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Re: Sequential PK PD

From: Leonid Gibiansky <LGibiansky>
Date: Wed, 10 Feb 2010 09:20:24 -0500

Nail,

Your PD model should be OK as long as your PK model is working properly,
but I cannot figure out how PK part works in your code. I do not see any
control over drug amount in the depot compartment: you should keep K0=0
before the time ALAG1, and then switch K0 to zero again as soon as
A(1)=0, how it is done in your code? Is it outside of what we see, in
the definition of KK0 in the input file? Also, the role of this K0 is
not clear: you separate the dose into the "first order" part that goes
to the first compartment, "zero order" part that goes to the second
compartment, and then use K0 to move more drug from the first
compartment to the second one, was it intentional?

Regarding your specific questions:
Q1: According to your code, K0=KK0, and the KK0 should be provided in
the $INPUT
Q2: ALAG1 and ALG2 are delays of the dose to the first and the second
compartment, respectively, and nonmem will interpret it correctly

My guess is that you should set K0=0, and then everything will work as
you intended (the PK model should be identical to the PK part of the PD
model).

Thanks
Leonid

--------------------------------------
Leonid Gibiansky, Ph.D.
President, QuantPharm LLC
web: www.quantpharm.com
e-mail: LGibiansky at quantpharm.com
tel: (301) 767 5566




Indranil Bhattacharya wrote:
> Hi, I have a question regarding how NONMEM reads the code when doing a
> sequential PK/PD run.
> I fit the PK data (extravascular admin) using a KOKA model with
> sequential absorption. The data was based described by this sequential
> model where K0 process starts after Ka. To fit the data I used ADVAN4
> TRANS4 (2 COMP model).
> Now the next step is to fit the PD data and here is where I am confused.
> For the PK parameters I designate them under $PK as shown in the code
> provided. CL and V2 had individual values which were included in the
> data set. Also in the PD data was set up to show zero and first order
> absorption (2 dosing lines, RATE=0 or RATE=-2, COMP#)
> Question -1- Does NONMEM understand that K0 values are to be calculated
> from F2.DOSE/D2 or should I have to provide it in the data set ?
> Question-2- For ALAG1 and ALAG2 again, does NONMEM understand how to use
> them or I have to specify that under $DES using IF (T.LE.ALAG1) etc.?
>
> $MODEL
> NCOMP=5
> COMP=(DEPOT,DEFDOSE)
> COMP=(CENTRAL)
> COMP=(TISSUE)
> COMP=(RESPONSE)
> COMP=(TISSUE)
> $PK
> CL=CCL
> V2=VV2
> Q=0.01
> V3=2.94
> KA=0.004
> K0=KK0
> TLAG1=1.17
> ALAG1=TLAG1
> TLAG2=4.7
> ALAG2=TLAG1+TLAG2
> F1=0.7
> F2=0.3
> D2=108.96
> S2=V2/1000
>
>
> ;PD MODEL
>
> E0= THETA(1)
> KIN=(THETA(2))*(EXP(ETA(1)))
> KILL=THETA(3)*(EXP(ETA(2)))
> K45=THETA(4)
> K54=THETA(5)
> KOUT=KIN/E0
> A_0(4)=E0
> A_0(5)=K45*E0/K54
>
> $DES
> CONC=A(2)/V2
> S=CONC
> DADT(1)=-KA*A(1)-K0
> DADT(2)=-CL/V2*A(2)+Q/V3*A(3)-Q/V2*A(2)+KA*A(1)+K0
> DADT(3)=Q/V2*A(2)-Q/V3*A(3)
> DADT(4)= KIN- KOUT*A(4)-(KILL)*S*A(4)-K45*A(4)+K54*A(5)
> DADT(5)=K45*A(4)-K54*A(5)
>
> $ERROR
> EFF=LOG(A(4))
> IPRED=EFF
> Y=EFF+ERR(1)
>
> Regards
>
> Neil
>
> --
> Indranil Bhattacharya
>
Received on Wed Feb 10 2010 - 09:20:24 EST

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