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The following message was posted to: PharmPK
Dear NONMEM users,
I would like to use NONMEM to do some population modeling and I have
a couple of questions.
First, is the data item specified correctly for the following
single-dose infusion type data (Inf. time=2)? Second what kind of
structural model would be appropriate for these data, and is it
reasonable to assume that the ADVAN1 or 3 /Trans1 or 4 could give an
adequate model for such data?
For about 75 subjects, we have a single-dose infusion (Time of
infusion, IDUR=2 hrs.) applied daily.
I treat these data as a zero order infusion with idur=2, and I used
the folowing data item for one
subject:
DV is concentration in ng/mL, time is in hour, and AMT(dose) is in mg.
Sub. Dosemg Time-hrs. DV-ng/ml RATE IDUR MDV EVID
1 150 0 0 -1 2 1 0
1 . 0 0 . . 0 0
1 . 0.1 . . . 1 0
1 . 1 1.328 . . 0 0
1 . 2 1.68 . . 0 0
1 . 2.083 1.28 . . 0 0
1 . 2.167 1.2 . . 0 0
1 . 2.33 1.024 . . 0 0
1 . 2.5 0.936 . . 0 0
1 . 3 0.752 . . 0 0
1 . 4 0.472 . . 0 0
1 . 5 0.38 . . 0 0
1 . 8 0.18 . . 0 0
1 . 14 0.12 . . 0 0
2 340 0 0 -1 2 1 1
2 . 0 0 . . 0 0
2 . 0.1 . . . 1 0
2 . 1 3.34 . . 0 0
2 . 2 3.52 . . 0 0
2 . 2.083 2.9 . . 0 0
2 . 2.167 2.58 . . 0 0
2 . 2.33 2.06 . . 0 0
2 . 2.5 1.86 . . 0 0
2 . 3 1.4 . . 0 0
2 . 4 0.45 . . 0 0
2 . 5 0.53 . . 0 0
2 . 8 0.315 . . 0 0
2 . 14 0.167 . . 0 0
I tried 2 little control streams as follow:
One Comp.:
$PROB Population PK 1 comp.
$INPUT ID AMT TIME DV RATE IDUR MDV EVID
$DATA Data_Inf
$SUBS ADVAN1 TRANS2
$PK
V=THETA(1)+ETA(1)
CL=THETA(2)+ETA(2)
S1=V/1000 ;where Dose is in mg and DV is in ng/ml
IF(AMT.GT.0) NRT=AMT/IDUR ;NRT is nominal rate of infusion
R1=NRT
$ERROR
Y=F+ERR(1)
$THETA
(0.0001,150,10000)
(0.0001,50,10000)
$OMEGA 0.25 0.25
$SIGMA 0.04
$EST NOABORT SIGDIGITS=4 MAXEVAL=900 POSTHOC PRINT=5
$COV
$TABLE ...
Two Comp.:
$PROB Population PK 2 comp.
$INPUT ID AMT TIME DV RATE IDUR MDV EVID
$DATA Data_Inf
$SUBS ADVAN3 TRANS4
$PK
CL=THETA(1)+ETA(1)
V1=THETA(2)+ETA(2)
Q=THETA(3)+ETA(3)
V2=THETA(4)+ETA(4)
S1=V1/1000 ; where Dose is in mg and DV is in ng/ml.
IF(AMT.GT.0) NRT=AMT/IDUR ; NRT is the nominal rate of infusion.
R1=NRT
$ERROR
Y=F+ERR(1)
$THETA
(0.00001,25,100000)
(0.00001,30,100000)
(0.00001,100,100000)
$OMEGA 0.04 0.04 0.04 0.04
$SIGMA 0.2
$EST NOABORT SIGDIGITS=4 MAXEVAL=900 POSTHOC PRINT=5
$COV
$TABLE ...
I tried some of the basic models but I am not getting expected
estimations as I obtained by STS (standard two stage) or the program
is terminated by round-off error, so I question whether the way the
data step specified is correct or some changes have to be made on
control stream(s).
If someone has any advice, comments, on the above specification, or
suggestions for how to model such data, I would really appreciate it.
Thanks in advance.
Sam T.
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The following message was posted to: PharmPK
Amir,
I would start by referring you to recent answer
provided by Lewis Sheiner to a similar question
(copied below)... "
3. The additive etas may give you trouble in the
posthoc step; it's probably safer to use
$PK
V=THETA(1)*EXP(ETA(1))
CL=THETA(2)*EXP(ETA(2))
4. You should probably start with a full OMEGA, not a
diagonal one; you can then see if a diagonal one
suffices. Thus you might start with
$OMEGA BLOCK(2) 0.25 .1 0.25
LBS."
Additionally, with this relatively rich data set you
may want to try the first-order conditional estimation
method (Method=1) with interaction versus the default
first-order method. In your case, you may change the
default using:
$EST SIGDIGITS=4 MAXEVAL=999 METHOD=1 INTERACTION
PRINT=5
My final suggestion would be to define your typical
value (poulation mean) VSS as TVSS, rather than TVVSS.
NONMEM will only read 4 letters of a user defined
variable. This may help your Bayesian estimated
(POSTHOC) individual VSS estimates. Another
diagnostic: Was the gradient for ETA4 zero? Or was the
final estimate for ETA4 zero or the same as the
initial estimate?
Hope this helps.
Matthew Riggs
PharmPK Discussion List Archive Index page
Copyright 1995-2010 David W. A. Bourne (david@boomer.org)