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 [EMAIL PROTECTED]
Thank you!
________________________________________________________________________________
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
[EMAIL PROTECTED]
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
