RE: The double peak
Dear Maurice,
Your logical explanation is fine, this is what you would expect with
2-compartment model with 2 different absorption rates. You do not need
any additional LAG (i.e. LAG4) to describe this except absorption lag
times. Also LAG4 would not work anyway: you are not putting any dose in
the peripheral compartment, and LAG works only to delay this event.
Third, you will have hard time estimating individual lag times, since
lag introduces discontinuous gradients. You may want to check other
approaches, e.g. absorption models with transit compartments or mixture
models (J.E.Ahn and T.Ludden just had a poster at AAPS "Estimating
Variability of Infusion Rate or Duration and Lag Time Using Mixture
Models"). Separately from the absorption part, your estimation crashes
when you divide by IPRED (IWRES = IRES/IPRED). You need to use CALLFL=0,
to not do this division at dosing records, or use other ways to avoid
division by 0.
Katya
------------------------------------
Ekaterina Gibiansky
Director, PK/PD
Clinical Development
MedImmune, Inc.
[EMAIL PROTECTED]
Quoted reply history
________________________________
From: [EMAIL PROTECTED] [mailto:[EMAIL PROTECTED]
On Behalf Of Chenguang Wang
Sent: Friday, November 16, 2007 10:28 AM
To: [email protected]
Subject: [NMusers] The double peak
Dear Nonmem users,
I am working with a double peaks PK model. I refered to a recent
question about this topic and tried the double absorption compartment
model suggested by somebody.
Howerver, in my real data, the Ka and Ke for each peak are different.
The ka of the first peak is greater than that of the second, and the ke
of the first is also greater than the second. Therefore, the profile has
a sharp peak at first, then a flat peak after that. If I use the double
absorption compartment model, it can give me two different Ka, but can't
give me two different Ke in different time.
Then I wanted to add a periphal compartment to solve this problem. My
idea is after the admin, part of drug(F1) gets into the plasma
quickly(Ka1) then quickly goes to the periphal. So there will be a big
Kcp (from central to periphal). In the same time, drug eliminates to
outside from plasma in a speed of Ke, which is very small. After a
period of time, the drug in periphal begins to flow back to central in a
same speed of Kcp( Kpc=Kcp). This will retain the drug concentration in
the plasma and prevent the fast drop after the second peak in the c-t
profile. Also, a sencond part of drug(F2) will be absorbed with a slower
Ka2 after a proper lag time. Finally, the drug will eliminate outside in
the speed of Ke, which is very slow.
In order to do this, I use lag time between periphal and central. I am
not sure if it is permitted by NONMEM, but at least I didn't find error
message when I did simulation. Also, I don't know if my model can really
work as I expected. But when I did the estimation, it crashed.
Would someone have some good idea about this or can tell me if there is
any wrong in my script?
Thank you in advance!
My model is :
$DATA ****.csv
$SUBROUTINES ADVAN6 TRANS1 TOL=3
$MODEL NCOMP=4
COMP=(ABS1)
COMP=(ABS2)
COMP=(CENTRAL)
COMP=(PERI)
$PK
K13 =THETA(1)
K23 =THETA(2)
KE =THETA(3)*EXP(ETA(1))
ALAG2=THETA(4)*EXP(ETA(2))
F1 = THETA(5)
F2 = 1- F1
K34 =THETA(6)*EXP(ETA(3))
K43 =THETA(7)*EXP(ETA(4))
ALAG4=THETA(8)*EXP(ETA(5))
$DES
DADT(1)=-K13*A(1)
DADT(2)= -K23*A(2)
DADT(3)= K13*A(1)+K23*A(2)-KE*A(3)-K34*A(3)+K43*A(4)
DADT(4)= K34*A(3)-K43*A(4)
$ERROR IPRED= F
Y = IPRED * (1+ERR(1)) + ERR(2)
IRES = DV - F
IWRES = IRES/IPRED
$THETA 1 FIX ; K13
0.6 FIX ; K23
(0.0001,0.001,0.01) ; KE
(20,40,60) ; ALAG2
0.7 FIX ; F1
(0.5,0.75,1) ; K34
(0.5,0.75,1) ;K43
(20,40,60) ;ALAG4
$OMEGA
0.2
0.1
0.1
0.1
0.1
$SIGMA
0.1
0.1
$ESTIMATION METHOD=1 PRINT=1 MAXEVAL=9999 NOABORT SIGDIGITS=3 POSTHOC
INTERACTION
MSFO=msfo.outputfile
................
Maurice