RE: Any solutions to both "minimization terminated" and "high" relative bioavailability
Hong-Guang
Analyses across so many studies are notoriously difficult, especially with different routes of administration. My personal experience is that the most common cause for this sort of thing is errors in the data set.
Make sure that the dose and concentration units are the same for all studies, as well as weight, height etc. If the populations are (relatively) the same across the studies, and the drug is the same (same formulation), and one study isn't with ketoconazole (or other inhibitor/inducer), the error is almost certainly in the data set. Again, in my experience, additional doses are a frequent source of error. Also check that you are administering the drug in the correct compartment. I assume that the dose for the iv is going into compartment 2 for ADVAN4? All observtions are compartment 2? (You'll need to specifiy the compartment the dose and observation goes into for this model, since, I think you'll have doses going into comp 1 and 2, extravascular and iv)
I have a few plots that I like to make:
-Cumulative dose for each person vs time
-Histogram of interdose intervals (this will pick up a common one for me, where I give one too many additional doses - you'll have an interdose interval of 0, two doses given at the same time).
-Histogram of interval between observation and most recent dose.
Mark Sale MD
Next Level Solutions, LLC
www.NextLevelSolns.com
919-846-9185
Quoted reply history
-------- 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 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 "MINIMIZATION TERMINATED DUT TO ROUNDING ERRORS (ERROR4)" 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 <div>========= ............ $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
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 $ESTIMATION NOABORT MAXEVAL99 POSTHOC PRINT=5 SIGDIGITS=3 MSFO METHOD=CONDITIONAL INTERACTION ;$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= ========
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