From: Hong-Guang Xie <*hongg.xie*>

Date: Thu, 21 Aug 2008 18:14:56 -0400

Hi Nick:

Thank you for your quick response to my inquiry email.

In my control stream (see above), the initial values for the "fixed effects"

parameters (such as f13, f15, and f16) were obtained from each terminated

run after typing and running "nmctl runname" in order to fix a more

important problem --"minimization terminated". In addition, I used to try

the *constraints* as you suggested, and finally the minimization was still

"terminated" but not "successful" (plus, COV: NONE). If the final parameters

returned from each terminated run were used as initial values used in the

$THETA section (as seen in my last email), both "minimization terminated"

and high F1 values came together. It there a good solution to the two

problems at the same time?

Your saying -- "you can ignore the rounding error and additional problem

warnings. They dont mean anything useful."-- means that we do NOT need to

care about them too much, even if minimization is "terminated" and

covariance step "aborted" or "NONE", right? My understanding was from your

abstract (http://www.page-meeting.org/?abstract=992) and another similar

abstract (CPT, 2005; 77:p2) by Gastonguay MR et al. If this is the case at

any time or even at most time, the NONMEM run would not seem to be too

tough.

I will follow your suggestions to check if the model fits the data well

later.

Thank you,

Hong-Guang

------------------------------------------------------------------------------------------------------------------------------------------------------------

On 8/21/08, Nick Holford <n.holford

*>
*

*> 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
*

*> n.holford *

*> http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford
*

*>
*

*>
*

*>
*

Received on Thu Aug 21 2008 - 18:14:56 EDT

Date: Thu, 21 Aug 2008 18:14:56 -0400

Hi Nick:

Thank you for your quick response to my inquiry email.

In my control stream (see above), the initial values for the "fixed effects"

parameters (such as f13, f15, and f16) were obtained from each terminated

run after typing and running "nmctl runname" in order to fix a more

important problem --"minimization terminated". In addition, I used to try

the *constraints* as you suggested, and finally the minimization was still

"terminated" but not "successful" (plus, COV: NONE). If the final parameters

returned from each terminated run were used as initial values used in the

$THETA section (as seen in my last email), both "minimization terminated"

and high F1 values came together. It there a good solution to the two

problems at the same time?

Your saying -- "you can ignore the rounding error and additional problem

warnings. They dont mean anything useful."-- means that we do NOT need to

care about them too much, even if minimization is "terminated" and

covariance step "aborted" or "NONE", right? My understanding was from your

abstract (http://www.page-meeting.org/?abstract=992) and another similar

abstract (CPT, 2005; 77:p2) by Gastonguay MR et al. If this is the case at

any time or even at most time, the NONMEM run would not seem to be too

tough.

I will follow your suggestions to check if the model fits the data well

later.

Thank you,

Hong-Guang

------------------------------------------------------------------------------------------------------------------------------------------------------------

On 8/21/08, Nick Holford <n.holford

Received on Thu Aug 21 2008 - 18:14:56 EDT