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Re: CrcL or Cr in pediatric model

From: Leonid Gibiansky <LGibiansky>
Date: Mon, 12 Jan 2009 18:30:02 -0500

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 - 18:30:02 EST

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