- On 1 Dec 1997 at 10:57:42, David_Bourne (david.-at-.pharm.cpb.uokhsc.edu) sent the message

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[Various replies - db] From: "A.J.Macdonald"

To: PharmPK.at.pharm.cpb.uokhsc.edu

Date: Fri, 28 Nov 1997 14:27:48 +0000

MIME-Version: 1.0

Subject: Experience with MATLAB

Priority: normal

Paul,

I have been using Matlab for PBPK modelling. Using the GUI add-on

Simulink, differential equations can be modelled and linked easily.

They can be represented in transfer function or state space form, or

you can model the equations yourself.

Two stiff system algorithms are available with Simulink, Gear and Linsim.

Runge Kutte23 and 45, Adams and Euler algorithms are also available.

There is a Systems Identification toolbox for parameter estimation and

a Statistics Toolbox that provides methods for parameter sensitivity

analysis and optimization. There are a couple of IEEE papers that will give

you some idea of Matlabs capabilities.

Wada, D.R., Ward, D.D. (1994), "The hybrid model: a new

pharmacokinetic model for computer-controlled infusion pumps," IEEE

Transactions on Biomedical Engineering., vol. 41, No. 2.

Wada, D.R., Stanski, D.R., Ebling, W.F. (1995), "A PC-based graphical

simulator for physiological pharmacokinetic models", Computer Methods

and Programs in Biomedicine., vol. 46, pp. 245-255.

Hope this helps

Regards

Alex MacDonald

Graduate Student

Dept of Medicine and Pharmacology and

Dept of Automatic Control and Systems Engineering

University of Sheffield

UK

Tel. (01142) 225608

Fax. (01142) 731729

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Date: Fri, 28 Nov 1997 15:14:43 +0000

From: "Russell Wada"

Subject: Experience with MATLAB

To: PharmPK.at.pharm.cpb.uokhsc.edu

Comments: Authenticated sender is

Reply-to: russellw.-at-.pharsight.com

Priority: normal

I have used MATLAB/SIMULINK for many things, have found it an easy

tool to use for modeling and simulation, and have not felt limited by the

software.

Some examples: (1) population PKPD estimation - linearization methods, global

two-stage (2) optimal sampling (3) PBPK modeling and simulation (4) nonlinear

feedback control (5) ANOVA (6) EEG signal processing

MATLAB is a command-line, interpretive, matrix-based language with

scripts. It has good graphics and reasonable data handling capabilities.

To do

simple things, the user can interact at the command line. To do more

complex things, the user needs to write equations in the MATLAB language,

store the equations in user-defined subroutines, and call

user-defined subroutines or built-in subroutines where needed.

MATLAB can do linear ODE's.

MATLAB is a general-purpose tool. It has no specific tools for

pharmaceutics, as an example.

To be useful for PKPD applications requires extra MATLAB toolboxes.

I have used the toolboxes for Optimization, Splines, Control, and

Signal Processing. I would like the toolbox for Stats, although the

basic tools are present in the standard package (i.e. F-distributions)

I have found SIMULINK to be very useful for nonlinear simulation, although

this

is also an extra package. SIMULINK is a graphical simulator, with

about 6 different integration routines (i.e. gear, rk45). SIMULINK models

can be simulated from the graphical simulator window, or the command-line.

I find the latter more useful, because it allows, for example,

parameter estimation and Monte-Carlo simulation.

SIMULINK models are saved as MATLAB files. Thus if one needs to

write a general ODE which cannot be expressed in SIMULINK, then one

can (probably) write the MATLAB file directly. I think that SIMULINK

files are still needed to simulate the ODE.

Some limitations of MATLAB 4.0 are: (1) User needs familiarity with

matrices, and engineering/applied math concepts;

(2) Previous experience with language such as C/FOrtran;

(3) Sometimes simulator doesn't give proper results (stiff PBPK

models) Needs careful attention to choice of algorithm/simulation

parameters. (4) difficult to handle discrete events.

D. Russell Wada

Pharsight Corp

299 California Ave, Suite 300

Palo Alto CA 94306

Ph: (650) 462-5607

Fx: (650) 462-5610

Em: russellw.at.pharsight.com

---

Date: Fri, 28 Nov 1997 10:03:58 -0800

From: "Traub, Richard J"

Subject: PharmPK Experience with MATLAB

To: "'PharmPK.-at-.pharm.cpb.uokhsc.edu'"

MIME-version: 1.0

X-Priority: 3

Hello:

Paul Damian asks:

Can anyone tell me if MATLAB is a good tool for modeling

using systems

of differential equations based on their experience with

the program?

In my work I use MATLAB and SIMULINK to model the transport of

radionuclides in the body.

A current project is to calculate the exhalation rate of Rn-220

(Thoron) following an inhalation of thorium oxide. (a later task will

be to calculate the radiation doses) To do this I have implemented what

I call a six stage hybrid biokinetic model. I model the kinetics of

each nuclide starting with Th-232 explicitly (thus six stages), the

first 5 nuclides are modeled using the biokinetic models recommended by

the ICRP while the biokinetic model for thoron is a model described by

Peterman for inert gases (thus a hybrid model). All totaled, the model

contains about 350 compartments. The model is stiff (transfer

coefficients between the compartments range over 9 orders of magnitude,

the half-life of Th-232 is on the order of 10^10 years and the half life

of thoron is 55 sec.).

So far as I can tell, the MATLAB/Simulink combination is

working well. MATLAB allows the user to choose which differential

equation solver to use both stiff and nonstiff solvers. In my opinion,

MATLAB is very powerful and is capable of doing just about anything you

want it to.

For simple pharmacokinetic systems, you would not need to use

Simulink but then you would need to write your own MATLAB routines that

describe the differential equations and the jacobian (Simulink does that

for you). The nice thing about Simulink is that it provides a nice

graphical tool to build compartmental systems such as you find in

pharmacokinetics. You can "build" a single compartment and then

replicate the compartment and connect the compartments using a line

drawing tool.

If you use MATLAB and don't want to write your own routines for

optimization, probability distributions, etc. you will probably need to

add various MATLAB toolboxes. So you might want to get Matlab,

Simulink, the optimization tool box, the statistics toolbox, and

perhaps, the splines toolbox. All of which add to the cost. The

learning curve for MATLAB and Simulink is steep, and in my opinion the

manuals that come with MATLAB are not as helpful as they might be.

Hope this helps.

Richard Traub

PNNL

All disclaimers apply - On 1 Dec 1997 at 08:42:14, Koplowitz Barry (Koplowitz_Barry.PRILVMS1.-at-.msmail.bms.com) sent the message
To: PharmPK.aaa.pharm.cpb.uokhsc.edu

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Unfortunately I have not used METLAB but I have been using a similar program

called MathCad for the same purpose as you describe. I have not seen these

types of programs used in pharmacokinetics and feel there is a large potential

for their use. I have used MathCad to solve differential equations resulting

from compartment model. Included are functions to solve stiff equation,

Fourier transform, nonlinear regression anaylsis, convolution and

deconvolution, Symbolic solver for example: Laplace transform, integration and

differential equations, all of which I've applied to pharmacokinetic problems.

I am really happy to see others are applying programs like METLAB and MathCad

to the field of pharmacokinetics.

Best Of Luck

Barry Koplowitz

Bristol-Myers Squibb - On 8 Dec 1997 at 14:09:38, PAUL_DAMIAN.-at-.ccmail.rustei.com (PAUL DAMIAN) sent the message

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Many thanks to all of you who responded to my request for information

about MATLAB. I believe David Bourne has posted most of the replies to

the list. I found the information very helpful.

Paul Damian PhD,MPH

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