Xiao,
Try running a SIMONLY simulation first. If you are using an additive or
additive + constant CV error model, simulation will sometimes generate
negative or very tiny DV values. If this is the case, it will cause
problems with fitting the model to the simulated data.
Luann
Xiao Hu wrote:
Dear Luann, Andreas and others,
Both parts are very clear to me now. Thank you very much!
My problem was, when I tried to simulate the differential equation
model with parameters from ADVAN2, it did not work. The error message
is listed below. This was not an issue during the model switch when D1
was not included in ADVAN2. I then tried to derive the parameters from
the differential equation model directly. But there were >10 error
messages like below issued. Do you have any insight why this happens?
0PRED EXIT CODE = 1
0INDIVIDUAL NO. 1 ID= 2.00100000000000E+03 (WITHIN-INDIVIDUAL)
DATA REC NO. 18
THETA=
4.19E+00 1.22E+01 9.10E+00 1.07E+01 1.20E+01 8.89E+00
0.00E+00 1.50E-03 2.63E-01 2.28E+00
2.87E+00
NUMERICAL DIFFICULTIES WITH INTEGRATION ROUTINE.
MAXIMUM NO. OF EVALUATIONS OF DIFFERENTIAL EQUATIONS, 1000000,
EXCEEDED.
Best regards,
Shelley
========================================
Xiao Hu (Shelley), Ph.D.
Scientist,
Development Pharmacokinetics & Disposition
Biogen Idec, Inc.
14 Cambridge Center
Cambridge, MA 02142
*Luann Phillips <luann.phill...@cognigencorp.com>*
10-Aug-2010 01:29 PM
Message Size: *6.6 KB*
To
Xiao Hu <xiao...@biogenidec.com>
cc
nmusers <nmusers@globomaxnm.com>
Subject
Re: [NMusers] Translate ALAG1 and D1 in ADVAN2 to differential equations
Xiao Hu,
Part 1)
NONMEM handles the input of all doses automatically via the dataset
structure. Therefore, generally there is no need to initialize
compartments or to code infusion rates in the $DES block. An exception
to this rule is when you are dosing or modeling endogenous substances.
Assuming your drug is not an endogenous substance, the differential
equations for ADVAN2 with ALAG1 and D1 are shown below (using ADVAN6).
Part 2)
"I'm not very clear what's the meaning of D1 and KA when both are modeled."
Based upon the ADVAN that you are using, NONMEM is putting the dose into
the depot compartment as a constant rate infusion with a duration of D1
(hours, days, etc.). It starts the infusion into the depot compartment
at time=ALAG1 (hours,days, etc.) after each dose. The dose is then
transferred from the depot compartment to the central compartment using
a first-order process (Ka 1/hr or 1/day, etc.)
I hope this information helps,
Luann Phillips
---------------------------------------------
Example Code:
$SUBROUTINES ADVAN6 TOL=5
$MODEL
COMP=(DEPOT,DEFDOSE)
COMP=(CENTRAL,DEFOBS)
COMP=(PD1)
etc.
$PK
KASC=THETA(4)
VSC=THETA(5)
CLSC=THETA(6)
LGSC=THETA(8)
MU_4=KASC
MU_5=VSC
MU_6=CLSC
MU_8=THETA(11)
SD=THETA(9)
SIG=SD
KA=EXP(MU_4+ETA(4))
V=EXP(MU_5+ETA(5))
CL=EXP(MU_6+ETA(6))
K=CL/V
S2=V/1000; DOSE IN 1000 U, CONC in U, VOLUME IN mL
ALAG1=LGSC*EXP(ETA(10))
D1=EXP(MU_8+ETA(8))
$DES
DADT(1) = -KA*A(1)
DADT(2) = KA*A(1) - K*A(2)
DADT(3) = equations for PD cmt 1
etc.
--------------------------------------------------
Xiao Hu wrote:
>
> Dear NMusers,
>
> I'm using ADVAN2 to model the PK of a drug. To best fit the profile,
> the model includes ALAG1 and D1. For the next step, the ADVAN2 needs to
> be translated into differential equation to include a PD compartment.
> How should I write the differential equation for ALAG1 and D1? As you
> can see, there is Ka in the ADVAN2 model. I'm not very clear what's the
> meaning of D1 and KA when both are modeled. Any hint or previous link
> would be appreciated. Thanks in advance!
>
> $SUBROUTINES ADVAN2
> $PK
>
> KASC=THETA(4)
> VSC=THETA(5)
> CLSC=THETA(6)
> LGSC=THETA(8)
>
> MU_4=KASC
> MU_5=VSC
> MU_6=CLSC
> MU_8=THETA(11)
>
> SD=THETA(9)
> SIG=SD
>
> KA=EXP(MU_4+ETA(4))
> V=EXP(MU_5+ETA(5))
> CL=EXP(MU_6+ETA(6))
> K=CL/V
> S2=V/1000; DOSE IN 1000 U, CONC in U, VOLUME IN mL
> ALAG1=LGSC*EXP(ETA(10))
> D1=EXP(MU_8+ETA(8))
>
> Final parameter estimates:
>
> $THETA
> 12 ;THETA5
> 8.89 ;THETA6
> 0.0015;THETA8
> 0.263 ; THETA9
> 2.87; THETA11
>
> Best regards,
> Shelley
>
> ========================================
> Xiao Hu (Shelley), Ph.D.
> Scientist,
> Development Pharmacokinetics & Disposition
> Biogen Idec, Inc.
> 14 Cambridge Center
> Cambridge, MA 02142
