questions about IOV

Dear All, I am a new NONMEM user and now trying to model clnical PK data with a two-compartment model. More than half of patients in our trial had escalated dose in the second cycle. So I should have inter-occasion variability. But I got a couple of questions here. First, what parameters should be estimated with IOV? I have seen some models with IOV on CL, but not on others (maybe because I have seen too few models). Now I have IOV on CL, V1 and Q and it run successfully. But when I run with either two of them, I got minimization problem. But, am I having too many IOVs in the model? Second, I was wondering how to model IOV. Now I have the code as ; Define IOV, DESC = DOSE ESCALATION DESC=0 IF (TIME.GE.100) DESC=1 ETCL = ETA(1) + DESC*ETA(5) ETV1 = ETA(2) + DESC*ETA(6) ETQ = ETA(3) + DESC*ETA(7) ETV2 = ETA(4) So IOV is modeled as additive relationship to IIV. But what about multiplying relationship? Like ; Define IOV, DESC = DOSE ESCALATION DESC=0 IF (TIME.GE.100) DESC=1 ETCL = ETA(1)*(1+DESC*ETA(5)) ETV1 = ETA(2)*(1+DESC*ETA(6)) ETQ = ETA(3)*(1+DESC*ETA(7)) ETV2 = ETA(4) When I run with this multiplying relationship, I got increased OFV and minimization terminated due to rounding error. But I didn't understand why it is not working. Thank you so much for your patience and time! Jia