Pharmacokinetics and Biopharmaceutics
Advanced Course

This website: https://www.boomer.org/c/p4/
The eBook: Basic Pharmacokinetics and other eBooks for the iPad^®
and Apps for the iPhone^®, iPad^® and AppleTV^®

Course Description

Pharmacokinetics and Biopharmaceutics

Development of pharmacokinetic equations using Laplace transforms. Modeling pharmacokinetic data using computer programs such as Boomer.

Basic Pharmacokinetics and Biopharmaceutics

Description and quantitation of factors affecting the absorption, distribution, and metabolism, and excretion of drugs. Development of appropriate dosage regimens and graphical analysis of drug concentration data sets. Bioequivalence and drug product testing. Drug analysis in biological matrix.

Application of biopharmaceutical and pharmacokinetic theory to clinical problems involved in optimizing and monitoring drug use in patients

Course Objectives

• Demonstrate an understanding of the differential and integrated equations associated with pharmacokinetic models
• Derive integrated equations associated with pharmacokinetic models
• Model pharmacokinetic data using computer programs such as Boomer

• Demonstrate an understanding and assess factors which affect the absorption, distribution, metabolism and excretion of drugs
• Calculate parameter values from appropriate data using graphical and computer techniques
• Calculate appropriate dosing regimens using appropriate criteria
• Describe the techniques used to determine drug concentrations in biological and formulation matrices

Instructor: David W.A. Bourne, B.Pharm., Ph.D.

E-mail Address

• david@boomer.org

Related Resources

References text - see the online list of pharmacokinetic text

Course Outline

1. Online Resources
2. Background Mathematical Material
3. Biopharmaceutics and Pharmacokinetic Introduction

Modeling
• Modeling
• Summarize Data
• Explore Mechanisms
• Make Predictions
• General Method
• Mathematical Models
• Least Squares Criteria
• Parameter Adjustment

Program Set-Up
• Program Set-Up
• Program Set-Up - General approach
• Program Set-Up - Boomer
  • Boomer (Boomer On-line Manual - Chapter Four and Boomer On-line Manual - Chapter Six)
    • Multi IV Bolus Dose Simulation - Two Compartment
    • Simultaneous fit to IV and Oral Data - Two Compartment IV Bolus (IV and Oral Data files)
• Program Set-Up - Phoenix WinNonlin
• Workshop Exercise
  Download and run Boomer

Program Output
• Program Output
• Final Parameter Values
• Data Output
• Statistical Results
• Graphical Output
• Additional Output Files
4. One Compartment IV Bolus
5. Analysis of Urine Data
6. Intravenous Infusion
7. Routes of Drug Administration
8. Pharmacokinetics of Oral Administration
9. Calculation of Bioavailability Parameters
10. Bioavailability Studies
Analytical Integration - Integrating Differential Equations using Laplace Tranforms
• Integrating Differential Equations using Laplace Tranforms
• More Laplace transforms
  • More about the Laplace Transform Method
  • Finger Print Method, Inverse Laplace Transform
  • Finger Print Method - Example 1
  • Finger Print Method - Example 2
  • Multi Compartment Pharmacokinetic Models
  • Finger Print Method - Example 3
  • Convolution
• Workshop Exercise
  More practice problems

Numerical integration
• Numerical Integration
• Euler's Method
  • Spreadsheet example for stepsize adjustment with Euler's method
• Runge-Kutta Methods
• Multi-Step Methods
• Comparison Between Integration Methods

Optimization
• Optimization
• Optimization Examples
• Optimization Algorithms
• Steepest Descent Method
• Gauss-Newton Methods
• Nelder-Mead (Simplex) Method
• Grid Search Method
• Optimization Methods - Notes on Use with Boomer
• Workshop Exercise
  Integration methods
  • Runge-Kutta method .BAT file
  • Runge-Kutta-Fehlberg method .BAT file
  • Gear's method .BAT file
  
  Optimization methods
  • Gauss-Newton (Damping) method .BAT file
  • Simplex method .BAT file
  • Simplex > Gauss-Newton (Damping) method .BAT file
  • Simplex > Gauss-Newton (Damping) method - multiple runs .BAT file use eBest to pick best fit
  
  More complex problems
  • Simultaneous fit to four lines (Drug and metabolite in plasma and urine) .BAT file
  • Simultaneous fit to IV and oral data .BAT file
  • Simultaneous fit to three lines (After three different IV doses) .BAT file

Weighting Schemes
• Weighting Data
• Weighting Methods
• Equal Weight
• Reciprocal Variance
• Weighting Schemes
• Iteratively Reweighted Least Squares (IRWLS)
• Extended Least Squares (ELS)
• Weighting Example

  ---

  Tutorial for determining 'a' and 'b' for your PHAR 7633 project data with a Spreadsheet Example for Determining 'a' and 'b' (NOTE: this file uses a Macro)
  Tutorial illustrating the entry of data weight values directly with the x and y values
  A two data sets .BAT file (Ch9905b.BAT) with the required data sets (Ch9905bp.DAT and Ch9905bu.DAT). The output file is Ch9905.OUT
• Workshop Exercise
  • Simultaneous fit to plasma and urine data .BAT file with plasma and urine .DAT files
  • Simple fit to IV data with equal weight .BAT file
  • Simple fit to IV data with weight 1/val(obs) .BAT file
  • Simple fit to IV data with weight 1/val(obs)^2 .BAT file
  • The .BAT files that created the previous data .BAT file
11. Physiological Factors Affecting Oral Absorption
12. Physical-Chemical Factors Affecting Oral Absorption
13. Formulation Factors
Selection of the "best" model
• Selection of the "best" model
• Evaluation of Graphical Output
• Parameter Variability
• Statistical Criteria
• Workshop Exercise
  • Simultaneous fit to three lines (after three different IV doses) .BAT file - as above
  • ... Michaelis-Menten elimination replaces first order kinetics .BAT file
  • ... after adding a second compartment .BAT file
14. Multiple IV Bolus Dose Administration
15. Multiple Oral Dose Administration
16. Routes of Excretion
17. Metabolism
18. Drug Distribution
19. Multi-Compartment Pharmacokinetic Models
20. Noncompartmental Analysis
21. Non-Linear Pharmacokinetic Models
22. Non-Linear Regression Analysis of Pharmacokinetic Data
Identifiability
• Identifiability
• Identifiability - Definitions
• Identifiability - Examples
• Identifiability - Numerical Approaches
• Identifiability - Analytical Approaches
• Workshop Exercise
  • Fitting model to Drug and Metabolite in plasma (only) .BAT file
  • Fitting model to Drug and Metabolite in plasma (only) .BAT file Multiple runs
  • ... adding Drug in Urine data .BAT file
  • ... fitting all four data sets .BAT file as above
Optimal sampling
• Optimal Sampling

Bayesian Analysis
• Bayesian Analysis

Population Pharmacokinetic (PopPK) Modeling
• Slides in PDF Format
23. Pharmacodynamic and Physiologically Based Pharmacokinetic Models
24. Pharmaceutical Analysis
25. Clinical Applications of Pharmacokinetics

Assignments

• Plotting Data on Linear Graph Paper - Chapter 2
• Plotting Data on Semi-Log Graph Paper - Chapter 2
• AUC Calculation Using the Trapezoidal Rule - Chapter 2
• Calculate One Compartment Parameters - Chapter 4
• Non-Linear Program - Chapter 4
• Where did the Poison come from? - Chapter 4
• Analysis of Urine Data using ΔU/Δt - Chapter 5
• Intravenous Infusion 1 - Chapter 6
• Intravenous Infusion 2 - Chapter 6
• Intravenous Infusion 3 - Chapter 6
• Method of Residuals - Chapter 9
• Wagner-Nelson Method - Chapter 9

• Homework Set #6 [Calculation of F] Chapter 9 - Submit Your Answer
• Homework Set #7 [Multiple IV Bolus 1] Chapter 14 - Submit Your Answer
• Available for Practice - Practice Homework [Multiple IV Bolus 2] Chapter 14
• Available for Practice - Practice Homework [Multiple IV Bolus 3] Chapter 14
• Available for Practice - Practice Homework [Multiple IV Bolus 4] Chapter 14
• Homework Set #8 [Multiple IV Bolus 5] Chapter 14 - Submit Your Answer
• Homework Set #9 [Multiple Oral Dose 1] Chapter 15 - Submit Your Answer
• Available for Practice - Practice Homework [Multiple Oral Dose 2] Chapter 15
• Available for Practice - Practice Homework [Multiple Oral Dose 3] Chapter 15
• Available for Practice - Practice Homework [Multiple Oral Dose 4] Chapter 15
• Available for Practice - Practice Homework [Multiple Oral Dose 5] Chapter 15
• Homework Set #10 [Estimate Elimination Rate Constant] Chapter 16 - Submit Your Answer
• Available for Practice - Practice Homework [Multi-Compartment Micro to Macro] Chapter 19
• Available for Practice - Practice Homework [Multi-Compartment Macro to Micro] Chapter 19
• Available for Practice - Practice Homework [Multi-Compartment Method Residuals] Chapter 19
• Available for Practice - Practice Homework [Multi-Compartment Dosing Problem] Chapter 19
• Available for Practice - Practice Homework [Non-compartmental Analysis] Chapter 19
• Available for Practice - Practice Homework [Non-linear Elimination Kinetics] Chapter 20