From: Leonid Gibiansky <*LGibiansky*>

Date: Wed, 14 Jan 2009 08:49:12 -0500

Hi Jakob,

I am sorry, I made an error in that model, it should be

CL=THETA(1)*(WT/70)^(3/4) * [1+THETA(2)*(RF-RF0)]

For subjects with the normal RF (RF=RF0) the second term is one. As

always, all covariate expressions should be centered at "normal" values.

Leonid

--------------------------------------

Leonid Gibiansky, Ph.D.

President, QuantPharm LLC

web: www.quantpharm.com

e-mail: LGibiansky at quantpharm.com

tel: (301) 767 5566

Ribbing, Jakob wrote:

*> 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 - 08:49:12 EST

Date: Wed, 14 Jan 2009 08:49:12 -0500

Hi Jakob,

I am sorry, I made an error in that model, it should be

CL=THETA(1)*(WT/70)^(3/4) * [1+THETA(2)*(RF-RF0)]

For subjects with the normal RF (RF=RF0) the second term is one. As

always, all covariate expressions should be centered at "normal" values.

Leonid

--------------------------------------

Leonid Gibiansky, Ph.D.

President, QuantPharm LLC

web: www.quantpharm.com

e-mail: LGibiansky at quantpharm.com

tel: (301) 767 5566

Ribbing, Jakob wrote:

Received on Wed Jan 14 2009 - 08:49:12 EST