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

From: Hong-Guang Xie <hongg.xie>
Date: Fri, 22 Aug 2008 12:43:21 -0400

Hi Mark:

Thank you for your suggestions. I checked the whole data set again and am
sure that the units for doses and plasma drug concentrations as well as
other covariates of each subject (such as age, weight,...) were the
same across all studies, but the drug's formulations varied by different
routes of administration. Because only a single dose of that drug was given
for all subjects, there were no additional doses and interdose intervals. As
for the compartment (CMT) setting, 1 and 2 were picked up for extra-vascular
and iv dosing, respectively, for the dose event, whereas only number 2 was
set for the concentration event (i.e., all observations). Now a problem is
that there was some co-medication in some studies as you expected, but no
significant drug-drug interactions exist between that drug and other drugs
being co-administrated according to currently available knowledge. Do I need
to add co-medication as a covariate?

Another possibility might be related to a very *narrow* range of the plasma
drug concentrations, for example, 0.1 - 0.72 ng/ml in subjects taking 42 -
280 mcg of that drug (a single oral dose each) for the study 6 (a study of
its oral bioavailability). How about this issue?

Thank you,

----------------------------------
Hi Nick:

Thank you for your response. I am sorry for my unclear sentence ("If this is
the case at any time or even at most time, the NONMEM run would not seem to
be too tough."), which should have read "If this is the case at any time or
even at most time, the NONMEM run would not be too tough." It is the same as
what you said -- "using NONMEM is much easier if we ignore these termination
warnings". Thank you.

Hong-Guang
-------------------------------

On 8/21/08, Mark Sale - Next Level Solutions <mark
wrote:
>
> 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 <http://www.nextlevelsolns.com/>
> 919-846-9185
>
> -------- 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 "*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=
>
> ===================================================================================
>
>
>

Received on Fri Aug 22 2008 - 12:43:21 EDT

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