help on problem with baseline estimation

I am really struggling with something. I am trying to do an adaptive dosing problem. I have a PKPD model with 2-compartment IV pharmacokinetic model (compartment 1 and 2) and an indirect response model for Compartment 3. What I need is a way to get the observed baseline 24 h after dosing and then make a dosing recommendation based on the observed value. I thought this would work $INPUT ID AGE WGT GEN CLO V1O QO V2O EVID MDV CMT TIME AMT RATE NSIM GRP DV TRT $SUB ADVAN8 TOL=5 $MODEL COMP= (CENTRAL) COMP= (PER) COMP= (RESPONSE, DEFOBS) $PK ;PD parameters (IDR model, Elimination-Inhibition) CALLFL= -1 IF (NEWIND .EQ. 1) DELTA=0 CL= CLO V1= V1O Q= QO V2= V2O K= CL/V1 K12= Q/V1 K21= Q/V2 PLA= -THETA(3)*EXP(ETA(3))*TIME KIN= THETA(1) BASE= THETA(4)+ETA(2) KOUT= KIN/BASE IMAX= 1 IC50= THETA(2)*EXP(ETA(1)) A_0(3)= BASE F1 = 0 IF (CMT .EQ. 1 .AND. EVID .EQ. 1) F1 = 1 IF (CMT .EQ. 1 .AND. EVID .EQ. 1 .AND. TIME .EQ. 24 .AND. DELTA .LE. 4) F1 = 1 IF (CMT .EQ. 1 .AND. EVID .EQ. 1 .AND. TIME .EQ. 36 .AND. DELTA .LE. 4) F1 = 1 IF (CMT .EQ. 1 .AND. EVID .EQ. 1 .AND. TIME .EQ. 24 .AND. DELTA .GT. 4 .AND. DELTA .LE. 8) F1 = 1 IF (CMT .EQ. 1 .AND. EVID .EQ. 1 .AND. TIME .EQ. 36 .AND. DELTA .GT. 4 .AND. DELTA .LE. 8) F1 = 0 IF (CMT .EQ. 1 .AND. EVID .EQ. 1 .AND. TIME .EQ. 24 .AND. DELTA .GE. 8) F1 = 0 IF (CMT .EQ. 1 .AND. EVID .EQ. 1 .AND. TIME .EQ. 36 .AND. DELTA .GE. 8) F1 = 0 $DES DADT(1)=-K12*A(1) +K21*A(2) -K*A(1) DADT(2)= K12*A(1) -K21*A(2) DADT(3)= KIN+PLA -KOUT*A(3)*(1-IMAX*(A(1)/V1)/(IC50+(A(1)/V1))) $ERROR IPRE= F Y= F + EPS(1) IF (TIME .EQ. 0 .AND. CMT .EQ. 3 .AND. EVID .EQ. 0) BASE2 = Y IF (TIME .LT. 24) DELTA = 0 IF (TIME .EQ. 24) DELTA = Y - BASE2 My thought was that I could use F1 to turn on and off a dose. But this did not work. What I need is for BASE2 to be retained in subsequent records so that it can be used to calculate DELTA. Here are the first couple of observations for Patient 10001 TABLE NO. 1 ID EVID MDV CMT TIME IPRE DV BASE2 DELTA BASE AMT F1 NSIM 1.0001E+04 1.0000E+00 1.0000E+00 1.0000E+00 0.0000E+00 1.1433E+02 0.0000E+00 0.0000E+00 0.0000E+00 1.1433E+02 2.7150E+00 1.0000E+00 0.0000E+00 1.0001E+04 1.0000E+00 1.0000E+00 3.0000E+00 0.0000E+00 1.1533E+02 0.0000E+00 0.0000E+00 0.0000E+00 1.1433E+02 1.0000E+00 0.0000E+00 0.0000E+00 1.0001E+04 0.0000E+00 0.0000E+00 3.0000E+00 0.0000E+00 1.1533E+02 1.1769E+02 1.1769E+02 0.0000E+00 1.1433E+02 0.0000E+00 0.0000E+00 0.0000E+00 1.0001E+04 0.0000E+00 0.0000E+00 3.0000E+00 5.0000E-01 1.1546E+02 1.1359E+02 0.0000E+00 0.0000E+00 1.1433E+02 0.0000E+00 0.0000E+00 0.0000E+00 1.0001E+04 0.0000E+00 0.0000E+00 3.0000E+00 1.0000E+00 1.1567E+02 1.1713E+02 0.0000E+00 0.0000E+00 1.1433E+02 0.0000E+00 0.0000E+00 0.0000E+00 1.0001E+04 0.0000E+00 0.0000E+00 3.0000E+00 2.0000E+00 1.1593E+02 1.1454E+02 0.0000E+00 0.0000E+00 1.1433E+02 0.0000E+00 0.0000E+00 0.0000E+00 1.0001E+04 0.0000E+00 0.0000E+00 3.0000E+00 4.0000E+00 1.1616E+02 1.1740E+02 0.0000E+00 0.0000E+00 1.1433E+02 0.0000E+00 0.0000E+00 0.0000E+00 1.0001E+04 0.0000E+00 0.0000E+00 3.0000E+00 6.0000E+00 1.1628E+02 1.1775E+02 0.0000E+00 0.0000E+00 1.1433E+02 0.0000E+00 0.0000E+00 0.0000E+00 1.0001E+04 0.0000E+00 0.0000E+00 3.0000E+00 1.2000E+01 1.1640E+02 1.1497E+02 0.0000E+00 0.0000E+00 1.1433E+02 0.0000E+00 0.0000E+00 0.0000E+00 1.0001E+04 0.0000E+00 0.0000E+00 3.0000E+00 2.3900E+01 1.1611E+02 1.2103E+02 0.0000E+00 0.0000E+00 1.1433E+02 0.0000E+00 0.0000E+00 0.0000E+00 1.0001E+04 1.0000E+00 1.0000E+00 1.0000E+00 2.4000E+01 1.1610E+02 0.0000E+00 0.0000E+00 1.1656E+02 1.1433E+02 2.7150E+00 1.0000E+00 0.0000E+00 1.0001E+04 0.0000E+00 0.0000E+00 3.0000E+00 2.4500E+01 1.1623E+02 1.1715E+02 0.0000E+00 1.1656E+02 1.1433E+02 0.0000E+00 0.0000E+00 0.0000E+00 1.0001E+04 0.0000E+00 0.0000E+00 3.0000E+00 2.8000E+01 1.1688E+02 1.1774E+02 0.0000E+00 1.1656E+02 1.1433E+02 0.0000E+00 0.0000E+00 0.0000E+00 1.0001E+04 0.0000E+00 0.0000E+00 3.0000E+00 3.6000E+01 1.1697E+02 1.1702E+02 0.0000E+00 1.1656E+02 1.1433E+02 0.0000E+00 0.0000E+00 0.0000E+00 1.0001E+04 1.0000E+00 1.0000E+00 1.0000E+00 3.6000E+01 1.1697E+02 0.0000E+00 0.0000E+00 1.1656E+02 1.1433E+02 2.7150E+00 0.0000E+00 0.0000E+00 1.0001E+04 0.0000E+00 0.0000E+00 3.0000E+00 3.6500E+01 1.1697E+02 1.1600E+02 0.0000E+00 1.1656E+02 1.1433E+02 0.0000E+00 0.0000E+00 0.0000E+00 1.0001E+04 0.0000E+00 0.0000E+00 3.0000E+00 4.0000E+01 1.1687E+02 1.1249E+02 0.0000E+00 1.1656E+02 1.1433E+02 0.0000E+00 0.0000E+00 0.0000E+00 1.0001E+04 0.0000E+00 0.0000E+00 3.0000E+00 4.8000E+01 1.1645E+02 1.1227E+02 0.0000E+00 1.1656E+02 1.1433E+02 0.0000E+00 0.0000E+00 0.0000E+00 1.0001E+04 0.0000E+00 0.0000E+00 3.0000E+00 6.0000E+01 1.1556E+02 1.1372E+02 0.0000E+00 1.1656E+02 1.1433E+02 0.0000E+00 0.0000E+00 0.0000E+00 1.0001E+04 0.0000E+00 0.0000E+00 3.0000E+00 7.2000E+01 1.1460E+02 1.1265E+02 0.0000E+00 1.1656E+02 1.1433E+02 0.0000E+00 0.0000E+00 0.0000E+00 1.0001E+04 0.0000E+00 0.0000E+00 3.0000E+00 8.4000E+01 1.1367E+02 1.1345E+02 0.0000E+00 1.1656E+02 1.1433E+02 0.0000E+00 0.0000E+00 0.0000E+00 1.0001E+04 0.0000E+00 0.0000E+00 3.0000E+00 9.6000E+01 1.1283E+02 1.1508E+02 0.0000E+00 1.1656E+02 1.1433E+02 0.0000E+00 0.0000E+00 0.0000E+00 The baseline is 117.7 but DELTA has values of 116.6. I cannot figure out what NONMEM is doing. Can anyone offer any suggestions. Thanks, pete bonate Peter L. Bonate, PhD Senior Director Global Head - Pharmacokinetics, Modeling, and Simulation Global Clinical Pharmacology & Exploratory Development Astellas Pharma Global Development Three Parkway North Deerfield, IL 60015 phone: (847) 282-5855 cell: 224-619-4901 email: [email protected] "Confidence is what you have before you understand the problem" - Woody Allen

Pete, I haven't got to grips with all of your code but I think the problem may lie here: IF (TIME .EQ. 0 .AND. CMT .EQ. 3 .AND. EVID .EQ. 0) BASE2 = Y IF (TIME .LT. 24) DELTA = 0 IF (TIME .EQ. 24) DELTA = Y - BASE2 You are relying on computing values of BASE2 and DELTA in one record and retaining those value for a subsequent record. Because BASE2 and DELTA involve random variables (i.e. variables associated with ETAs) the value of BASE 2 and DELTA is set to zero for each new record unless you explicitly assign it with every record with this trick. IF (NEWIND.LE.1) THEN ; this is 'safer' than NEWIND.EQ.1 because it explicitly assigns BASE2 andd DELTA for the first record for the data set. NEWIND is 0 for the first record of the first subject. BASE2=0 DELTA=0 ENDIF IF (TIME .EQ. 0 .AND. CMT .EQ. 3 .AND. EVID .EQ. 0) THEN BASE2 = Y ELSE BASE2=BASE2 ENDIF IF (TIME .EQ. 24) THEN DELTA = Y - BASE2 ELSE DELTA=DELTA ENDIF Best wishes, Nick

hello Pete, I think you have to instruct NONMEM to remember the variable value when it's looping over the dataset. Could you try if it works if you change the 3rd line in $error to: IF (TIME .EQ. 0 .AND. CMT .EQ. 3 .AND. EVID .EQ. 0) THEN BASE2 = Y ELSE BASE2 = BASE2 ENDIF best regards, Ron