local minimum

From: "Milly de Jonge" <Apmil@SLZ.NL> Subject: [NMusers] local minimum Date: Fri, 21 Dec 2001 08:10:56 +0100 Dear NONMEM users, I have got a question concerning the minimization's of my NONMEM runs. At the moment I am working on a two-compartment model of an iv given compound (control stream below). I am not using ADVAN3 but defined the PK-model with differential equations (ADVAN6), since I am planning to extent the model with non-linear pk-components (distribution, etc). My data are log transformed and I am working with the FO method. On fitting the data nonmem indicates that the run has ended successfully (without any error messages). However my PRED vs DV plot looks bad and the parameter estimates are not as expected, indicating that nonmem has finished on a local minimum. I have tried to avoid the local minimum by increasing TOL and SIG, but this did not work. Could someone tell me how to solve this problem? Thanks in advance. Milly de Jonge Netherlands Cancer Institute Department of Pharmacy and Pharmacology Louwesweg 6 1066 EC Amsterdam $PROBLEM 2 COMP MODEL $INPUT DROP=IDUC ID DROP=LN DROP=STAT DAT1=DROP TIME AMT1=DROP RAT1=DROP DV1=DROP CMT AMT RATE DVN=DROP DV KUUR DAY EVID MDV $DATA DATARUN218.CSV IGNORE=# $SUBROUTINES ADVAN6 TOL5 $MODEL COMP=(CENTR) COMP=(PER) $PK CL=THETA(1)*EXP(ETA(1)) V1=THETA(2)*EXP(ETA(2)) K12=THETA(3) K21=THETA(4) S1=V1 $DES DADT(1)=-CL*A(1)/S1-K12*A(1)+K21*A(2) DADT(2)=K12*A(1)-K21*A(2) $ERROR CALLFL=0 W=SQRT(THETA(5)**2) IPRED=LOG(F) IRES=DV-IPRED IWRES=IRES/W Y=IPRED+W*EPS(1) $THETA (0,35) ;1 Cl (0,50) ;2 V1 (0,0.3) ;3 k12 (0,0.9) ;4 k21 (0,0.1) ;5 add $OMEGA 0.04 0.04 $SIGMA 1 FIXED $ESTIMATE PRINT=5 MAXEVAL=9999 POSTHOC NOABORT METHOD=0 MSFO=RUN218.MSF $COVARIANCE $TABLE ID TIME IPRED IWRES NOPRINT ONEHEADER FILE=SDTAB218 $TABLE ID CMT CL V1 K12 K21 NOPRINT ONEHEADER FILE=PATAB218