- On 12 Dec 2002 at 11:47:53, "Hutmacher, Matthew [Non-Employee/1820]" (matthew.hutmacher.at.pharmacia.com) sent the message

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The following message was posted to: PharmPK

Hello all,

A colleague of mine is attempting to fit a 0-order absorption profile to

some data where the length of infusion is not known. I regret, that I

don't

know anything about that software so I can not help him. If you could

let

us know how to model this in SAAM it would be greatly appreciated.

Matt

[I'm not sure that SAAM II will do this (by design) but happy to be

corrected...however Boomer can ;-) I have put a .BAT (control) files in

various formats at http://www.boomer.org/pkin/pk/infit.sit - db] - On 12 Dec 2002 at 13:31:01, "Jackson, Andre J" (JACKSONAN.-a-.cder.fda.gov) sent the message

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The following message was posted to: PharmPK

You can use the XUF function in SAAM.

For example :IC(7)=10

L(1,7)=1

l(0,7)=-1

The negative on l(0,7) is to maintain mass balance. This results in a

constant amount of 10 units /time being delivered to compartment 1.

Under HDAT set XUF=1.

If you want to solve for the infusion rate you need to give an initial

estimate with upper and lower limits.

This example is presented in the online manual on the WINSAAM web site

http://www.winsaam.com/

[This seems to allow a zero order infusion (I seem to remember an

F-dependence in the old SAAM-23/25 that would do this as well) but can

you make the duration of the infusion adjustable? Fitting across a

discontinuity (when the infusion stops) seemed to upset some ;-) - db] - On 13 Dec 2002 at 12:41:30, gianluca.2.nucci.-at-.gsk.com sent the message

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The 0-th order absorption is not built in in the current SAAM II

version but this empirical solution works well.

You need to define (in the exogenous input equation ) a function that

is 1 before time t1 and 0 afterwards. For instance this is the

possibility I will suggest:

ex1=Rate*(1-t^n/(t^n+T50^n))

In this case fixing a high value for n (n= 50 or more) enables a sharp

transition. Therefore the estimated T50 will be an excellent

approximation of the infusion time. Of course it is possible to use

other 100 fantasy equations doing exactly the same things.

Needless to say that the total dose is known and therefore you may want

to put the constraint

Rate = Dose / T50

in the equation canvass.

Hope this helps,

Gianluca Nucci

GlaxoSmithKline

CPK-Modeling & Simulation

Psychiatry - Verona - On 13 Dec 2002 at 08:11:07, "Jackson, Andre J" (JACKSONAN.aaa.cder.fda.gov) sent the message

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The following message was posted to: PharmPK

You can adjust the rate either by using T-interrupts see example 12 on

the

web site(Infusions with T-interrupts). In the example instead of

changing

UF(1)=0 one sets it to another value.

Also in my previous reply I should have categorized the methods as:

1.using the XUF function ie XUF(1)=1 gives a constant infusion of 1

unit/time

2.Alternative method:

IC(7)=10

L(1,7)=1

l(0,7)=-1

which results in 10 units per time

Your question related to function dependence may be addressed by

example 13

on the web site which shows how to use QO functions to control infusions

H DAT

XUF(1)=F(2)*p(1)/p(3)

102QO

0 1

2 0

What happens is that the infusion is terminated at 2 hours with the rate

being p(1)=150000. One can also use the QO to change infusion rates.

I do not believe that there is a problem fitting across a

discontinuity (when the infusion stops). However if you require a

rigorous

explanation you can contact Ray Boston whose E-mail address is

available at

the web site. - On 14 Dec 2002 at 11:37:37, "Durisova Maria" (exfamadu.-a-.savba.sk) sent the message

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The following message was posted to: PharmPK

> I do not believe that there is a problem fitting across a

> discontinuity (when the infusion stops).

Neither do I.

An example of the model of the drug behavior in the body

during both the infusion and post-infusion time period

can be found for example in our study:

DedĚk, L., Durisov·, M., B·torov·, A. Weighting function used for

adjustment of multiple-bolus drug dosing.

Meth Find Exper Clin Pharmacol 2000, 22: 543-549.

The model mentioned above was not determined using the

software SAAM, but using the software CTDB. A version of the latter

software can be found at the www site accessible from the link

given in my signature.

Regards,

Maria Durisova, PhD, D.Sc,

Head of Department of Pharmacokinetics

and Scientific Secretary

Institute of Experimental Pharmacology

Slovak Academy of Sciences

842 16 Bratislava

Slovak Republic

http://www.uef.sav.sk/durisova.htm - On 14 Dec 2002 at 09:42:25, Walt Woltosz (walt.aaa.simulations-plus.com) sent the message

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GastroPlus handles this effortlessly - discontinuities and all. You can

mix dosage forms as well, such as an IV bolus at time zero, with an IV

infusion starting also at time zero, then an oral dose at some later

time, and a different oral dose at another later time, etc. And you can

fit PK and PD parameters across such combinations. It's quite easy to

do.

Walt Woltosz

Chairman & CEO

Simulations Plus, Inc. (SIMU)

1220 W. Avenue J

Lancaster, CA 93534-2902

U.S.A.

http://www.simulations-plus.com

E-mail: walt.-at-.simulations-plus.com - On 16 Dec 2002 at 11:15:18, "Hugh Barrett" (pbarrett.-a-.cyllene.uwa.edu.au) sent the message

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The following message was posted to: PharmPK

Further to the discussion of zero order input and optimizing the

duration of

an input.

If we assume a 2 pool model, comp 1 to comp 2, impulse input into comp

1 at

zero time. The input into comp 2 is a zero order function with can be

defined as

k(2,1)=k21/q1, where k21 is a new parameter and q1 is the mass in

compartment 1

If the input into comp 2 runs for an unknown duration the heaviside

function, below, can be used to switch off the input at time tlag, a

parameter that can be optimized during fitting. The function and its

integration into the transfer between comp 1 and comp 2 is given below.

heaviside=0.5*(1+atan(lambda*(t-tlag))*2/3.141592653)

k(2,1)=(1-heaviside)*k21/q1

k(0,2) 0.100000

k21 1.000000

lambda 100.000000

tlag 50.000000

If anyone would like the SAAM II model file with this capability please

email me at pbarrett.-a-.cyllene.uwa.edu.au

Hugh - On 17 Dec 2002 at 09:27:09, "J.H.Proost" (J.H.Proost.-a-.farm.rug.nl) sent the message

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The following message was posted to: PharmPK

Dear colleagues,

With respect to problems in fitting and discontinuities: Please note

that the plasma concentration profile is continuous (of course!), but

the derivatives are discontinuous at the time point of stopping an

infusion or true 0-order input (and, e.g., at the start of input after

a lag-time). Many optimization algorithms use these derivatives for

finding the best solution. This may cause a problem in 'crossing' a

time point of measurement, but not necessarily so. This depends on the

typical problem and, of course, on the software.

As an example: assume measurements at each time point 1, 2, 3, etcetera

(arbitrary time units). The best fitting duration of the infusion is

3.5 time units. If you start the analysis with an initial estimate for

this duration between 3 and 4, you will most probably get the correct

result. But if you start with an initial estimate of, e.g., 2.5 or 4.5,

you may get a different solution; either a local minimum with an

infusion time of, say, 2.84, or a value very close to, e.g., 3, i.e.

at the point of the discontinuous derivative. The latter may be

recognized easily, but the former may be unnoticed.

In my experience the problem does not occur always, but you should be

aware of it.

Best regards,

Hans Proost

Johannes H. Proost

Dept. of Pharmacokinetics and Drug Delivery

University Centre for Pharmacy

Antonius Deusinglaan 1

9713 AV Groningen, The Netherlands

Email: j.h.proost.-a-.farm.rug.nl

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