Hi everyone,

I have a rich data set for a drug administered orally. The drug has slow 
absorption (Tmax 4 hours) and rapid elimination (2 hours half life). A tlag 
model was sufficient to describe the data but I ran into difficulties with the 
error model.


If I use a proportional or combined error model, the model is unstable and I 
get unrealistic estimates (very large Vd, Cl and residual variability) . It is 
only stable if:

1) I use a constant error model

2) Use a combined error model and fix the a part


When I use a constant error model, the diagnostic plots clearly show the error 
is not constant


Not sure what the cause for this is, I tried several things to fix it like 
changing initial estimates or structural model (transit compartment, zero 
order,....), deleting outliers or low concentrations near the BLQ but the 
problem still persists.


Any suggestions


Thanks,

Abdullah Sultan

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