Any solutions to both "minimization terminated" and "high" relative bioavailability
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=
===================================================================================