From: "HUTMACHER, MATTHEW [Non-Pharmacia/1825]" <matthew.hutmacher@pharmacia.com>
Subject: Suspicious CL/F vs. CLCR and SGOT values
Date: Tue, 1 May 2001 14:47:00 -0500

Hello everyone,

I am building a population PK model for a drug based on sparse sampling in an outpatient setting. I am fitting a one-compartment model with first-order absorption with a lag time and elimination to known 2-compartment kinetics in healthy volunteers. A simulation study was used to design the study, and the data appear to be well behaved with reference to the data that was simulated. The simulation study demonstrated that only 5-7% bias is expected in the CL/F population mean parameter, so that inference on CL/F is most likely trustworthy. I am getting some curious results, however, with regards to some covariates. I am finding that increases in calculated creatinine clearance correlate with decreases in CL/F and that increases with SGOT (liver) correlate with increased CL/F. The drug is mainly metabolized by the liver. I need to do a randomization test to see if these results are spurious, but if not, does anyone have any experience or explanation for this?

Thanks for your time in advance.

Matt

 

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From: "Janet R Wade" <jwade@pharsight.com>
Subject: RE: Suspicious CL/F vs. CLCR and SGOT values
Date: Tue, 1 May 2001 23:37:19 +0200

Hi Matt

Some time ago (1994! - time flies!) I did some work with Nancy Sambol and Stuart Beal on the interaction between the structural (one vs. two compartment), statistical (variability) and the covariate model in a situation very similar to what you describe. I found that if I fit a one compartment model to sparse data simulated from a two compartment model then I got artifactual covariate effects and a more complex statistical model in the one compartment model (JPB, Vol 22 p165-177). I also tried a couple of real data examples where the data were so sparse as to not support using the a priori known two compartment model and again found covariates in the one compartment model that were not included when a two compartment model was fit to the data. The situation with real data is hard to pin down to spurious effects since we never really know the truth. In my case the covariate effects in the one comp model did seem reasonable. One of our conclusions was that any covariate effect that is to be included in the model should be biologically plausible. This would seem to be good advice in your situation since including creatinine clearance for a drug that is eliminated metabolically does not seem to be biologically plausible (unless that covariate is a surrogate for something else, age for example). I would suggest that you rerun your model using a two compartment structural model (fix some parameter values to a priori values if necessary) and retest to see if the covariates you found with the one compartment model are still significant. A last thing to bear in mind is to look at the size of the effect that your covariates have in the one compartment situation, if the effect is not clinically relevant then maybe you don't want to retain those covariates in the model anyway (but that does depend on what you want to do with the results of your analysis).

I hope this is of some help,
Janet Wade