- On 3 Apr 2001 at 10:34:05, "Sam T" (samt4.at.hotmail.com) sent the message

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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. - On 11 Apr 2001 at 11:13:34, Matthew Riggs (riggsmm.-at-.yahoo.com) sent the message

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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

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