From: Joseph Standing <*joseph.standing*>

Date: Wed, 11 Nov 2009 09:12:29 +0100

Dear Jia,

Firstly I would say make sure you do want to model IOV. As your patients

have higher doses on the second occasion, then you need to be sure the PK is

linear, otherwise changes in CL would better be modelled with nonlinearity

in CL. As for what parameters to try, my approach in the past has been to

sequentially add IOV to each parameter, and see which gave the biggest OFV

drop/reduction in residual and interindividual variability. Then have IOV

on just that parameter, although you may then want to test for additional

IOV on other parameters.

As for your coding, for each occasion you need an eta (modelled with the

same omega using SAME option - see below), and one for IIV - so in your case

3 etas for every parameter with IIV and IOV. You could code it like this:

OCC=1

IF(TIME.GE.100)OCC=2

IOV = 0

IF(OCC.EQ.1) IOV=ETA(2)

IF(OCC.EQ.2) IOV=ETA(3)

IIVCL = ETA(1)

ETCL = IIVCL + IOV

..

$OMEGA 0.1 ; IIV ON CL

$OMEGA BLOCK(1) 0.05

$OMEGA BLOCK(1) SAME ; IOV ON CL

If you are using NONMEM 7, there are some suggestions in the manual as to

how to code it with MU parameterisation.

Best wishes,

Joe

_____

From: owner-nmusers

Behalf Of Jia Ji

Sent: den 11 november 2009 03:03

To: nmusers

Subject: [NMusers] questions about IOV

Dear All,

I am a new NONMEM user and now trying to model clnical PK data with a

two-compartment model. More than half of patients in our trial had escalated

dose in the second cycle. So I should have inter-occasion variability. But I

got a couple of questions here.

First, what parameters should be estimated with IOV? I have seen some models

with IOV on CL, but not on others (maybe because I have seen too few

models). Now I have IOV on CL, V1 and Q and it run successfully. But when I

run with either two of them, I got minimization problem. But, am I having

too many IOVs in the model?

Second, I was wondering how to model IOV. Now I have the code as

; Define IOV, DESC = DOSE ESCALATION

DESC=0

IF (TIME.GE.100) DESC=1

ETCL = ETA(1) + DESC*ETA(5)

ETV1 = ETA(2) + DESC*ETA(6)

ETQ = ETA(3) + DESC*ETA(7)

ETV2 = ETA(4)

So IOV is modeled as additive relationship to IIV. But what about

multiplying relationship? Like

; Define IOV, DESC = DOSE ESCALATION

DESC=0

IF (TIME.GE.100) DESC=1

ETCL = ETA(1)*(1+DESC*ETA(5))

ETV1 = ETA(2)*(1+DESC*ETA(6))

ETQ = ETA(3)*(1+DESC*ETA(7))

ETV2 = ETA(4)

When I run with this multiplying relationship, I got increased OFV and

minimization terminated due to rounding error. But I didn't understand why

it is not working.

Thank you so much for your patience and time!

Jia

Received on Wed Nov 11 2009 - 03:12:29 EST

Date: Wed, 11 Nov 2009 09:12:29 +0100

Dear Jia,

Firstly I would say make sure you do want to model IOV. As your patients

have higher doses on the second occasion, then you need to be sure the PK is

linear, otherwise changes in CL would better be modelled with nonlinearity

in CL. As for what parameters to try, my approach in the past has been to

sequentially add IOV to each parameter, and see which gave the biggest OFV

drop/reduction in residual and interindividual variability. Then have IOV

on just that parameter, although you may then want to test for additional

IOV on other parameters.

As for your coding, for each occasion you need an eta (modelled with the

same omega using SAME option - see below), and one for IIV - so in your case

3 etas for every parameter with IIV and IOV. You could code it like this:

OCC=1

IF(TIME.GE.100)OCC=2

IOV = 0

IF(OCC.EQ.1) IOV=ETA(2)

IF(OCC.EQ.2) IOV=ETA(3)

IIVCL = ETA(1)

ETCL = IIVCL + IOV

..

$OMEGA 0.1 ; IIV ON CL

$OMEGA BLOCK(1) 0.05

$OMEGA BLOCK(1) SAME ; IOV ON CL

If you are using NONMEM 7, there are some suggestions in the manual as to

how to code it with MU parameterisation.

Best wishes,

Joe

_____

From: owner-nmusers

Behalf Of Jia Ji

Sent: den 11 november 2009 03:03

To: nmusers

Subject: [NMusers] questions about IOV

Dear All,

I am a new NONMEM user and now trying to model clnical PK data with a

two-compartment model. More than half of patients in our trial had escalated

dose in the second cycle. So I should have inter-occasion variability. But I

got a couple of questions here.

First, what parameters should be estimated with IOV? I have seen some models

with IOV on CL, but not on others (maybe because I have seen too few

models). Now I have IOV on CL, V1 and Q and it run successfully. But when I

run with either two of them, I got minimization problem. But, am I having

too many IOVs in the model?

Second, I was wondering how to model IOV. Now I have the code as

; Define IOV, DESC = DOSE ESCALATION

DESC=0

IF (TIME.GE.100) DESC=1

ETCL = ETA(1) + DESC*ETA(5)

ETV1 = ETA(2) + DESC*ETA(6)

ETQ = ETA(3) + DESC*ETA(7)

ETV2 = ETA(4)

So IOV is modeled as additive relationship to IIV. But what about

multiplying relationship? Like

; Define IOV, DESC = DOSE ESCALATION

DESC=0

IF (TIME.GE.100) DESC=1

ETCL = ETA(1)*(1+DESC*ETA(5))

ETV1 = ETA(2)*(1+DESC*ETA(6))

ETQ = ETA(3)*(1+DESC*ETA(7))

ETV2 = ETA(4)

When I run with this multiplying relationship, I got increased OFV and

minimization terminated due to rounding error. But I didn't understand why

it is not working.

Thank you so much for your patience and time!

Jia

Received on Wed Nov 11 2009 - 03:12:29 EST