PKfit - A Pharmacokinetic Data Analysis Tool in R

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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

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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 http//www.pharsight.com
• Boomer http//www.boomer.org

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User Interface

• Menu-driven mode
• Users need not require to be familiar with
  programming of R
• Analyses data step by step

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

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Model fitting
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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 Akaikes Information Criterion (by
  Jose Pinheiro and Douglas Bates)
• stats4
• BIC function Bayesian information criterion

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Coding process
7
2020/9/15
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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)
• Akaikes Information Criterion (AIC)
• Schwarzs Bayesian Criterion (SBC)
• Diagnostic plots
• Linear plots
• Semi-log plots
• Residual plots

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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)

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Comparison of software
WinNonlin WinNonlin WinNonlin Boomer Boomer Boomer PKfit PKfit PKfit
equal 1/Cp 1/Cp2 equal 1/Cp 1/Cp2 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)
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Comparison of software
WinNonlin WinNonlin WinNonlin Boomer Boomer Boomer PKfit PKfit PKfit
equal 1/Cp 1/Cp2 equal 1/Cp 1/Cp2 equal 1/Cp 1/Cp2
Model 5 ? ? ? ? ? ? ? ? ?
Model 6 ? ? X ? ? ? ? ? ?
Model 7 ? ? X ? ? ? ? ? ?
Model 8 ? X X ? ? ? ? ? ?
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 Absorption and Linear
Elimination without Lag Time Model 8
One-Compartment PK Model Extravascular
Single-Dose with Zero-Ordered
Absorption and Nonlinear Elimination without Lag
Time ? Running O.K. (AE ? 5) X Not
acceptable for final PK parameters (AE gt 5)
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Comparison of software
WinNonlin WinNonlin WinNonlin Boomer Boomer Boomer PKfit PKfit PKfit
equal 1/Cp 1/Cp2 equal 1/Cp 1/Cp2 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 gt 5)
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Comparison of software
WinNonlin WinNonlin WinNonlin Boomer Boomer Boomer PKfit PKfit PKfit
equal 1/Cp 1/Cp2 equal 1/Cp 1/Cp2 equal 1/Cp 1/Cp2
Model 12 ? ? ? ? ? ? ? ? ?
Model 13 ? ? ? ? ? ? ? ? ?
Model 14 X X X ? ? ? ? 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 gt 5) X
Crashed
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Simulation
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Packages required

• stats
• runif function random uniform distribution
  derivates
• rnorm function random normal distribution
  derivates

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Coding process
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2020/9/15
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Output information

• Time and concentration
• Linear plot
• Semi-log plot

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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. Conc. Conc.
0.5 12.39 12.39 12.39
1 22.29 22.29 22.29
2 36.15 36.15 36.15
3 44.14 44.14 44.14
4 48.08 48.08 48.08
6 48.64 48.64 48.64
8 44.33 44.33 44.33
10 38.37 38.37 38.37
12 32.27 32.27 32.27
16 21.82 21.82 21.82
20 14.34 14.34 14.34
24 9.314 9.314 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)
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Thanks to

• Dr. Woodrow Setzer for odesolve
• Dr. Jasjeet Sekhon for rgenoud
• Dr. Anthony Rossini for scripting

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Reference

• R Installation and Administration, Version 2.0.1,
  2001.
• (http//cran.r-project.org/doc/manuals/R-admi
  n.html)
• R Language Definition, Version 1.9.1, 2004.
• (http//cran.r-project.org/doc/manuals/R-lang
  .html)
• Sekhon, J.S. and Mebane, W.R.Jr., Genetic
  Optimization Using Derivatives Theory and
  Application to Nonlinear Models. Political
  Analysis, 7187-210, 1998.
• Setzer, R.W., The odeslove Package, 2004.
• The R Project for Statistical Computing.
• (http//www.r-project.org)
• Writing R Extensions, Version 1.9.1, 2004.
• (http//cran.r-project.org/doc/manuals/R-exts
  .html)

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Thanks for your attention!