NONMEM Users Network Archive

Hosted by Cognigen

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

From: Hong-Guang Xie <hongg.xie>
Date: Thu, 21 Aug 2008 14:30:11 -0400

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 Thu Aug 21 2008 - 14:30:11 EDT

The NONMEM Users Network is maintained by ICON plc. Requests to subscribe to the network should be sent to: nmusers-request@iconplc.com.

Once subscribed, you may contribute to the discussion by emailing: nmusers@globomaxnm.com.