Basic Pharmacokinetics and Pharmacodynamics: An Integrated Textbook with Computer Simulations

Transcription

1 Basic Pharmacokinetics and Pharmacodynamics: An Integrated Textbook with Computer Simulations Rosenbaum, Sara E. ISBN-13: Table of Contents 1 Introduction to Pharmacokinetics and Pharmacodynamics. 1 Introduction: Drugs and Doses. 2 Introduction to Pharmacodynamics. 2.1 Drug Effects at the Site of Action. 2.2 Agonists, Antagonists and Concentration Response Relationships. 3 Introduction to Pharmacokinetics. 3.1 Plasma Concentration of Drugs. 3.2 Processes in Pharmacokinetics. 4 Dose-Response Relationships. 5 Therapeutic Range. 5.1 Determination of the Therapeutic Range. 6 Summary. 2 Passage of Drug Through Membranes. 2 Structure and Properties of Membranes. 3 Passive Diffusion. 3.1 Transcellular Passive Diffusion. 3.2 Paracellular Passive Diffusion. 4 Carrier Mediated Transport: Transport Proteins. 4.1 Uptake Transporters: SCL Superfamily. 4.2 Efflux Transporters: ABC Superfamily. 4.3 Characteristics of Transporter System. 4.4 Simulation Exercise. 4.5 Clinical Examples of Transporter s Involvement in Drug Response. 3 Drug Absorption. 1 Introduction: Local and Systemic Administration. 2 Common Routes of Systemic Drug Administration. 2.1 Intravascular Direct Systemic Administration. 2.2 Extravascular Parenteral Routes. 2.3 Other Extravascular Routes. 3 Overview of Oral Absorption. 4 The Extent of Absorption. 4.1 Bioavailability Factor (F). 4.2 Individual Bioavailability Factors. 5 Determinants of the Bioavailability Factor. 5.1 Disintegration. 5.2 Dissolution. 5.3 Formulation Excipients. 5.4 Adverse Events within the Gastrointestinal Lumen. 5.5 Transcellular Passive Diffusion. 5.6 Paracellular Passive Diffusion. 5.7 Uptake and Efflux Transporters. 5.8 Presystemic Intestinal Metabolism or Extraction. 5.9 Presystemic Hepatic Metabolism or Extraction. 6 Factors Controlling the Rate of Drug Absorption. 6.1 Dissolution Controlled Absorption. 6.2 Membrane Penetration-Controlled Absorption. 7 Biopharmaceutics Classification System (BCS). 8 Problems. 4 Drug Distribution. 2 Extent Of Distribution. 2.1 Distribution Volumes. 2.2 Tissue Binding and Plasma Protein Binding: Concentrating Effects. 2.3 Assessment of Extent of Distribution: Apparent Volume of Distribution (Vd).

2 2.4 Plasma Protein Binding. 3 Rate of Distribution. 3.1 Perfusion Controlled Drug Distribution. 3.2 Diffusion Controlled Drug Distribution. 4 Distribution To The Central Nervous System. 5 Problems. 5 Drug Elimination. 1.1 First Order Elimination. 1.2 Determinants of the Elimination Rate Constant and the Half-Life. 2 Clearance. 2.1 Definition and Determinants of Clearance. 2.2 Total Clearance, Renal Clearance and Hepatic Clearance. 2.3 Relationship Between Clearance, Volume of Distribution, Elimination Rate Constant and the Half-Life. 2.4 Primary and Secondary Parameters. 3. Renal Clearance. 3.1 Glomerular Filtration. 3.2 Tubular Secretion. 3.3 Tubular Reabsorption. 3.4 Putting Meaning into the Value of Renal Clearance. 4. Hepatic Clearance Phase I and Phase II Metabolism. 4.3 The Cytochrome P450 Enzyme System. 4.4 Glucuronidation. 4.5 Drug-Drug Interactions. 4.6 Hepatic Drug Transporters. 4.7 Kinetics of Drug Metabolism. 4.8 Hepatic Clearance. 5. Measurement of Clearances. 5.1 Total Body Clearance. 5.2 Renal Clearance. 5.3 Fraction of the Drug Excreted Unchanged. 6 Problems. 6 Compartmental Models. 2 Expressions For Component Parts of the Dose-Plasma Concentration Relationship. 2.1 Dose: Effective Dose. 2.2 Rate of Absorption. 2.3 Rate of Elimination. 2.4 Rate of Distribution. 3 Putting Everything Together: Compartments and Models. 3.1 One Compartment Model. 3.2 Two Compartment Model. 3.3 Three Compartment Model. 4 Examples of Complete Compartment Models. 4.1 Intravenous Injection in a One Compartment Model with First Order Elimination. 4.2 Intravenous Injection in a Two Compartment Model with First Order Elimination. 4.3 First Order Absorption in a Two Compartment Model with First Order Elimination. 5 Application of Compartment Model to Study Metabolite Pharmacokinetics. 6 Selecting and Applying Models. 7 Problems. 7 Pharmacokinetics of an Intravenous Bolus Injection In a One Compartment Model. 2 One Compartment Model. 3 Pharmacokinetic Equations. 3.1 Basic Equation. 3.2 Half-Life. 3.3 Time to Eliminate a Dose. 4 Simulation Exercises. 4.1 Basic Model Characteristics. 4.2 Effect of Dose. 4.3 Effect of Clearance. 4.4 Effect of Volume of Distribution. 5. Application of the Model. 5.1 Predicting Plasma Concentrations. 5.2 Duration of Action. 5.3 Dose to Give a Desired Initial Plasma Concentration. 5.4 Intravenous Loading Dose.

3 6. Determination of Pharmacokinetic Parameters Experimentally. 6.1 Study Design for Determination of Parameters. 6.2 Pharmacokinetic Analysis. 6.3 Example. 7 Pharmacokinetic Analysis in Clinical Practice. 8 Problems. 8 An Intravenous Bolus Injection in the Two Compartment Model. 2 Tissue and Compartmental Distribution of the Drug. 2.1 Drug Distribution to the Tissues. 2.2 Compartmental Distribution of Drug. 3 The Basic Equation. 3.1 Distribution: A, a and the distribution t 1/ Elimination: B, ß and the beta& t 1/2. 4 Relationship Between the Macro and Micro-Rate Constants. 5 The Primary Pharmacokinetic Parameters Clearance. 5.3 Distribution Clearance. 5.4 Volume of Distribution. 6 Simulation Exercises. 7 Determination of the Pharmacokinetic Parameters. 7.1 Determination of the Intercepts and Macro Rate Constants. 7.2 Determination of the Micro Rate Constants. 7.3 Determination of the Primary Pharmacokinetic Parameters. 7.4 Example. 8 Clinical Application of the Two Compartment Model. 8.1 Measurement of the Elimination half-life in the Post Distribution Phase. 8.2 Determination of the Loading Dose. 8.3 Evaluation of Dose. Monitoring Plasma Concentrations and Patient-Response. 9 Problems. 9 Pharmacokinetics of Extravascular Drug Administration. 2 First Order Absorption in a One Compartment Model. 2.1 Model And Equations. 2.2 Parameter Determination. 2.3 Absorption Lag-Time. 2.4 Flip Flop Model. 2.5 Determinants of Cmax and Tmax. 3 Bioavailability. 3.1 Bioavailability Parameters. 3.2 Absolute Bioavailability. 3.3 Relative Bioavailability. 3.4 Bioequivalence. 4 Simulation Exercises. 5 Problems. 10 Introduction to Non-Compartmental Analysis. 2 Mean Residence Time. 3 Determination of Other Important Pharmacokinetic Parameters. 4 Different Routes of Administration. 5 Application of NCA To Clinical Studies. 5.1 Example Drug-Drug Interaction Study. 11 Pharmacokinetics of the Intravenous Infusion In A One Compartment Model. 2 Model And Equations. 2.1 Basic Equation. 2.2 Application of Basic Equation. 2.3 Simulation Exercise Part 1. 3 Steady State Plasma Concentration. 3.1 Equation For Steady State Plasma Concentrations. 3.2 Application of the Equation. 3.3 Basic Formula Revisited. 3.4 Factors Controlling the Steady State Plasma Concentration. 3.5 Time to Steady State. 3.6 Simulation Exercise Part 2.

4 4 Loading Dose. 4.1 Loading Dose Equation. 4.2 Example Calculation. 4.3 Simulation Exercise Part 3. 5 Termination of Infusion. 5.1 Equations for Termination Before or After Steady State. 5.2 Simulation Exercise Part 4. 6 Monitoring and Individualizing Therapy. 7 Problems. 12 Multiple Intravenous Bolus Injections In The One Compartment Model. 2 Terms And Symbols Used in Multiple Dosing Equations. 3 Mono-Exponential Decay During A Dosing Interval. 3.1 Calculation Of Dosing Interval To Give Specific Steady State Peaks And Troughs. 4 Basic Equations For Multiple Doses. 4.1 Principle Of Superposition. 4.2 Equations that Apply Before Steady State. 4.3 Application Of Equations: Example. 5 Steady State. 5.1 Steady State Equations. 5.2 Average Plasma Concentration at Steady State. 5.3 Fluctuation. 5.4 Accumulation. 5.5 Time To Reach Steady State. 5.6 Loading Dose. 6 Basic Formula Revisited. 7 Pharmacokinetic-Guided Dosing Regimen Design. 7.1 General Considerations for the Selection of the Dosing Interval. 7.2 Protocols For Pharmacokinetic Guided Dosing Regimens. 8 Simulation Exercises. 9 Problems. 13 Multiple Intermittent Infusions. 2 Steady State Equations for Multiple Intermittent Infusions. 3 Mono-exponential Decay During A Dosing Interval: Determination of Peaks, Toughs and Elimination Half-Life. 3.1 Determination of Half-Life. 3.2 Determination of Peaks and Troughs. 4 Determination of the Volume of Distribution. 5 Individualization of Dosing Regimens. 6 Simulation Exercises. 7 Problems. 14 Multiple Oral Doses. 2 Steady State Equations. 2.1 Time to Peak Steady State Plasma Concentration (TMAX,SS). 2.2 Value of Peak Steady State Plasma Concentration (CMAX,SS). 2.3 Value of Trough Steady State Plasma Concentration (CMIN,SS). 2.4 Average Steady State Plasma Concentration (Cpav,SS). 2.5 Overall Effect of Absorption Parameters on a Steady State Dosing Interval. 3 Equations Used Clinically to Individualize Oral Doses. 4 Simulation Exercises. 15 Nonlinear Pharmacokinetics. 1 Linear Pharmacokinetics. 2 Non-Linear Processes In Absorption, Distribution, Metabolism and Excretion. 3 Pharmacokinetics Of Capacity Limited Metabolism. 3.1 Kinetics of Enzymatic Processes. 3.2 Plasma Concentration-Time Profile. 4 Phenytoin Basic Equation Basic For Steady State. 4.3 Estimation of Doses and Plasma Concentrations. 4.4 Influence of Km and Vmax and Factors Affecting These Parameters. 4.5 Time to Eliminate the Drug. 4.6 Time to Reach Steady State. 4.7 Individualization of Doses of Phenytoin. 5. Problems. 16 Introduction to Pharmacodynamic Models and Integrated Pharmacokinetic- Pharmacodynamics (PK-PD)

5 Models. 2 Classical Pharmacodynamic Models Based on Receptor Theory. 2.1 Receptor Binding. 2.2 Response-Concentration Models. 3 Empirical Pharmacodynamic Models Used Clinically. 3.1 Sigmoidal Emax and Emax Model. 3.2 Linear Adaptations. 4 Integrated PK-PD Models: Intravenous Bolus Injection in the 1-Compartment Model and the Sigmoidal Emax Model. 4.1 Simulation Exercise. 5 Hysteresis and the Effect Compartment. 5.1 Simulation Exercise. 17 Mechanism Based Integrated Pharmacokinetic-Pharmacodynamic Models. 2 Alternative Models For the Drug-Receptor Interaction: Operational Model of Agonism. 2.1 Simulation Exercise. 3 Physiological Turnover Model and its Characteristics. 3.1 Points of Drug Action. 3.2 System Recovery After Change in Baseline Value. 4 Indirect Effect Models Characteristics of Indirect Effect Drug Responses. 4.3 Characteristics of Indirect Effect Models Illustrated Using Model I. Inhibition of kkin. 4.4 The Other Indirect Models. 5 Transduction and Transit Compartment Models. 5.1 Simulation Exercise. 6 Tolerance Models. 6.1 Counter-Regulatory Force Model. 6.2 Precursor Pool Depletion Model. 7 Irreversible Drug Effects. 7.1 Application of the Turnover Model to Irreversible Drug Action. 7.2 Model For Hematological Toxicity of Anticancer Drugs. 8 Disease Progression Models. 8.1 Generation of Drug Response. 8.2 Drug Interaction With the Disease. 8.3 Disease Progression Models. Appendices. Appendix :1 Review of Exponents and Logarithms. 1 Exponents. 2 Logarithms: Log and Ln. 3 Performing Calculations in the Logarithm Domain. 3.1 Multiplication. 3.2 Division. 3.3 Reciprocals. 3.4 Exponents. 4 Examples of calculations using exponential expressions and logarithms. 5 The Decay Function. 6 The Growth Function. 7 The Decay Function in Pharmacokinetics. 8 Problems. Appendix 2: Rates of Processes. 2 Order of a Rate Process. 3 Zero Order Process. 4 First Order Process. 4.1 Equation For a First Order Process. 4.2 Time For 50% Completion: The Half-Life. 5 Comparison of Zero and First Order Processes. 6 Detailed Example of First Order Decay in Pharmacokinetics. 6.1 Equations and Semi-logarithmic Plots. 6.2 The Half-Life. 6.3 Fraction or Percent Completion of a First Order Process Using First Order Elimination as an Example. 7 Examples of the Application of First Order Kinetics to Pharmacokinetics. Appendix 3: Creation of Excel Worksheets for Pharmacokinetic Analysis. 1 Measurement of AUC and Clearance. 1.1 Trapezoidal Rule. 1.2 Excel Worksheet to Determine AUC0 8 and Clearance.

6 2 Analysis of Data from an Intravenous Bolus Injection in a One-Compartment Model. 3 Analysis of Data from an Intravenous Bolus Injection in a Two-Compartment Model. 4 Analysis of Oral Data in One Compartment Model. 5 Non-Compartmental Analysis of Oral Data. Appendix 4: Derivation of the Equations For Multiple Intravenous Bolus Injections. 1 Assumptions. 2 Basic Equation for Plasma Concentrations After Multiple Intravenous Bolus Injections. 3 Steady State Equations. Appendix 5: Summary of the Properties of the Fictitious Drugs Used in the Text. Glossary of Common Abbreviations and Symbols.