- On 8 Nov 2003 at 00:14:53, "LIU,QI" (liuqi.at.ufl.edu) sent the message

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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 - On 8 Nov 2003 at 07:32:17, "bvatul" (bvatul.at.verizon.net) sent the message

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Hello Qi

Could you check your equation DADT(4)?

Venkatesh Atul Bhattaram

CDER, FDA. - On 9 Nov 2003 at 11:20:05, Nick Holford (n.holford.at.auckland.ac.nz) sent the message

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"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/ - On 9 Nov 2003 at 00:13:09, qi (liuqi.-a-.ufl.edu) sent the message

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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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