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RE: CrcL or Cr in pediatric model

From: Ribbing, Jakob <Jakob.Ribbing>
Date: Tue, 13 Jan 2009 00:53:12 -0000

Correction, I meant WT 50 and 75 in the example below:
75^0.75/(50^0.75)=1.36

-----Original Message-----
From: Ribbing, Jakob
Sent: 13 January 2009 00:50
To: nmusers
Subject: RE: [NMusers] CrcL or Cr in pediatric model

Leonid,

I usually prefer multiplicative parameterisation as well, since it is
easier to set boundaries (which is not necessary for power models, but
for multiplicative-linear models). However, boundaries on the additive
covariate models can still be set indirectly, using EXIT statements (not
as neat as boundaries directly on the THETAS, I admit).

In this case it may possibly be more mechanistic using the additive
parameterisation: For example if the non-renal CL is mainly liver, the
two blood flows run in parallel and the two elimination processes are
independent (except there may be a correlation between liver function
and renal function related to something other than size). A
multiplicative parameterisation contains an assumed interaction which is
fixed and in this case may not be appropriate. If the drug is mainly
eliminated via filtration, why would two persons, with WT 50 and 70 kg
but otherwise identical (including CRCL and any other covariates, except
WT), be expected to differ by 36% in CL? This is what you get using a
multiplicative parameterisation. The fixed interaction may also drive
the selection of the functional form (e.g. a power model vs a linear
model for CRCL on CL). I do not know anything about Peter's specific
example so this is just theoretical.

Regarding 3 below, is the suggestion to estimate independent allometric
models on CL for each level of renal function?

Thanks

Jakob

-----Original Message-----
From: owner-nmusers
On Behalf Of Leonid Gibiansky
Sent: 12 January 2009 23:30
To: Bonate, Peter
Cc: nmusers
Subject: Re: [NMusers] CrcL or Cr in pediatric model

Hi Peter,

If allometric exponent is fixed, collinearity is not an issue from the
mathematical point of view (convergence, CI on parameter estimates,
etc.). However, in this case CRCL can end up being significant due to
additional WT dependence (that could differ from allometric) rather than

  due to renal function influence (that is not good if you need to
interpret it as the renal impairment influence on PK).

Few points to consider:
   1. I usually normalize CRCL by WT^(3/4) or by (1.73 m^2 BSA) to get
rid of WT - CRCL dependence. If you need to use it in pediatric
population, normalization could be different but the idea to normalize
CRCL by something that is "normal CRCL for a given WT" should be valid.
   2. In the pediatric population used for the analysis, are there any
reasons to suspect that kids have impaired renal function ? If not, I
would hesitate to use CRCL as a covariate.
   3. Often, categorical description of renal impairment allows to
decrease or remove the WT-CRCL correlation
   4. Expressions to compute CRCL in pediatric population (note that
most of those are normalized by BSA, as suggested in (1)) can be found
here:
      http://www.globalrph.com/specialpop.htm
      http://www.thedrugmonitor.com/clcreqs.html
   5. Couple of recent papers:
      http://www.clinchem.org/cgi/content/full/49/6/1011
      http://www.ajhp.org/cgi/content/abstract/37/11/1514

Thanks
Leonid

P.S. I do not think that this is a good idea to use additive dependence:

TVCL=THETA(X)*(WT/70)**0.75+THETA(Y)*CRCL
--------------------------------------
Leonid Gibiansky, Ph.D.
President, QuantPharm LLC
web: www.quantpharm.com
e-mail: LGibiansky at quantpharm.com
tel: (301) 767 5566




Bonate, Peter wrote:
> I have an interesting question I'd like to get the group's collective
> opinion on. I am fitting a pediatric and adult pk dataset. I have
> fixed weight a priori to its allometric exponents in the model. When
I
> test serum creatinine and estimated creatinine clearance equation as
> covariates in the model (power function), both are statistically
> significant. CrCL appears to be a better predictor than serum Cr (LRT
=
> 22.7 vs 16.7). I have an issue with using CrCL as a predictor in the
> model since it's estimate is based on weight and weight is already in
> the model. Also, there might be collinearity issues with CrCL and
> weight in the same model, even though they are both significant. Does

> anyone have a good argument for using CrCL in the model instead of
serum Cr?
>
> Thanks
>
> Pete bonate
>
>
>
> Peter L. Bonate, PhD, FCP
> Genzyme Corporation
> Senior Director
> Clinical Pharmacology and Pharmacokinetics
> 4545 Horizon Hill Blvd
> San Antonio, TX 78229 USA
> _peter.bonate
> phone: 210-949-8662
> fax: 210-949-8219
> crackberry: 210-315-2713
>
> alea jacta est - The die is cast.
>
> Julius Caesar
>
>
Received on Mon Jan 12 2009 - 19:53:12 EST

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