- On 21 May 2003 at 17:02:17, Evan Minty (eminty.at.ualberta.ca) sent the message

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The following message was posted to: PharmPK

Firstly, as a newcomer to the area of pharmacokinetics, I would like to

thank all of you who regularly contribute to this mailing list, I have

found

it to be an extremely valuable resource for helping to climb this

learning

curve.

But onto a different kind of curve, with which I've had a little more

experience. I have had modest exposure to what is known here as

multi-exponential "curve stripping" in MRI T2 analysis, where

amplitudes and

characteristic times have well established theoretical interpretations

as

the size of an aqueous pool, and the respective spin-spin relaxation

time

for the protons within that pool.

I was first drawn to pharmacokinetics by the prospect of an analogous

system

where my experience in curve fitting might be applicable.

As I understand it, one of the key assumptions behind 'classical'

multi-exponential clearance is that of 'well stirred compartments', an

assumption which is presumably satisfied at later timescales in an

experiment. However, sampling rates generally thin out at these

timescales,

where true multi-exponential behavior is theoretically expected. In my

preliminary observations, this leads to curve stripping using a very

limited

number of points that generally have low "signal to noise" ratios,

which is

a dangerous game regardless of the algorithm used.

I understand that there are important logistical concerns RE: sampling

rates, however I'm wondering if there might be an experimental protocol

that

I've overlooked that might be more compatible with the goals of a 'curve

stripping' experiment.

I am hoping that the experience on this list might point me to a

potential

system that:

1) Adheres to a classical "multi-exponential" clearance model.

2) Logistically allows for continued aggressive sampling throughout the

time

domain (pkin imaging, perhaps?).

Any references relevant to the issues I've raised would be very much

appreciated.

Sincerely,

Evan Minty - On 22 May 2003 at 09:33:21, "David S. Farrier" (DFarrier.aaa.SummitPK.com) sent the message

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The following message was posted to: PharmPK

Dear Evan,

For curve-stripping in pharmacokinetics, let me suggest you look at PK

Solutions. At www.SummitPK.com you will find a demo, a tour, and long

listing of the pharmacokinetic equations this program calculates.

Curve-stripping in PK Solutions is fun, easy, graphical, and flexible.

Once you have extracted the exponential terms from your plasma curve, a

click of the mouse will calculate, tabulate, and graph some 75

pharmacokinetic parameters, including projection of single does data to

multiple does kinetics. Try it. It will make you an instant expert in

pharmacokinetics!

Regards,

David S. Farrier

David S. Farrier, Ph.D. Phone: 970-249-1389

Summit Research Services Fax:: 970-249-1360

68911 Open Field Dr. Email: DFarrier.at.SummitPK.com

Montrose, CO 81401 Web: http://www.SummitPK.com - On 22 May 2003 at 19:07:42, Roger Jelliffe (jelliffe.aaa.usc.edu) sent the message

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Dear Evan and David:

I would be careful about curve stripping. How much credibility

do you give to each data point? Further, many say it is

ill-conditioned, and depends on the particular points which are

selected to belong to each phase. People tell me that it is much better

to use weighted nonlinear least squares, MAP Bayesian fitting, or

probably best, population modeling, to get the best parameter

estimates. You might consider going to our web site www.lapk.org, and

clicking around on teaching topics. Don't look for curve stripping,

though. We just don't do it.

Very best regards,

Roger Jelliffe

Roger W. Jelliffe, M.D. Professor of Medicine,

Division of Geriatric Medicine,

Laboratory of Applied Pharmacokinetics,

USC Keck School of Medicine

2250 Alcazar St, Los Angeles CA 90033, USA

Phone (323)442-1300, fax (323)442-1302, email= jelliffe.-a-.usc.edu

Our web site= http://www.lapk.org - On 23 May 2003 at 17:05:33, Nick Holford (n.holford.aaa.auckland.ac.nz) sent the message

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The following message was posted to: PharmPK

Evan,

I fully agree with Roger Jelliffe's comments. In addition I would say

curve stripping should be used to provide initial estimates for more

intelligent methods of parameter estimation. Personally I cannot recall

the last time I used curve stripping. Adeqaute initial estimates of

parameters typically come from inspection of the curve and some back of

the envelope calculations.

I would also suggest that you think more carefully about what you want

to obtain from the data. Choice of model and parameterization is

important so that you learn what you want to know rather than what some

black box method spits out as output.

If your application is best interpreted in terms of amplitudes and

characteristic times then I suggest you use these as parameters.

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 23 May 2003 at 13:31:00, "Durisova Maria" (exfamadu.-a-.savba.sk) sent the message

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The following message was posted to: PharmPK

In the resent message Dr. Farrier wrote:

> Curve-stripping in PK Solutions is fun, easy, graphical, and flexible.

> Once you have extracted the exponential terms from your plasma curve, a

> click of the mouse will calculate, tabulate, and graph some 75

> pharmacokinetic parameters, including projection of single does data to

> multiple does kinetics. Try it. It will make you an instant expert in

> pharmacokinetics!

I sincerely hope that the last sentence of the paragraph above

was indented to be funny. For those who are interested why,

I recommend the study by Aldo Rescigno:

The rise and fall of compartmental analysis, Pharmacol Res, 44, 2001,

335-340.

Similarly to the group of Prof. Jelliffe, my group also do not utilize

the curve striping method. The approach employed in our work is

outlined in

our recent paper:

Durisova M, Dedik L.: A system approach method for the adjustment

of time-varying continuous drug infusion in individual

patients: A simulation study. J Pharmacokin Pharmacodyn, 29,

2002,427-444.

With best regards,

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 23 May 2003 at 11:21:04, Evan Minty (eminty.-at-.ualberta.ca) sent the message

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The following message was posted to: PharmPK

Dear Roger,

I regret that I have not been clear in my line of questioning. I know

that

"curve stripping" refers to a particular method of parameter estimation,

however I was under the impression that in pharmacokinetics the term was

broadly used to refer to ANY method that seeks to fit clearance data and

extract relevant parameters. I apologize.

I agree completely with your assessment of the dangers of curve

stripping.

The techniques I've had experience with in MRI are also Least Squares

techniques.

My concerns regarding experimental methodology and the challenges it

poses

to accurate curve fitting still stand. Specifically, I would be

interested

in hearing about experiments on a system that:

1) Adheres to a classical "multi-exponential" clearance model.

2) Logistically allows for continued aggressive sampling throughout the

time

domain (pkin imaging, perhaps?).

I'm sorry I wasn't more clear. Thanks for any advice that might be

sent my

way.

Sincerely,

Evan Minty - On 24 May 2003 at 13:49:07, "Durisova Maria" (exfamadu.at.savba.sk) sent the message

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The following message was posted to: PharmPK

In the recent message Assoc. Prof. N. Holford wrote:

> I would also suggest that you think more carefully about what you want

> to obtain from the data. Choice of model and parameterization is

> important so that you learn what you want to know rather than what some

> black box method spits out as output.

For those who are not familiar with the connection between model

functions

which

are commonly used in pharmacokinetics and the dynamic-system theory and

for

those who are interested to learn about this connection I can recommend

e.g. the following classic pharmacokinetic resources:

1. Wagner JG. Fundamentals of clinical pharmacokinetics, Drug

Intelligence

Publication, Inc. Hamilton, Illinois, 1975, pp.231-245.

2. Gibaldi M, Perrier D. Pharmacokinetics, (Second edition), Marcel

Dekker,

Inc. New York and Basel, 1982, pp. 419-424.

In the practical use of tools of the dynamic-system theory for modeling

purposes,

the system under study is frequently portrayed by employing a

representation,

generally known as the black-box representation. In this case the

notation

"black-box" does not have any pejorative meaning.

It simply implies that this representation does not convey any

information

about components of the system and about the nature of their

interconnection.

Regards,

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

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