residual variability

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