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Covariate modelling, covaraite effects

From: joan hern <joanhc0603>
Date: Tue, 13 Apr 2010 23:07:59 +0200

Dear NMusers,



I would like to have your help on the following issue:



I am trying to model the PK of a parent compound and two metabolites (M1 is
the major and M2 is the minor metabolite), both metabolites are mainly
eliminated by renal excetion although a minor biliar excretion pathway
exists. Creatinine clearance (CLCR) values in the studied population range
form 10 to 100 mL/min. The plots of eta vs CLCR show a relationship in both
cases The inclusion of CLCR on CLM1 as covariate decreases significantly the
OFV value in 1779 units with respect to the base model, and a decrease of
about 30% is observed in the IIV of this parameter (CLM1).



In the case of the second metabolite (M2) the inclusion of CLCR on CLM2
decreases the OFV around 700 units but no reduction of IIV of CLM2 is
observed when compared with the base model. For the second metabolite,
 reduction
in the residual error with respect to the base model is very low (around
10%).



The way I entered the covariates was in both cases

TVCL= theta(x)*(CLCR/mean population CLCR value)**(theta(y)).



In both cases, all the model parameters were estimated correctly. Then my
question is if I should leave CLCR in CLM2 or I should remove it. I would
appreciate your comments and suggestions about how to deal with this and
about what could be the reasons of this.

Best regards

joann

Received on Tue Apr 13 2010 - 17:07:59 EDT

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