Simulation problems

From: Toufigh Gordi - tgordi@buffalo.edu Subject: [NMusers] Simulation problems Date: 2/4/2004 4:54 PM Dear all, I am trying to simulate oral dosing of a compound following a bi-exponential decline with saturable CL and its binding to receptors, which is described by a simple E-max model. Part of the control stream is given here: COMP=(GUT DEFDOSE) COMP=CENT COMP=PERIPH $PK VM=THETA(1)*EXP(ETA(1)) KM=THETA(2) V1=THETA(3)*EXP(ETA(2)) Q=THETA(4) V2=THETA(5)*EXP(ETA(3)) S2=V1 BASE=THETA(6) IMAX=THETA(7) IC50=THETA(8) KA=THETA(9) F1=0.6 $DES CON=A(2)/V1 DADT(1)=-KA*A(1) DADT(2)=KA*A(1)-A(2)*(VM/(KM+CON))/V1-A(2)*Q/V1+A(3)*Q/V2 DADT(3)=A(2)*Q/V1-A(3)*Q/V2 $ERROR CONC=F LAM=BASE-(IMAX*CONC/(IC50+CONC)) IF (PKPD.EQ.2) THEN Y=LAM ELSE Y=CONC+EPS(1) ENDIF $THETA (7.98 FIXED) ;1 VM $THETA (11.1 FIXED) ;2 KM $THETA (41.9 FIXED) ;3 V1 $THETA (0.395 FIXED) ;4 Q $THETA (39.2 FIXED) ;5 V2 $THETA (54.8 FIXED) ;6 BASE $THETA (53.7 FIXED) ;7 IMAX $THETA (0.579 FIXED) ;8 IC50 $THETA (0.01 FIXED) ;9 KA $OMEGA 0.0791 FIX ;1 IIV VM $OMEGA 0.0181 FIX ;2 IIV V1 $OMEGA 0.0918 FIX ;3 IIV V2 ;$OMEGA 0.00328 FIX ;4 IIV BASE ;$OMEGA 0.00424 FIX ;5 IIV IMAX ;$OMEGA 0.888 FIX ;6 IIV IC50 $SIGMA 0 FIX ;4 ADD ERROR PK All fixed values beside the bioavilability (0.6) and ka are model estimates using data from single iv doses. The problem I encounter is that when ka is increased to, let's say 0.03 or higher, the simulation results in a Fortran message of overflow. The model works, however below this value, or if no ETAs are presented on the PD parameters. Increasing dose will also result in success with higher ka values. My guess is that ETAs make the model unstable and result in a division by zero somewhere. My first question is how to fix the problem. The second is if there is any understandable reason for why ka should be the cause of the model collapse. Best regards, Toufigh Gordi