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Re: CrcL or Cr in pediatric model

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 Gibiansky, Ph.D.
President, QuantPharm LLC
e-mail: LGibiansky at
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

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