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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
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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]
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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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