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The following message was posted to: PharmPK
Dear all,
I have a question in doing PK-PD simulation by NONMEM. ADVAN6 TRANS1
was used as follows:
$DES
DADT(1)=-K12*A(1)*F0
DADT(2)=-(CL/V1+QP/V1)*A(2)*FU+QP/V2*A(3)+K12*A(1)
DADT(3)=QP/V1*A(2)*FU-QP/V2*A(3)
C=A(2)/S2*FU
E=C**HIL/(EC50**HIL+C**HIL)
DADT(4)=K0*A(4)-KM*E*A(4)
$ERROR
Q1=0
IF(CMT.EQ.2) Q1=1
Y1=F*EXP(ERR(1))
Q2=0
IF(CMT.EQ.3) Q2=1
Y2=F*(1+ERR(2))
Q3=0
IF(CMT.EQ.4) Q3=1
Y3=F*(1+ERR(3))
Q4=0
IF(CMT.EQ.5) Q4=1
Y4=F*(1+ERR(4))
Y=Q1*Y1+Q2*Y2+Q3*Y3+Q4*Y4
IPRED=F
$THETA
(80) ;VP1
(25.6) ;CLP
(60.3) ;QP
(208) ;VP2
(1.49);K12
(0.52);FU
(0.86);F0
(1.5);K0
(2.50);KM
(100);EC50
(2);HIL
When I use some relatively small values for EC50, like 50, 100, ...,
300, the program is running fine, but when I use some relatively big
values for EC50, like 500,1000,..., then the following error message
will be given:
"NUMERICAL DIFFICULTIES WITH INTEGRATION RUTINE.
MAXIMUM NO. OF EVALUATIONS OF DIFFERENTIAL EQUATIONS, 100000, EXCEEDED.
MESSAGE ISSUED FROM SIMULATION STEP"
Could anyone give me some advice on how to handle this problem? Thanks
in advance!
Qi
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The following message was posted to: PharmPK
Hello Qi
Could you check your equation DADT(4)?
Venkatesh Atul Bhattaram
CDER, FDA.
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The following message was posted to: PharmPK
"LIU,QI" wrote:
[stuff deleted]
> C=A(2)/S2*FU
> E=C**HIL/(EC50**HIL+C**HIL)
> DADT(4)=K0*A(4)-KM*E*A(4)
[stuff deleted]
> When I use some relatively small values for EC50, like 50, 100, ...,
> 300, the program is running fine, but when I use some relatively big
> values for EC50, like 500,1000,..., then the following error message
> will be given:
>
> "NUMERICAL DIFFICULTIES WITH INTEGRATION RUTINE.
> MAXIMUM NO. OF EVALUATIONS OF DIFFERENTIAL EQUATIONS, 100000, EXCEEDED.
> MESSAGE ISSUED FROM SIMULATION STEP"
>
> Could anyone give me some advice on how to handle this problem? Thanks
> in advance!
The ability to solve DADT(4) will depend on the the concs in CMT 2
relative to the EC50. If concs>>EC50 then the elimination rate constant
for DADT(4) will be approx. constant (E->1; effective rate
constant->KM) and the solution may be numerically simple. But when
concs<with time and have low values at low concs (including a value of zero
(!) when the conc in A(2) is zero). This big change in rate constants
can cause numerical integration difficulty.
My suggestion is to try using ADVAN9 (or ADVAN8) instead of ADVAN6.
ADVAN9 often works when ADVAN6 does not. In my experience ADVAN8 does
not work very well.
Nick
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
email:n.holford.-a-.auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
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The following message was posted to: PharmPK
Thanks a lot, Dear Dr. Holford and Dr. Bhattaram!
Yes! It is working fine in ADVAN9 :)
Thank you so much for your time!
Have a nice weekend!
Qi
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