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cyst size modeling

From: nele.plock
Date: Fri, 18 Jul 2008 14:15:01 +0200

Dear nmusers,

I would like to seek your advice on a PKPD modeling problem to maybe get
some further ideas on how to address this problem.
A pharmacological experiment in rats was performed, where cysts are placed =

by surgery. 3 weeks later, the size of all cysts is assessed (this time
point is defined as zero). In addition, I know the cyst size without
treatment 2 weeks and 4 weeks after. Overall, the size remains the same
for the first two weeks, but decreases afterwards. This is not unusual, as =

it is also known that the cysts will all eventually go away after a while, =

even without treatment. So I know that I would need a baseline model of
some sort in order to derive an additional compound effect.
The compound was tested in 3 different doses. Cyst size after treatment
with the two lower doses was only assessed after 4 weeks of treatment,
whereas for the highest dose the size is available after 2 and 4 weeks of
treatment. Thus, I have some information about effect over time (i.e. time =

zero, after 2 weeks and after 4 weeks).
My question is: What kind of baseline model would be a good choice? Does
anybody have experience with cyst modeling and can share what would be
pharmacologically plausible? What should be the natural course of cyst
shrinkage (linear, turnover)?
Moreover I am wondering how to best describe the influence of the drug. I
know that it will not directly kill the cysts, so I thought about
including an effect compartment. I have written a Berkeley Madonna code to =

play around with the model. What are your thoughts on a model like this
(code below)? Would the available data be able to support the parameters?
The model is intended to find the dose that would result in cyst
eradication if the baseline effect would not be there.

Thank you and best regards
Nele

PS: If you send any answers, I would be very grateful if you could also
send a copy to neleplock
       Thank you!
_________________________=
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Berkeley Madonna code (parameters were chosen arbitrarily as no analysis
has been performed yet):
METHOD RK4

STARTTIME = 0
STOPTIME=696
DT = 0.2

INIT (gut) = X
INIT (central) = 0
INIT(effect)=0
INIT(PD)=1

D/DT(gut)=-KA*gut+DOSING
D/DT(central)=KA*gut -K20*central
D/DT(effect)= KEO*central-KEO*effect
D/DT(PD) = KIN - KOUT*FAC*PD- KOUT*effect*PD

cyst=100*PD ;100 as real cyst size at the start of the experiment

Ccentral=central/V2*1000

CL=0.387
V2=1.83
KA=0.724
KEO=0.01
KIN=0.0001
KOUT=KIN
FAC=IF TIME < 336 THEN 0 ELSE 10

X=0.1
K20=CL/V2

;--------MULTIPLE DOSING--------
DOSING=PULSE(DOS,START,INTERVAL)
DOS= IF TIME < 100000 THEN X ELSE 0
START= 24
INTERVAL=24
_________________________=
_________________________=
_________________________=
_____
Dr. Nele Plock
Bayer Schering Pharma AG
Drug Metabolism & Pharmacokinetics
Development Pharmacokinetics
Scientific Expert Development Pharmacokinetics
D- 13342 Berlin

Phone : +49-30-468 15146
Fax: +49-30-468 95146
nele.plock
http://www.bayerscheringpharma.de

Vorstand: Arthur J. Higgins, Vorsitzender | Werner Baumann, Andreas Busch, =

Ulrich Köstlin, Kemal Malik, Gunnar Riemann
Vorsitzender des Aufsichtsrats: Werner Wenning
Sitz der Gesellschaft: Berlin | Eintragung: Amtsgericht Charlottenburg 93
HRB 283
Received on Fri Jul 18 2008 - 08:15:01 EDT

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