Re: Any solutions to both "minimization terminated" and "high" relative bioavailability

Hong-Guan, You can ignore the rounding error and additional problem warnings. They dont mean anything useful. You should look at your parameter values to see if they are sensible (clearly they are not for 2 of the bioavailibility fractions) and also use things like a VPC to decide if the model is fitting the data (see http://www.page-meeting.org/pdf_assets/8694-Karlsson_Holford_VPC_Tutorial_hires.pdf ). To avoid unrealistic estimates for bioavailability you can try setting initial estimates for bioavailability fractions to something sensible and use constraints e.g. instead of this (0,4.93) ;f13 write this (0,.7,1) ;f13 Nick Hong-Guang Xie wrote: > Dear NONMEM Users, > > Recently I combined six popPK studies (STDY) together as a whole and tried to re-estimate the pop PK parameters of that drug in the population with a wide range of the age and body weight. In the pooled dataset, all subjects were given with a single dose of that drug. Part of the control stream was provided as follows. Based on the prior knowledge that a two-compartment model with first-order absorption and elimination is used to describe its PK profile well, a two-compartment model was used for my meta-popPK analysis. After the NM run for the additive or proportional error model or both, the NM indicated that "*MIN*IMIZATION *T*ERMINATED DUT TO ROUNDING ERRORS (ERROR=134)" alone or in combination with "ADDITIONAL PROBLEMS OCCURED WITH THE MINIMIZATION. REGARD THE RESULTS OF THE ESTIMATION STEP CAREFULLY, AND ACCEPT THEM ONLY AFTER CHECKING THE COVARIANCE STEP PRODUCES REASONABLE OUTPUT". In addition, the typical values of the relative bioavailability (*F1*) was estimated as 5 - 8 for STDY 3 (that is, f13), 9 -14 for STDY 5 (or f15) and 0.4 - 0.53 for STDY 6 (f16). Obviously, only f16 seems to be reasonable. The drug used in the STDY 3 and 5 was given extravascularly, and thus their F1 values should be less than 1. To fix these problems, I have made many efforts but failed. For this, I would appreciate your time and suggestions. Thank you, Hong-Guang Xie ================== > > ............ > > $SUBROUTINE ADVAN4 TRANS4 > > $PK > ETAMX = 10 > > SI1=0 SI2=0 > > SI3=0 > SI4=0 > SI5=0 > SI6=0 > > IF (STDY .EQ. 1) SI1=1 ; iv > IF (STDY .EQ. 2) SI2=1 ; iv > IF (STDY .EQ. 3) SI3=1 ; epidural > IF (STDY .EQ. 4) SI4=1 ; iv > IF (STDY .EQ. 5) SI5=1 ; rectal > IF (STDY .EQ. 6) SI6=1 ; oral > > IV = SI1+SI2+SI4 ;intravascular dosing > > ;APPARENT CLEARANCE > TVCL=popcl > PPVCL=bsvcl > > IF (ABS(PPVCL) .GE. ETAMX) EXIT 1 10 CL=TVCL*EXP(PPVCL) ;CENTRAL VOLUME OF DISTRIBUTION > > TVV2=popv2 > PPVV2=bsvv2 > IF (ABS(PPVV2) .GE. ETAMX) EXIT 1 20 > V2=TVV2*EXP(PPVV2) > > ;INTERCOMPARTMENTAL CLEARANCE > TVQ=popq > PPVQ=bsvq > IF (ABS(PPVQ) .GE. ETAMX) EXIT 1 30 > Q=TVQ*EXP(PPVQ) > > ;PERIPHERAL VOLUME OF DISTRIBUTION > TVV3=popv3 > PPVV3=bsvv3 > IF (ABS(PPVV3) .GE. ETAMX) EXIT 1 40 > V3=TVV3*EXP(PPVV3) > > ;FIRST ORDER ABSORPTION RATE CONSTANT > TVKA=SI3*ka3+SI5*ka5+SI6*ka6 > > PPVKA=bsvka IF (ABS(PPVKA) .GE. ETAMX) EXIT 1 50 > > KA=TVKA*EXP(PPVKA) > > ;LAG TIME > TVLAG=SI3*lag3+SI5*lag5+SI6*lag6 > > PPVLAG=bsvlag IF (ABS(PPVLAG) .GE. ETAMX) EXIT 1 60 > > ALAG1=TVLAG*EXP(PPVLAG) > > ;BIOAVAILABILITY (BA) > TVF1=SI3*f13+SI5*f15+SI6*f16 > PPVF1=bsvf1 > IF (ABS(PPVF1) .GE. ETAMX) EXIT 1 70 > BA=TVF1*EXP(PPVF1) > > IF (IV .GE. 1) THEN > > F1=1 > ELSE > F1=BA > ENDIF > > ;ZERO ORDER ABSORPTION DURATION > TVD2=SI1*d21+SI2*d22+SI4*d24 > PPVD2=bsvd2 > IF (ABS(PPVD2) .GE. ETAMX) EXIT 1 80 > D2=TVD2*EXP(PPVD2) > > RMIN=AMT/(60*D2) ;mcg/minute > > ; SCALING FOR CENTRAL COMPARTMENT (I.E., CONCENTRATION COMPARTMENT) S2=V2 ; DOSE IN MCG, CONCENTRATION IN NG/ML=MCG/L > > $ERROR > > IPRED = F > > IF (MDV .EQ. 0) THEN > W = SQRT(add**2 + F*F*prop**2) > ELSE > W = 1 > ENDIF > > IRES=DV-IPRED > > IF (W .EQ. 0) THEN > IWRES=IRES > ELSE > IWRES=IRES/W > ENDIF > > Y=F+W*eps1*EXP(bsvres) > > $THETA (0,11.5) ;popcl > (0,24.1) ;popv2 > (0,12.9) ;popq > (0,8.22) ;popv3 > (0,0.14) ;ka3 > (0,0.109) ;ka5 > (0,0.397) ;ka6 > (0 FIX) ;lag3 > (0 FIX) ;lag5 > (0 FIX) ;lag6 > (0,4.93) ;f13 > (0,9.19) ;f15 > (0,0.523) ;f16 > (0,0.00072) ;d21 > (0,0.00007) ;d22 > (0,0.00003) ;d24 > (0, 0.01) ;add > (0, 0.05) ;prop > > $OMEGA 0.828 ;bsvcl > > $OMEGA 1.63 ;bsvv2 > $OMEGA 0 FIX ;bsvq > $OMEGA 0 FIX ;bsvv3 > $OMEGA 0 FIX ;bsvka > $OMEGA 0 FIX ;bsvlag > $OMEGA 0 FIX ;bsvf1 > $OMEGA 0 FIX ;bsvd2 > $OMEGA 0 FIX ;bsvres > > $SIGMA 1. FIX ; eps1 > > $ESTIMATION NOABORT MAXEVAL=9999 POSTHOC PRINT=5 SIGDIGITS=3 MSFO= > METHOD=CONDITIONAL INTERACTION > > ;$COV PRINT=E > > $TABLE ID STDY TIME DV IPRED AMT MDV CMT CL V2 Q V3 KA ALAG1 F1 D2 RATE RMIN ETA1 ETA2 ETA3 ETA4 ETA5 ETA6 ETA7 ETA8 ETA9 > > IWRES IRES WT BWT AGEY AGED GAGE > NOPRINT ONEHEADER FILE= > =================================================================================== -- Nick Holford, Dept Pharmacology & Clinical Pharmacology University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand [EMAIL PROTECTED] tel:+64(9)373-7599x86730 fax:+64(9)373-7090 http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford