1. PKfit - A Pharmacokinetic Data Analysis Tool in R
Speaker: Chun-ying Lee1
Advisor: Yung-jin Lee2
1Pharmacy Department, Changhua Christian Hospital
Changhua, Taiwan
2College of Pharmacy, Kaohsiung Medical University,
Kaohsiung, Taiwan

2. Motivation Using available packages in R to create the program
Selecting menu-driven mode as the user interface
Studying the application of genetic algorithm to PK
data analysis
Comparing with WinNonlin and Boomer
WinNonlin
Boomer
2017/4/14

3. User Interface Menu-driven mode
Users need not require to be familiar with programming of R
Analyses data step by step
2017/4/14

4. PK models included
Fourteen PK models are currently available (all single-dosed)
Intravenous drug administrations with i.v. bolus or i.v. infusion
Extravascular drug administrations, linear PK with 1st-order absorption/elimination or with nonlinear (Michaelis-Menten) elimination models
2017/4/14

5. Model fitting

6. Packages required odesolve (by R. Woodrow Setzer)
lsoda function: solving differential equations
rgenoud (by Walter R. Mebane and Jasjeet S. Sekhon )
genoud function: Genetic algorithm
stats
nls function: Gauss-Newton algorithm (by Douglas M. Bates and Saikat DebRoy)
optim function: Nelder-Mead simplex method
logLik function: Log-Likelihood (by Jose Pinheiro and Douglas Bates)
AIC function: Akaike’s Information Criterion (by Jose Pinheiro and Douglas Bates)
stats4
BIC function: Bayesian information criterion
2017/4/14

7. Coding process 7
2017/4/14

8. Output information Summary table
Time, observed and calculated concentrations
Weighted residuals
Area under plasma concentration curves (AUC)
Area under the first moment curves (AUMC)
Final values of PK parameters
Model selection criteria
Log-Likelihood (LL)
Akaike’s Information Criterion (AIC)
Schwarz’s Bayesian Criterion (SBC)
Diagnostic plots
Linear plots
Semi-log plots
Residual plots
2017/4/14

9. Validation All the conditions are set the same in these three software
Data sets
Selected models
Initial values for parameters
Fitting algorithms and numerical integration tools
WinNonlin: Nelder-Mead Simplex method / RKF5
Boomer: Nelder-Mead Simplex  Gauss-Newton / RKF5
Criteria
Prediction (absolute) error (PE)
Percentage of prediction (absolute) error (%PE)
2017/4/14

10. Comparison of software
WinNonlin
Boomer
PKfit
equal
1/Cp
1/Cp2
Model 1 
Model 2
Model 3
Model 4
Model 1: One-Compartment PK Model I.V. Bolus Single-Dose with Linear Elimination
Model 2: One-Compartment PK Model I.V. Bolus Single-Dose with Nonlinear Elimination
Model 3: One-Compartment PK Model I.V. Infusion Single-Dose with Linear Elimination
Model 4: One-Compartment PK Model I.V. Infusion Single-Dose with Nonlinear Elimination
: Running O.K. (AE%  5%)
2017/4/14

11. Comparison of software
WinNonlin
Boomer
PKfit
equal
1/Cp
1/Cp2
Model 5 
Model 6 X
Model 7
Model 8
Model 5: One-Compartment PK Model Extravascular Single-Dose with First-Ordered
Absorption and Linear Elimination without Lag Time
Model 6: One-Compartment PK Model Extravascular Single-Dose with First-Ordered
Absorption and Nonlinear Elimination without Lag Time
Model 7: One-Compartment PK Model Extravascular Single-Dose with Zero-Ordered
Model 8: One-Compartment PK Model Extravascular Single-Dose with Zero-Ordered
: Running O.K. (AE%  5%)
X: Not acceptable for final PK parameters (AE% > 5%)
2017/4/14

12. Comparison of software
WinNonlin
Boomer
PKfit
equal
1/Cp
1/Cp2
Model 9 
Model 10
Model 11 X
Model 9: Two-Compartment PK Model I.V. Bolus Single-Dose with Linear Elimination
Model 10: Two-Compartment PK Model I.V. Infusion Single-Dose with Linear Elimination
Model 11: Two-Compartment PK Model Extravascular Single-Dose with First-Ordered
Absorption and Linear Elimination without Lag Time
: Running O.K. (AE%  5%)
X: Not acceptable for final PK parameters (AE% > 5%)
2017/4/14

13. Comparison of software
WinNonlin
Boomer
PKfit
equal
1/Cp
1/Cp2
Model 12 
Model 13
Model 14 X
Model 12: One-Exponential Term
Model 13: Two-Exponential Term
Model 14: Three-Exponential Term
: Running O.K. (AE%  5%)
X: Not acceptable for final PK parameters (AE% > 5%)
X: Crashed
2017/4/14

14. Simulation

15. Packages required stats
runif function: random uniform distribution derivates
rnorm function: random normal distribution derivates
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16. Coding process 16
2017/4/14

17. Output information Time and concentration Linear plot Semi-log plot
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18. Validation
All the simulation results in these three software are very similar with “Error type = No error” with four significant digits
WinNonlin
Boomer
PKfit
Time
Conc.
0.5
12.39 1
22.29 2
36.15 3
44.14 4
48.08 6
48.64 8
44.33 10
38.37 12
32.27 16
21.82 20
14.34 24
9.314
A one-compartment PK model with
extravascular, single-dose with
first-ordered absorption without lag
time and linear elimination
Dose= 500 (mg)
ka= 0.32 (1/hr)
kel= 0.11 (1/hr)
Vd= 5.8 (L)
2017/4/14

19. Thanks to… Dr. Woodrow Setzer for odesolve
Dr. Jasjeet Sekhon for rgenoud
Dr. Anthony Rossini for scripting
2017/4/14

20. Reference R Installation and Administration, Version 2.0.1, 2001.(
R Language Definition, Version 1.9.1, 2004. (
Sekhon, J.S. and Mebane, W.R.Jr., Genetic Optimization Using Derivatives: Theory and Application to Nonlinear Models. Political Analysis, 7: , 1998.
Setzer, R.W., The odeslove Package, 2004.
The R Project for Statistical Computing. (
Writing R Extensions, Version 1.9.1, 2004. (
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21. Thanks for your attention!