- On 19 Sep 2003 at 10:30:51, kim.travis.-a-.syngenta.com sent the message

Back to the Top

The following message was posted to: PharmPK

I'm an experienced modeller, but new to modelling animal/human systems.

I'm

trying to understand the established conventions in PK modelling and

wonder

if anyone can help me gain this kind of overview. The types of models

I can

see so far are 1/ non-compartmental, 2/ compartmental and 3/

physiologically

based. But in reality many non-compartmental approaches use sums of

exponentials and so are equivalent to a compartmental model, so what is

the

real distinction here? I thought that the compartmental models would be

initially calibrated based on animal metabolism data showing amounts in

various organs over time, and then applied to blood-only datasets. But

in

reality blood seems often to be the only compartment that is used to

fit a

compartment model, and much of the software is not designed to fit to

any

other kind of data (except perhaps organ/blood partitioning

coefficients?).

This way of using a compartment model makes it barely less empirical

than a

non-compartmental approach. So are physiologically based models ones

where

data from multiple compartments is genuinely used, or are they just as

empirical, but with all sorts of standard organ blood flows and volumes

included to make them appear less empirical?

Perhaps these conventions have evolved due to the strong focus on man,

where

blood concentration profiles are all that is readily available. If so,

then

is there another different class of models/software used for rodents,

where

individual organ data are more readily obtainable? Even in man, urine

concentration profiles are readily obtainable, so sometimes a

simultaneous

fitting of a model to blood and urine data would make sense - is this

done

and if so then with what software?

Kim Travis

A puzzled newcomer to PK-land - On 19 Sep 2003 at 21:42:26, "Sarah Anne Marston" (smarston.-at-.pharmastatsci.com) sent the message

Back to the Top

The following message was posted to: PharmPK

Dear Kim,

You can find examples of simultaneous fitting of plasma and urine data

in

"Pharmacokinetic and Pharmacodyamic Data Analysis: Concepts and

Applications" by Gabrielsson and Weiner

(http://www.pharsight.com/academic/aca_textbook.php). The book uses the

software WinNonlin. Innaphase (www.innaphase.com) also offers a

comprehensive PK-PD modeling software and they probably have relevant

examples of interest to you too.

There are a number of emerging companies offering tools to build

relatively

complex, mechanistic models, some designed to handle intracellular

processes. Most of the products provide links to databases providing the

opportunity to reference the estimates used in the model to the

information

source for the purpose of organizing your work. I don't know of a

specific

rodent model, most are focused on disease models and provide simulation

tools incorporating data from a range of sources. You can click on the

links

below for more information.

http://www.entelos.com/science/index.html

http://www.genomatica.com/science_technology.html

Sincerely,

Sarah - On 20 Sep 2003 at 12:13:16, "Durisova Maria" (exfamadu.-a-.savba.sk) sent the message

Back to the Top

The following message was posted to: PharmPK

Dear Kim,

> I'm an experienced modeller, but new to modelling animal/human systems.

> I'm trying to understand the established conventions in PK modelling

> and

> wonder if anyone can help me gain this kind of overview. The types of

models

> I can see so far are 1/ non-compartmental, 2/ compartmental and 3/

> physiologically based.

Two other approaches are as follows.

We use models in the form of linear differential equations

and the two approaches to modeling animal/human systems:

1) To build non-structured models we employ our traditional

approach which is based on the frequency

response method. This approach does not require a priori

information (or hypothesis) about the system under study

and is efficient even in situations when such information

is not available. Moreover, this approach starts

with a non-iterative method and thus:

a) it does not require initial estimates of model

parameters; b) it is very rapid.

2) To build models that exhibit physiologically interpretable

structures we use our new approach which is based on

a sequential simulation of those body systems which

play predominant role on the behavior of a biologically

active substance in the body.

For more information, please visit

the site http://www.uef.sav.sk/advanced.htm or

contact me.

With best regards,

Maria

Maria Durisova, PhD, DSc (Math/Phys),

Head of Department of Pharmacokinetics

and Scientific Secretary

Institute of Experimental Pharmacology

Slovak Academy of Sciences

841 04 Bratislava 4

Slovak Republic

Phone/Fax: +421 2 54775928

http://www.uef.sav.sk/durisova.htm - On 22 Sep 2003 at 08:31:34, (moate.-a-.cahp.vet.upenn.edu) sent the message

Back to the Top

The following message was posted to: PharmPK

To Kim Travis,

yes there are a number of different philosophies

regarding PK anlysis, compartmental models and

non compartmental models. Perhaps the best book

on the subject is " Investigating Biological Systems

Using Modeling - Strategies and Software. by Mery

E. Wastney, Blossom Patterson, Oscar A. Linares,

Peter C. Grief and Raymond C. Boston. Academic

Press. In this book, various modeling approaches

are discussed in detail and a number of kinetic

software programes are compared. Special

emphasis is given to WinSAAM (which can be

downloaded from WinSAAM.COM).

Note that with WinSAAM it is very easy to

simultaneously fit blood and urine data. Indeed, it is

easy to simultaneously fit data to many

compartments eg Blood, urine, feces and milk. In

the above book and in the help section in WinSAAM

many examples are given of fitting

multicompartment models (linear and non-linear

models).

Hope this helps,

Best wishes,

Peter Moate

Peter J. Moate

Research Associate

University of Pennsylvania,

School of Veterinary Medicine,

Biostatistics Section, Clinical Science,

New Bolton Center, 382 W. Street Road.

Kennett Square, PA 19348

Phone: 610-444-5800 Ext. 2146

Fax: 610-925-8123

Work Email: Moate.aaa.cahp2.nbc.upenn.edu - On 22 Sep 2003 at 12:12:41, "Edmond B. Edwards, Ph.D." (editr.aaa.sympatico.ca) sent the message

Back to the Top

The following message was posted to: PharmPK

Dear Kim,

Perhaps I can offer an overview of PBPK models for you, based on my

experience and previous training in their use at a CSU Workshop.

You ask:

“So are physiologically based models ones where

data from multiple compartments is genuinely used, or are they just as

empirical, but with all sorts of standard organ blood flows and volumes

included to make them appear less empirical?

In their purest form, PBPK models are based entirely on physiological

data derived from independent experiments – in this sense, they are

based on experimental data. In contrast, the PK models try to estimate

a set of parameters by their fit to a set of observed curves. Inasmuch

as the parameters are not directly related to anatomical or

physiological entities – the process is more analytical than

experimental.

Thus, conceptually the PBPK models are diametrically opposed to the PK

models. The PBPK models predict – the PK models fit. In practice, it

may happen that due to lack of some experimental data the PBPK model

must fit one or two parameters, but this should be regarded as a

temporary measure, or could be considered as a calibration to predict

the next set of data. In the PBPK world, a model is considered feasible

if it behaves reasonably close to the observed data and is tested by

how well it can be extrapolated to the next data set. If the mechanisms

in the model appear to be feasible, the model can be scaled

appropriately to the next individual or even to the next species.

It was emphasized during the CSU workshop that one of the first PBPK

models (Teorell, 1937 ) intended for drug distribution studies, had to

be abandoned for the time being due to the fact that it could only be

solved numerically. While preparing a presentation on PBPK models, I

noticed that as each new generation of computer arrived, attempts were

made to revive an interest in the PBPK approach. Jacquez, Bellman,

Kalaba (1960) for mainframes, and Bischoff, Brown and Deidrick (1973)

for minicomputers. The PBPK models seemed to be more favourably

received in the environmental health sector probably because of their

potential to predict the effect of toxic trace elements.

On the pharmaceutical side, now that sufficient computing power is

easibly accessible, the PBPK approach appears to be more acceptable.

There are many numerical packages on the market (e.g. ACSL – very

powerful, very expensive; SCoP – more than adequate, reasonably priced)

that can routinely solve the set of stiff differential equations that

are sometime encountered with the PBPK models. An excellent

presentation of the current potential of the PBPK approach in the

pharmaceutical industry can be found at this website:

http://cdds.georgetown.edu/conferences/PBPK2002.html.

At least two presentations at this conference make the argument that

PBPK models are the only serious way to describe drug action and

disposition.

Personally, as someone with a physiological & mathematical background,

I find the PBPK models to be more satisfying since they are based on

real organs, real blood flows, real anatomical topology and real

biochemical experiments. With these constraints to reality and one or

more feasible mechanisms (based on experiment), the modeller can

predict the next set of data, plan the next experiment, and convince

the government regulators of the soundness of his/her conclusions. But

why listen to me? Please see the presentations in the Georgetown

Conference and draw your own conclusions. I would be interested in

hearing your opinions.

Edmond Edwards, Ph.D.,

EDIT Research - On 22 Sep 2003 at 16:00:00, Xiaofeng Wang (xiaofeng.wang.at.bms.com) sent the message

Back to the Top

The following message was posted to: PharmPK

Dear Kim:

Since I have similar backgroud as yours, maybe I can offer some help to

you.

I was trained in Chemical Engineering, and had worked on process

analysis and

modeling before I switched to pharmacokinetic modeling when I started

to worked

for Dr. Bischoff. Then I have worked in enviromental toxicology and

pharmaceutical indursty.

There are four different appraoches in PK modeling:

1 noncompartmental modeling

2 classical compartmental modeling (people just call it as

compartmental

analysis)

3 PBPK modeling

4 population PK modeling

2~4 belong to compartmental modeling. Each approach has its advantages

and

limitations. In fact, noncompartmental modeling is a special case of

compartmental modeling: linear PK and one compartment. You can derive

all

results from noncompartmental modeling by compartmental modeling

assuming

linear pk and one compartment model. Therefore, from the assumption,

you can

see the limitation of this approach. However, it has advantages. just

from

numerical aspect, noncompartmental modeling is much simpler than

compartmental

modeling. the former calculates the AUC (intergration, which usually

offsets

the error), and the later is an optimization on either differential

equations

or integrate equations, where the error has more impact on the final

outputs.

In addition, AUC, Cmax provides information on safety and efficacy

required by

FDA. Therefore, approximately 80% of study analysis in drug

development only

needs noncompartmental analysis, which is quick and simple.

The difference between classical compartmental analysis and PBPK is in

that in

classical compartment modeling, the compartments and the parameters

have no

clear physiological meaning, while in PBPK modeling, the compartments

and the

parameters have clearer physiological meaning. However, mathematical

approaches are the same. The advantages of PBPK modeling were stated

by Dr.

Edwards in his response. Here I would only mention another advantages

of PBPK

approach towards population PK modeling.

Population PK modeling is based on classical PK modeling. Since

parameters in

classical PK model are lumped factors, it cannot explain the

interindividual

variability. For example, volume of distribution is the lumped factors

of body

weight, body composition, etc. for different individual, this

parameter will

be different. Population PK builds the correlation between individual

information (called covariates) to the parameter (called covariate

model), so

that the difference between different individual can be explained (if no

covariate model, the distribution of the interindividual variability

can be

estimated). For example, rather just giving the different values of

the volume

of distribution in classical PK modeling, popPK also provides you with

the

information on why volume of distribution for each individual is

different, and

how to estimate the volume of distribution for different individuals.

At this stage, the covariate model in popPK is built largely on

statistical

analysis. Since PBPK model has physiological meaning and the

parameters has

clearer physiological meanings, ideally PBPK model can interpret

interindividual variability. Due to the limitation of available data,

it is

difficult to apply PBPK modeling to drug development. However, applying

PBPK

modeling and lumping can help us build the covariate model through

mechanistic

process rather than pure statistical analysis.

I would like to suggest you some references:

Gibaldy and Perrier, pharmacokinetics, 2nd ed. With this book, you

will know

more or less about classical compartment modeling and noncompartmental

analysis.

FDA guidlines: you will know why noncompartmental analysis dominate 80%

of data

analysis in drug development

Bischoff and Brown (1965), you can see what a critical assumption

Bischoff and

Brown was made, so the problem that stopped Bellman, et al, was solved.

Bischoff and Dedrick's late 60s and early 70s work established the

foundation

of PBPK modeling, and species extrapolation through PBPK modeling.

Andersen and Clewell applied PBPK modeling to enviromental toxicology,

risk

assessment. They have done a tremandous work on species

exptrapolation, dose

extrapolation by applying PBPK modeling..

Sheiner and Beal's publications on population PK modeling.

From those references, you will be able to find which approach will

benifit to

your study.

with regards,

xiaofeng wang - On 22 Sep 2003 at 17:26:13, "Prof. Walter Wolf" (wwolfw.-at-.usc.edu) sent the message

Back to the Top

The following message was posted to: PharmPK

Ed:

Your comments on the importance of using physiological principles in

the develpment of models (Yes, Virginia, Physiology still exists) are

very important.

What needs to be reemphasized is that models are not an end in itself:

they are simplified representations of events in a living system, and

their importance is directly proportional to the extent that they

either clarify the mechanism of action of a drug or allow better

decision making on how to optimize the use of that drug.

The problem until now with physiologically based models was in the

limitation of the available data. Measuring drug levels in organs and

tissues using the classical methods that are being used to measure drug

levels in blood and other accessible body fluids is simply not

possible. You may be able to get an occasional biopsy, or measure drug

levels in surgical specimens or post-mortem, but that gives you a very,

very limited number of time points.

Noninvasive methods, on the other hand, can give you many time points.

Indeed, in many of our studies, we drown in data!. And because such

methods are noninvasive (e.g,, they do not perturb the system that is

being studied) they can be repeated and the subject is his/her own

control.

The approach we use is somewhat different from the classic

Bischoff-Dedrick method, which uses a complete model. We use the

simplest model that is predictive of the action of the drug, and we use

only data gleaned from that one subject. It is likely that at some

point in time, when there has been a sufficient amount of noninvasive

data measured in patients with different diseases, drugs, age, etc, we

may also be able to use a population modeling approach.

Professor Walter Wolf, Ph.D. President, Correlative Imaging Council,

Society of Nuclear Medicine

Distinguished Professor of Pharmaceutical Sciences

Director, Pharmacokinetic Imaging Program

Department of Pharmaceutical Sciences, School of Pharmacy

University of Southern California 1985 Zonal Ave., Los Angeles, CA

90089-9121

E-Mail: wwolfw.at.usc.edu

Telephone: 323-442-1405

Fax: 323-442-9804 - On 23 Sep 2003 at 15:51:26, walter.schmitt.ws.-at-.bayertechnology.com sent the message

Back to the Top

The following message was posted to: PharmPK

Dear Kim,

it was very interesting to follow the discussion that you initiated

with your

question. I fully agree that the use of the same term "modeling" for

very

different concepts is quite confusing for a newcomer in PK.

As it was already pointed out by others, the different methods are

useful for

different purposes. Classical "PK-modelling" approaches, particularly

non-compartmental modeling, are in first instance methods to analyse

experimental data rather than modeling methods. They generate numbers

which

characterize measured concentration curves and are useful and important

to

compare different results. However, there are methods available which

use these

numbers to make extrapolations to not investigated scenarios what is of

course

some kind of modeling and therefore justifies the naming.

PBPK-modeling on the other hand is a "real" modeling method in the

sense that it

tries to describe the physical and physiological processes which

determine the

pharmacokinetics of a substance with mathematical models and make

predictions of

what will happen in reality. However, there is one important aspect

that has not

been mentioned in the discussion hitherto. Because a large part of the

above

mentioned physical processes are influenced by the physical or chemical

properties of a substance, PBPK-modeling allows to make the connection

between

PK and such less complex properties. Therefore PBPK-modeling is the

method of

choice to really interpret and understand pharmacokinetic behavior in

terms of

substance properties. By this it can be a very helpful tool to better

assess a

new compound in drug research and find out how to optimize it in terms

of its

ADME properties.

More about this last aspect you can read at www.pk-sim.com.

There you also find a universal solution that is able to contradict the

opinion

that PBPK-modeling needs lots of data and information and is therefore

hardly

applicable for daily problems.

Best Regards

Walter Schmitt

Bayer Technology Services

Biophysics

Want to post a follow-up message on this topic? If this link does not work with your browser send a follow-up message to PharmPK@boomer.org with "PK modelling philosophies" as the subject

PharmPK Discussion List Archive Index page

Copyright 1995-2010 David W. A. Bourne (david@boomer.org)