Proper way to handle the pre-first dose PK observation for non-endogenous drug

Dear NONMEM Users, I'd like to get some advice from you with regard to how to handle the pre-first dose PK observation when the drug is not an endogenous substance. I tried too different approaches, one approach is treating them as missing values (DV=0, EVID=0, MDV=1), another is treating them as true 0s (DV=0, EVID=0, MDV=0). My error structure is proportional + additive. There were very little difference for all parameters except for the SD of the additive error. When these pre-first dose concentrations were treated as missing, the estimated omega for additive error is 3.92, and when they were treated as true 0s, the sigma became 2.85. To me, in theory, these values provide no information about the model parameters because the system will predict them to be 0 at time 0 anyway for any point in the parameter space. Is what happened here that because DV is exactly the same as prediction, therefore the estimation of additive residual error variance has been brought down? Which way is more appropriate? I'd really appreciate it if you can share your experience/insight. Yaming Hang, Ph.D. Pharmacometrics Biogen Idec 14 Cambridge Center Cambridge, MA 02142 Office: 781-464-1741 Fax: 617-679-2804 Email: [email protected]<mailto:[email protected]>