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

From: Mark Sale - Next Level Solutions <mark>
Date: Thu, 21 Aug 2008 13:49:53 -0700

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Received on Thu Aug 21 2008 - 16:49:53 EDT

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Hong-Guang
 Analyses a= cross so many studies are notoriously difficult, especially with different = routes of administration.  My personal experience is that the most com= mon cause for this sort of thing is errors in the data set.
Make sure th= at the dose and concentration units are the same for all studies, as well a= s weight, height etc.  If the populations are (relatively) the same ac= ross the studies, and the drug is the same (same formulation), and one stud= y 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 administerin= g the drug in the correct compartment.  I assume that the dose for the= iv is going into compartment 2 for ADVAN4?  All observtions are compa= rtment 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 ma= ke:
-= 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 dose= s - you'll have an interdose interval of 0, two doses given at the same tim= e).

-Histogram of interval between observation and most recent dose.
 


Mark= Sale MD
Next Level Solutions, LLC
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 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=
================ ========================== ========================== ==================