- On 8 Feb 2004 at 09:14:25, Nick Holford (n.holford.-a-.auckland.ac.nz) sent the message

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Maria and Ladislav,

Thanks for bringing the CTDB package to my attention. I have not yet

had time to explore the CTDB system but I have a couple of comments

based on reading the introduction.

The introduction on http://www.uef.sav.sk/advanced.htm states "the

terms pharmacokinetics and pharmacodynamics had been created by using

the Greek words kinetics and dynamics" but then appears to ignore their

original Greek meaning in attempting to justify the term dynamics to

encompass both pharmacokinetic and pharmacodynamic processes.

"From my limited knowledge of Greek I would say that the word "kinetic"

comes from the Greek word "kinein" meaning "to move" while "dynamic"

comes from the Greek word "dynamis" meaning "power" or "force". E.g.

the moving meaning of kinetic is seen in the word cinematography where

"cine" refers to moving pictures while the force meaning of dynamic is

seen in dyne referring to units of force in the CGS system.

"

Given that a lot of pharmacokinetics can be thought of as describing

the movement of drug molecules into through and out of the body then

the kinetic suffix seems appropriate. Similarly pharmacodynamics

describes the responses to drug concentration, which at least in the

early days of pharmacology were observed by expressing forces generated

by organs, so that dynamics seems a suitable suffix for this class of

processes.

Perhaps you would like to offer an explanation for why you choose to

use the term dynamics to describe both pharmacokinetics and

pharmacodynamics when it seems to me that these terms have commonly

accepted and linguistically separate meanings?

Later on the same page you say "If functions, such as

poly-exponentials, are fitted to the [...] profiles without taking into

consideration the inputs of the drug into the body (which is a common

way in PK methods)...". This seems strange to me. I cannot recall the

use of closed form pharmacokinetic models involving sums of

exponentials that did not explicitly define an input process e.g.

bolus, zero-order, first-order, unless it was using some

semi-parametric method such as splines when the input process was

ill-defined a priori and not readily described by an explicit

parametric input process. Could you provide some justification for your

assertion that polyexponential models are commonly used without

consideration of the drug input?

Nick

Nick Holford, Dept Pharmacology & Clinical Pharmacology

University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New

Zealand

email:n.holford.-a-.auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556

http://www.health.auckland.ac.nz/pharmacology/staff/nholford/ - On 11 Feb 2004 at 16:23:42, "Durisova Maria" (exfamadu.at.savba.sk) sent the message

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Nick,

We tried to discuss this issue in the PharmPK in 1998. Unfortunately,

there was no interest in this issue at that time. At the beginning we

can

remind

two studies:

D. M. Fisher. (Almost) Everything you learned about pharmacokinetics was

(somewhat) wrong! Anesth. Analg. 1996, 83: 901-903.

J. M. van Rossum, J. E. de Bie, G. van Lingen, H. W. Teeuwen.

Pharmacokinetics

from a dynamic systems point of view. J. Pharmacokin. Biopharm.

1989, 17: 365-392.

As follows from the title of the first work, there are problems in the

field

of pharmacokinetics. The title of the second study indicates that the

term

"dynamic system" is not new in the given field.

> Given that a lot of pharmacokinetics can be thought of as describing

> the movement of drug molecules into through and out of the body then

> the kinetic suffix seems appropriate.

In practice, such a movement cannot be directly measured. This is the

main

problem if the conception based on the movement of drug molecules is

used

as the basis of pharmacokinetics. We only know what is the cause of

such

a movement, i.e. a drug input into the body, and what is an outcome,

i.e. a resultant drug concentration-time profile in blood.

The relationship between the given cause and outcome is determined by

the drug behavior in the body. The drug behavior in the body is a

dynamic

process that develops over a course of time and that depends on:

the actual drug input into the body, "the body history" (e.g. on

preceding

drug inputs into the body), and on the actual physiological or

pathological

state of the body. It follows then that, time is an essential

independent

variable of the model of the drug behavior in the body. This is what

the adjective "dynamic" in the term "dynamic process" refers to.

The analogous understanding of the term "dynamic process" is

common also in other scientific fields (1). A drug effect, a drug

dissolution,

bioavailability of a drug, e.t.c., also are dynamic processes.

Based on this fact, the drug behavior, drug effect, drug dissolution,

drug bioavailability, and many other dynamic processes can be modeled

in a conceptually, methodologically, and computationally unified way,

employing methods of the dynamic-system theory. Methods for such

modeling are implemented in the package CTDB. Using this package,

optimal structures and point estimates of parameters of models of

diverse

dynamic processes can be determined using a non-iterative method,

i.e. the method which does not require initial estimates of model

parameters.

Thereafter, the models can be refined and interval estimates of

parameters

can be determined, employing iterative procedures. The use of the

non-iterative

method in the package CTDB markedly simplifies and speeds up modeling

procedures.

> I cannot recall the

> use of closed form pharmacokinetic models involving sums of

> exponentials that did not explicitly define an input process

In practice, polyexponential functions (which are solutions of linear

compartment

models for single instantaneous drug inputs into the body, obtained

after

adopting well known simplifying assumptions about the drug behavior in

the

body)

are very frequently fitted to measured drug concentration data in blood.

These procedures yield models of data, because resulting model functions

are fundamentally restricted to the given drug inputs. Additionally,

they

do

not explicitly employ the given inputs in fitting procedures. In

contrast to

this,

models obtained by the package CTBD are mathematical structures,

i.e. differential equations, that after introducing mathematically

described

diverse drug inputs into the body originate profiles describing

resultant

respective concentration-time profiles of drugs in blood.

The use of the models obtained by the package CTBD can be exemplified

as follows: As seen in the figure given at

http://www.uef.sav.sk/Slide1.JPG,

the model of the dynamic system that represented the behavior of FVIII

in

the body was determined using a test-dose of FVIII given in a short-time

infusion.

Thereafter, this model was used to simulate the concentration-time

profile

of FVIII resulting from multiple-bolus doses of FVIII given at

non-equidistantly spaced times. The figure at

http://www.uef.sav.sk/Slide2.JPG

shows that the given model can be also utilized in an "opposite" way,

i.e. to determine a FVIII infusion, necessary to reach and maintain

required levels of FVIII.

1. Ljung, L. System identification - theory for the user. 2nd ed.

PTR Prentice Hall: Upper Saddle River 1999.

Regards,

Maria Durisova

and

Ladislav Dedik - On 12 Feb 2004 at 10:29:52, Nick Holford (n.holford.-a-.auckland.ac.nz) sent the message

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Maria, Ladislav,

I have read the editorial by Denis Fisher (Fisher DM. (Almost)

everything you learned about pharmacokinetics was (somewhat) wrong!

Anesth Analg 1996;83(5):901-3.). But it sheds no light on why one

should prefer the term dynamics over kinetics. I am aware that others

like to speak of dynamic systems in the context of pharmacokinetics but

this terminology is used by only a minority of authors.

The reason for my comments on your web page was to try to get you to

provide some convincing reason for changing the name from kinetics to

dynamics. I am afraid your response does not convince me that there is

any reason to change the name.

Whatever you call it I think that you and I generally use very similar

models. Can we agree that a rose by any other name would smell as

sweet? I'll stick to pharmacokinetics and pharmacodynamics and you can

lump everything into system dynamics.

Nick

Nick Holford, Dept Pharmacology & Clinical Pharmacology

University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New

Zealand

email:n.holford.aaa.auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556

http://www.health.auckland.ac.nz/pharmacology/staff/nholford/ - On 12 Feb 2004 at 15:11:58, "Durisova Maria" (exfamadu.aaa.savba.sk) sent the message

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Nick,

"

The reason for my comments on your web page was to try to get you to

provide some convincing reason for changing the name from kinetics to

dynamics. I am afraid your response does not convince me that there is

any reason to change the name.

"

Despite this, linear deterministic compartment models commonly

used in the methods called PK methods, i.e. sets of ordinary

differential

equations without time delays are also dynamic models, as far as

the mathematical nature of these models is concerned (1).

"

Whatever you call it I think that you and I generally use very similar

models.

"

Yes, to some extent. All the linear deterministic models can be written

written in the form used in the CTDB package, as exemplified in

study (2) for a two-compartment linear deterministic model. However,

the CTDB package enables to determine many more complex

models than are the linear deterministic compartment models,

e.g. models containing time-delays (2), or shunts (3). See some examples

of models determined by the package CTDB

at http://www.uef.sav.sk/examples.doc .

1. B. Hannon, M. Ruth, Dynamic Modeling, Springer-Verlag, New

York, 1994, 248 pp.

2. Durisova, M., Dedik, L., Batorova, A., Sakalova, A., Hedera, J.

Pharmacokinetics of factor VIII in hemophilia A patients assessed

by frequency response method. Methods Find Exp Clin Pharmacol

1998, 20: 217-26.

3. M. Durisova, Dedik, L., Balan, M. Building a structured model

of a complex pharmacokinetic system with time delays.

Bull Math Biol 1995; 57: 787-808.

4. L. Dedik, M. Durisova, Frequency response method used

in modelling environmental systems - a working example.

Ecol Modelling 1997, 101: 175-184.

Regards,

Maria Durisova

and

Ladislav Dedik

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