From: Ribbing, Jakob <*Jakob.Ribbing*>

Date: Wed, 14 Jan 2009 09:10:48 -0000

Leonid,

As I understand the linear model you suggested it can be simplified* to

this structure:

THETA(1)*((WT/70)^(3/4)+THETA(2)*CRCL)

I call this additive, because the two covariates affect TVCL in an

absolute sense, without interaction. My main message was that I find

this model appealing, because it has the properties:

a)There is a linear increase of CL with CRCL

b)An increase in CRCL increases CL with an absolute number which is the

same for two subjects with different WT

The same can not be said about this model:

TVCL=THETA(1)*(WT/70)^(3/4) * RF^GAMMA

The latter model carries a built-in interaction which may provide a

better description of the data in situations where e.g. non-renal

elimination decreases with CRCL or where the secretory component of

renal elimination is more important for creatinine than for the drug.

However, in the opposite situations the interaction would be working in

the wrong direction (assuming GAMMA<1). Maybe we can leave what

basic-model assumption we want to use as a matter of personal or

drug-specific preference?

Best

Jakob

PS

Nonmem users is like an octopus: Just when you think you are free one of

its threads pulls you back in again :>)

Much of this discussion is around additivity. If I have understood the

definition of additivity wrong, then I apologies on beforehand, so that

this can still be my final "contribution" to this thread. Likewise if I

misunderstood what model Leonid was actually suggesting...

DS

*This is how I have simplified the suggested linear model:

TVCL=THETA(1)*(WT/70)^(3/4) * (1+THETA(2)*RF)=

=THETA(1)*(WT/70)^(3/4) * (1+THETA(2)*CRCL/(WT/70)^(3/4)) =

=THETA(1)*(WT/70)^(3/4)+THETA(1)*(WT/70)^(3/4)*THETA(2)*CRCL/(WT/70)^(3=

/

4)=

=THETA(1)*((WT/70)^(3/4)+THETA(2)*CRCL)

Or =THETA(1)* (WT/70)^(3/4)+THETA(1)*THETA(2)*CRCL

Similar: THETA(1)* (WT/70)^(3/4)+THETA(2)*CRCL (where the interpretation

of THETA(2) changed from the line before)

-----Original Message-----

From: owner-nmusers

On Behalf Of Leonid Gibiansky

Sent: 13 January 2009 22:50

To: nmusers

Subject: Re: [NMusers] CrcL or Cr in pediatric model

Jakob,

The model that I mentioned is not additive; it is multiplicative:

Parameter= MeanValue*Effect1(WT)*Effect2(RF)

but the effect of RF is expressed as a linear function of RF

Effect2(RF) = 1 + THETA()*RF

Leonid

Received on Wed Jan 14 2009 - 04:10:48 EST

Date: Wed, 14 Jan 2009 09:10:48 -0000

Leonid,

As I understand the linear model you suggested it can be simplified* to

this structure:

THETA(1)*((WT/70)^(3/4)+THETA(2)*CRCL)

I call this additive, because the two covariates affect TVCL in an

absolute sense, without interaction. My main message was that I find

this model appealing, because it has the properties:

a)There is a linear increase of CL with CRCL

b)An increase in CRCL increases CL with an absolute number which is the

same for two subjects with different WT

The same can not be said about this model:

TVCL=THETA(1)*(WT/70)^(3/4) * RF^GAMMA

The latter model carries a built-in interaction which may provide a

better description of the data in situations where e.g. non-renal

elimination decreases with CRCL or where the secretory component of

renal elimination is more important for creatinine than for the drug.

However, in the opposite situations the interaction would be working in

the wrong direction (assuming GAMMA<1). Maybe we can leave what

basic-model assumption we want to use as a matter of personal or

drug-specific preference?

Best

Jakob

PS

Nonmem users is like an octopus: Just when you think you are free one of

its threads pulls you back in again :>)

Much of this discussion is around additivity. If I have understood the

definition of additivity wrong, then I apologies on beforehand, so that

this can still be my final "contribution" to this thread. Likewise if I

misunderstood what model Leonid was actually suggesting...

DS

*This is how I have simplified the suggested linear model:

TVCL=THETA(1)*(WT/70)^(3/4) * (1+THETA(2)*RF)=

=THETA(1)*(WT/70)^(3/4) * (1+THETA(2)*CRCL/(WT/70)^(3/4)) =

=THETA(1)*(WT/70)^(3/4)+THETA(1)*(WT/70)^(3/4)*THETA(2)*CRCL/(WT/70)^(3=

/

4)=

=THETA(1)*((WT/70)^(3/4)+THETA(2)*CRCL)

Or =THETA(1)* (WT/70)^(3/4)+THETA(1)*THETA(2)*CRCL

Similar: THETA(1)* (WT/70)^(3/4)+THETA(2)*CRCL (where the interpretation

of THETA(2) changed from the line before)

-----Original Message-----

From: owner-nmusers

On Behalf Of Leonid Gibiansky

Sent: 13 January 2009 22:50

To: nmusers

Subject: Re: [NMusers] CrcL or Cr in pediatric model

Jakob,

The model that I mentioned is not additive; it is multiplicative:

Parameter= MeanValue*Effect1(WT)*Effect2(RF)

but the effect of RF is expressed as a linear function of RF

Effect2(RF) = 1 + THETA()*RF

Leonid

Received on Wed Jan 14 2009 - 04:10:48 EST