10. Dose and particle size dependency
1. Definitions and causes of dose non proportionality
2. Estimation of the dose and particle size effects
3. Effect of transporters
4. Analysis of in vivo data
11. Enabling formulations
1. Salts and co-crystals: Supersaturating API
2. Nano milled API particles
3. Self-emulsifying drug delivery systems (Micelle/emulsion solubilization)
4. Solid dispersion
5. Supersaturable formulations
6. Prodrugs to increase solubility
7. Prodrugs to increase permeability
8. Controlled release
9. Communication with therapeutic project team
12. Food effect
1. Physiological change by food
2. Types of food effects and relevant parameters in biopharmaceutical modeling
3. Effect of food type
4. Biopharmaceutical modeling of food effect
13. Biopharmaceutical modeling for miscellaneous cases
1. Stomach pH effect on solubility and dissolution rate
2. Intestinal first pass metabolism
3. Transit time effect
4. Other chemical and physical drug-drug interactions
5. Species difference
6. Permeabiltiy
7. Validation of GI site specific absorption models
14. Intestinal transporters
1. Apical influx transporters
2. Efflux transporters
3. Dual substrates
4. Difficulties in simulating carrier mediated transport
5. Summary of this section
15. Strategy in drug discovery and development
1. Library design
2. Lead optimization
3. Compound selection
4. API form selection
5. Formulation selection
6. Strategy to predict human Fa%
16. Epistemology of biopharmaceutical modeling and good simulation practice
1. Can simulation be so perfect?
2. Parameter fitting
3. Good simulation practice

• Appendix 1.General terminology

• Appendix 2.Fluid dynamics
• Navier Stokes equation and Reynolds number
• Boundary layer approximation
• The boundary layer and mass transfer
• The thickness of the boundary layer
• Sherwood number
• Turbulence
• Formation of eddies
• Computational fluid dynamics
• List of Abbreviations