- On 21 Nov 2002 at 13:49:49, "Dr.Dieter Hafner" (hafner.at.uni-duesseldorf.de) sent the message

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Hello,

I am looking for an ascii type model for use in WinNonlin which enables

multiple dosing (e.g. oral) using a model formulation based on

differential equations.

All examples found until now deal with multiple dosing in the context

of superposition of exponential functions.

My own formulation will not work under WinNonlin, the simulation runs

only show effect of the first dosis, the next ones are ignored. The

algorithm was tested before under SAS, so the logic should be ok, but

WinNonlin might evaluate the procedure differently, I do not know how.

The model part of interest looks like the following:

...........

START

FL=1

Z(1) = 0

Z(2) = 0

Z(3) = 0

z(4) = 0

END

remark - define differential equations

DIFFERENTIAL

j=1

do i=1 to ndose " NDOSE IS # of doses

j=j+2

if (t lt con(j)) or (fl gt i) then goto red " CON(1): dose #1;

CON(2): time of dose #1; CON(3), CON(4),... respectively

else

z(1)=z(1)+con(j-1)

fl=fl+1

red:

endif

next

DZ(1) = -k01*z(1) " Z(1) : Absorption

compartment

..........

I am triing to model the kinetics of betaine in patients with elevated

homocysteine plasma levels and the model should describe betaine and

one of its metabolite disposition as well as the effect of lowering

homocysteine.

I analyzed quite successfully data from single oral betaine

applications and want to include now patient data after different

dosing schemes.

Any help would be highly appreciated.

Thank you

Dieter Hafner

+ Office

+ Dr.Dieter Hafner

+ Institut fuer Pharmakologie

+ und klinische Pharmakologie

+ Heinrich-Heine-Universitaet

+ Moorenstr.5 email:

+ D-40225 Duesseldorf hafner.-a-.uni-duesseldorf.de - On 23 Nov 2002 at 11:03:07, "Durisova Maria" (exfamadu.at.savba.sk) sent the message

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The following message was posted to: PharmPK

Dear Dr. Hafner,

My reply does not refer to WinNonlin, however it refers to another

package and modeling technique which is based on a model in the form

of a differential equation. If such a model is determined using a test

dose

of the drug given to the patient, it can be employed e.g. for the

adjustment of multiple

dosing or infusion of this drug, aimed at reaching the required drug

concentration-time profile in this patient. This technique is

exemplified in

studies:

Dedik L, Durisova M, Batorova A. Weighting function used for

adjustment of

multiple-bolus

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

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, 2002, accepted.

The technique is implemented in the package CTDB (Clinical Trials

Database),

a version of which is available from the www address given in my

signature.

With best regards,

Maria Durisova, PhD, DSc,

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

[I'm sure there is also a WinNonlin approach but I thought I might

provide a Boomer solution too ;-) See

http://www.boomer.org/pkin/pk/MDosePD.sit which is a stuffit file with

three versions (UNIX - Mac OS X, Mac 'm', and DOS 'd') of a Boomer .BAT

file for a two compartment PK model with V from compartment one and a

Hill equation from compartment two with multiple doses. I must write

instructions and a tutorial for a Hill equation from an 'effect'

compartment using component 'cloning' after I finish grading Fridays

exam...BTW Boomer is available from http://www.boomer.org/ - db] - On 27 Nov 2002 at 13:08:41, David Czock (david.czock.-a-.medizin.uni-ulm.de) sent the message

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Dear Dr. Hafner,

I used a model with differential equations and multiple dosing for

simulation purposes recently. It is a little bit more simple, because

the administration interval was fixed at 12h (or a multiple of 12 hours

when the dose at a specific time point was set to zero). The dose was

the number of tablets administered at a given 12 hour interval. The

complicating aspect was the modeling of hemodialysis. Anyway, it should

be possible to modify the model to your need.

remark Z(1) : Main Compartment

remark Z(2) : 2nd Compartment

remark zero-order input, first-order elimination

remark CON(1)-CON(18) = Number of tablets at time point (12 h steps)

remark CON(19) = Creatinine Clearance

remark CON(20) = 0 - no hemodialysis applied; 1 - with

hemodialysis

COMMANDS

NFUN 1

NDER 2

NPARAMETERS 3

PNAMES 'V1','k10','AbsEnd'

NCON 20

END

TEMP

Time = X

OralDose = 323787 ; of one tablet (ng)

Gewicht = 70

CLcrea = CON(19)

Dialysis = CON(20)

'Some Definitions of V1, k10, AbsEnd, k12, k21, Fraction, AbsStart,

Kdial

'depending on CLcrea

END

START

Z(1) = 0

Z(2) = 0

END

DIFF

If Time LE AbsStart then

DZ(1) = 0

endif

do i = 0 to 17

if Time GT i*12 + AbsStart and Time LE i*12 + AbsEnd then

DZ(1) = Fraction * OralDose * CON(i+1) / (AbsEnd - AbsStart) - k10 *

Z(1) - k12 * Z(1) + k21 * Z(2)

endif

if Time GT i*12 + AbsEnd and Time LE (i+1)*12 + AbsStart then

if (Time GT 44 and Time LE 48 and Dialysis=1) or (Time GT 92 and

Time LE 96 and Dialysis=1) then

DZ(1) = - (k10 + kdial) * Z(1) - k12 * Z(1) + k21 * Z(2)

else

DZ(1) = - k10 * Z(1) - k12 * Z(1) + k21 * Z(2)

endif

endif

next

DZ(2) = k12 * Z(1) - k21 * Z(2)

END

FUNC 1

F = Z(1)/(V1 * Gewicht)

END

EOM

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