-------- Original Message --------
Subject: [NMusers] Any solutions to both "minimization terminated" and
"high" relative bioavailability
From: Hong-Guang Xie <hongg.xie Date: Thu, August 21, 2008 2:30 pm
To: nmusers
Dear NONMEM Users,
Recently I combined si=
x popPK studies (STDY) together as a whole and tried to re-estimate th=
e 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 follo=
ws. Based on the prior knowledge that a two-compartment model with fir=
st-order absorption and elimination is used to describe its PK pr=
ofile well, a two-compartment model was used for my meta-popPK analysi=
s. After the NM run for the additive or proportional error model or both,&n=
bsp;the NM indicated that "MINIMIZATION TERMINATED DUT TO ROUNDING ERRORS (ERROR=134)" alone or in combi=
nation with "ADDITIONAL PROBLEMS OCCURED WITH THE MINIMIZATION. REGARD THE =
RESULTS OF THE ESTIMATION STEP CAREFULLY, AND ACCEPT THEM ONLY AFTER CHECKI=
NG 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 f=
or STDY 5 (or f15) and 0.4 - 0.53 for STDY 6 (f16). Obviously, only f16 see=
ms to be reasonable. The drug used in the STDY 3 and 5 was given extravascu=
larly, and thus their F1 values should be less than 1. =
To fix these problems, I have made many efforts but failed. For this, I wou=
ld appreciate your time and suggestions.
Thank=
you,
Hong-Guang Xie
<=
div>==================
.....=
.......
$SUBROUTINE ADVAN4 TRANS4
$=
PK
ETAMX = 10
SI1=0=
SI2=0
=
; SI3=0
SI4=0
SI5=0
&n=
bsp; SI6=0
IF (STDY .EQ. 1) SI1=
=1 ; iv
IF (STDY .EQ. 2) SI2=1 &=
nbsp; ; iv
IF (STDY .EQ. 3) SI3=1 ; epi=
dural
IF (STDY .EQ. 4) SI4=1 ; iv
&n=
bsp; IF (STDY .EQ. 5) SI5=1 ; rectal
&nb=
sp; IF (STDY .EQ. 6) SI6=1 ; oral
&nbs=
p; 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 O=
F DISTRIBUTION
TVV2=popv2
PPV=
V2=bsvv2
IF (ABS(PPVV2) .GE. ETAMX) EXIT 1 20
=
V2=TVV2*EXP(PPVV2)
;INTERCOMPARTMENTAL CLE=
ARANCE
TVQ=popq
PPVQ=bsvq <=
br> IF (ABS(PPVQ) .GE. ETAMX) EXIT 1 30
&n=
bsp; Q=TVQ*EXP(PPVQ)
;PERIPHERAL VOLUME OF DISTRIBUTION
&nb=
sp; TVV3=popv3
PPVV3=bsvv3
=
IF (ABS(PPVV3) .GE. ETAMX) EXIT 1 40
V3=
=TVV3*EXP(PPVV3)
;FIRST ORDER ABSORPTION RATE CONSTANT
&nbs=
p; TVKA=SI3*ka3+SI5*ka5+SI6*ka6
PPVKA=
=bsvka
IF (ABS(PPVKA) .GE. ETAMX) EXIT 1 50<=
br> KA=TVKA*EXP(PPVKA)
;LAG TIME
&n=
bsp; TVLAG=SI3*lag3+SI5*lag5+SI6*lag6
PPVLAG=
=bsvlag
IF (ABS(PPVLAG) .GE. ETAMX) EXIT 1 6=
0
ALAG1=TVLAG*EXP(PPVLAG)
;BIOAVAILABILI=
TY (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
&n=
bsp; F1=1
ELSE
&n=
bsp; F1=BA
ENDIF
;ZERO ORDER ABS=
ORPTION DURATION
TVD2=SI1*d21+SI2*d22+SI4*d24
&n=
bsp; PPVD2=bsvd2
IF (ABS(PPVD2) .GE. ET=
AMX) EXIT 1 80
D2=TVD2*EXP(PPVD2)
=
; RMIN=AMT/(60*D2) ;mcg/minute
; SCA=
LING FOR CENTRAL COMPARTMENT (I.E., CONCENTRATION COMPARTMENT)
&nb=
sp;
S2=V2 ; DOSE IN MCG, CONCENTRATION IN NG=
/ML=MCG/L
$ERROR
=
IPRED = F
IF (MDV .EQ. 0) THEN
&nb=
sp; W = SQRT(add**2 + F*F*prop**2)
=
; ELSE
W = 1
=
; ENDIF
IRES=DV-IPRED
&nbs=
p; IF (W .EQ. 0) THEN
I=
WRES=IRES
ELSE
&nb=
sp; IWRES=IRES/W
ENDIF
&nbs=
p; Y=F+W*eps1*EXP(bsvres)
$THETA (0,11.5) &nb=
sp; ;popcl
=
(0,24.1) =
; ;popv2
&nb=
sp; (0,12.9) ;p=
opq
=
(0,8.22) ;popv3
&n=
bsp; (0,0=
.14) ;ka3
&n=
bsp; (0,0.109) &=
nbsp; ;ka5
=
(0,0.397) ;ka6
&n=
bsp; (0 FIX) &nb=
sp; ;lag3
&n=
bsp; (0 FIX) &nb=
sp; ;lag5
&n=
bsp; (0 FIX) &nb=
sp; ;lag6
(0,4.93) =
;f13
(0,9.19) &nbs=
p; ;f15
(0,0.523) &=
nbsp; ;f16
(0,0.00072) ;d21
=
;(0,0.00007) ;d22
(0,0.00003) ;d24
=
(0, 0.01) ;add
&n=
bsp; (0, 0.05) =
;prop
$OMEGA 0.828 ;bsvcl
$OMEGA 1.63 ;bsvv2$OMEGA 0 FIX ;bsvq
$OMEGA 0 FIX ;bsvv3
$OMEGA 0 FIX ;bsvka
$OME=
GA 0 FIX ;bsvlag
$OMEGA 0 FIX ;bsvf1
$OMEGA 0 FIX ;bsvd2
$OMEGA 0 =
FIX ;bsvres
$SIGMA 1. FIX ; eps1
$ESTIMATION=
NOABORT MAXEVAL=9999 POSTHOC PRINT=5 SIGDIGITS=3 MSFO=
&n=
bsp; METHOD=CONDITI=
ONAL INTERACTION
;$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 ETA=
4 ETA5 ETA6 ETA7 ETA8 ETA9
IWRES IR=
ES WT BWT AGEY AGED GAGE
NOPRINT O=
NEHEADER FILE=
================
==========================
==========================
==================
