Dear NONMEM Users, We have recently run into a rather puzzling problem with a PK/PD model and are hoping one of the NONMEM experts in the community can provide some insight. The model was originally developed, and ran well, using a previously used Unix-based version of NONMEM. However, when we attempted to re-implement the model with our current, windows-based NONMEM VI, the model would not run, giving a numerical difficulties error. The bones of the model are provided below:
$MODEL NCOMP=5 COMP(DEPOT,DEFDOSE) COMP(CENTRAL) COMP(PD1) COMP(PD2) COMP(PD3,DEFOBS) $PK "FIRST " COMMON /PRCOMG/ IDUM1,IDUM2,IMAX,IDUM4,IDUM5 " INTEGER IDUM1,IDUM2,IMAX,IDUM4,IDUM5 " IMAX=1000000 KA1=KAIN GAMA1=GAMA ALAG1=LAGI V=VIND CL=CLIN KAM=KAMI WB=(1-EXP((-(KA1*TIME)**GAMA1)))*KAM K20=CL/V S2=V/1000 BETA=0.00000003 PROD=1.736 V0=VIN0 TD=0.0001 DELT=THETA(1)*EXP(ETA(1)) CV=THETA(2)*EXP(ETA(2)) IC50=THETA(3)*EXP(ETA(3)) HG=THETA(4)*EXP(ETA(4)) T0=(DELT*CV)/(BETA*PROD) SYN=T0*(TD+(BETA*V0)) F3=T0 F4=(CV*V0)/PROD F5=V0 $DES DADT(1)=-WB*A(1) DADT(2)=WB*A(1)-K20*A(2) C2=A(2)*1000/V EFF=(C2**HG/(IC50**HG+C2**HG)) DADT(3)=SYN-A(3)*TD-BETA*A(3)*A(5) DADT(4)=BETA*A(3)*A(5)-DELT*A(4) DADT(5)=(1-EFF)*PROD*A(4)-CV*A(5) The PK parameters are fixed in the model. In order to get the model to run with our current version of NONMEM, we had to initialize the CENTRAL compartment with a nominal value (i.e. 1). This was done by modifying the data set to contain AMT=1 for CMT=2 at TIME=0 for each subject. The results obtained following this modification are in agreement with those obtained previously with the original model run in Unix. Has anyone run into a similar situation when running Unix-developed models in a windows environment? Has anyone ever encountered a situation where it was necessary to initialize a PK compartment? Any insight into this problem would be greatly appreciated. Regards, Josh
