Antwort: [NMusers] AUC Calculation in Simulation with and without EST

Dear Paul,

to avoid this, use your dataset, use the final estimated parameters and
use $EST, but set MAXEVAL=0. This way, you can estimate all your IDs' AUC=
s
simultaneously with the right parameters for each one. I always do this if =

I use ADVAN4 for estimation of parameters. Then if I want to compute AUC I =

use ADVAN 6 and add an AUC compartment. Below is a code that calculates
CMAX, AUC, time above IC50 and AUC above IC50 for different times.

Best wishes
Nele

$SUBROUTINES ADVAN6 TOL=3
$MODEL
 COMP=(GUT)
 COMP=(CENTRAL)
 COMP=(PERIPH)
 COMP=(TIMEOVER)
 COMP=(AUCOVER)
 COMP=(AUC)
 COMP=(TIMEOV2)
 COMP=(AUCOVER2)
 COMP=(AUC2)
$PK

"FIRST
" COMMON /PRCOMG/ IDUM1,IDUM2,IMAX
" INTEGER IDUM1,IDUM2,IMAX
" IMAX=500000
;
TVCL=THETA(1)
CL=TVCL
;
TVV2=THETA(2)
V2=TVV2
;
TVQ=THETA(3)
Q=TVQ
;
TVV3=THETA(4)
V3=TVV3
;
TVKA=THETA(5)
KA=TVKA

TVF1=THETA(6)
F1=TVF1*EXP(ETA(1))

S2=V2
K20=CL/V2
K23=Q/V2
K32=Q/V3
K12=KA

$DES
IF(TIME.EQ.0) THEN
 CMAX=0
 TMAX=0
ENDIF
CC=A(2)/V2
IF(CC.GT.CMAX) THEN
 CMAX= CC
 TMAX= T
ENDIF
IC50=0.0075
RT=0
IF(CC.GT.IC50) RT=1

DADT(1)=-KA*A(1)
DADT(2)= KA*A(1)-K23*A(2)+K32*A(3)-K20*A(2)
DADT(3)= K23*A(2)-K32*A(3)
DADT(4)= RT ;time above IC50
IF (T.GT.24) DADT(4)=0
DADT(5)= RT*(CC-IC50) ;AUC over IC50
IF (T.GT.24) DADT(5)=0
DADT(6)= A(2)/V2
IF (T.GT.24) DADT(6)=0
DADT(7)=0
IF (T.GE.48) DADT(7)=RT
DADT(8)=0
IF (T.GE.48) DADT(8)=RT*(CC-IC50)
DADT(9)=0
IF (T.GE.48) DADT(9)=A(2)/V2

;
$ERROR
  IPRED=F
  DEL=0
  IF (IPRED.EQ.0) DEL=0.0001
  W=F
  IRES=DV-IPRED
  IWRES=IRES/(W+DEL)
  Y=F+SQRT(THETA(8)*THETA(8)+THETA(7)*THETA(7)*F**2)*EPS(1)
  CC2=A(2)/V2
  TOI1=A(4)
  AOI1=A(5)
  AUC1=A(6)
  TOI2=A(7)
  AOI2=A(8)
  AUC2=A(9)

;
$THETA
...
;
$OMEGA
...
;
$SIGMA
1 FIX ;prop.error
;
$EST METHOD=1 INTERACTION MAXEVAL=0 PRINT=5 NOABORT MSFO=msf001
$TABLE ID TIME CL V2 V3 Q KA F1 CC2 TOI1 TOI2 AOI1 AOI2
AUC1 AUC2 CMAX NOPRINT ONEHEADER FILE=notab1
_________________________
Dr. Nele Plock
Bayer Schering Pharma AG
Drug Metabolism & Pharmacokinetics
Development Pharmacokinetics
Scientific Expert Development Pharmacokinetics
D- 13342 Berlin

Phone : +49-30-468 15146
Fax: +49-30-468 95146
nele.plock_at_bayerhealthcare.com
http://www.bayerscheringpharma.de

Vorstand: Arthur J. Higgins, Vorsitzender | Werner Baumann, Andreas Busch, =

Ulrich Köstlin, Kemal Malik, Gunnar Riemann
Vorsitzender des Aufsichtsrats: Werner Wenning
Sitz der Gesellschaft: Berlin | Eintragung: Amtsgericht Charlottenburg 93
HRB 283



Paul Hutson <prhutson_at_pharmacy.wisc.edu>
Gesendet von: owner-nmusers_at_globomaxnm.com
07.01.2008 06:59
Bitte antworten an
prhutson_at_pharmacy.wisc.edu


An
NMUSERS_at_GLOBOMAXNM.COM
Kopie

Thema
[NMusers] AUC Calculation in Simulation with and without EST






I have data from PO, IP, and SQ(pump) infusions of this compound that I am =

modeling using 2-3 samples per mouse (30 critters worth), and the fits for =

a 1 cmpt are pretty good. In order to obtain a smooth plot to compare to
the observed data, I have run N=1 simulations for a single "subject"
(ID=1) using the bootstrapped parameters from all animals (each receiving=
 
drug via a single route).

My question for the NMUSERS is this. When I just use $SIM without $EST,
my AUC calculated by F1*AMT/CL is wildly different than the AUC I obtain
by a quick trapezoidal check of my PRED column in the output file. When I =

use both $SIM and $EST as shown below, the integrated and trapezoidal AUCs =

agree. Why is there a difference? I presume that it is due to the use of
a dummy value of "1" for DV throughout my initial data file, but I don't
understand why. Thanks as always.
(csv file follows ctl)
(As always, any other suggestions to spruce up the code or my approach is
appreciated.) Paul

$PROBLEM CYCLOPAMIDE
$INPUT ID TIME AMT RATE ADDL II PMP DV CMP RTE EVID
$DATA ..\Lipinski_24PO.CSV IGNORE=#
$SIMULATION (1111)

$SUBROUTINES ADVAN2 TRANS2
$PK
ALAG1=0
RTE1=0
RTE2=0
RTE3=0
IF(RTE.EQ.1) RTE1=1
IF(RTE.EQ.2) RTE2=1
IF(RTE.EQ.3) RTE3=1

F1=1
IF(RTE.EQ.1) F1=THETA(1); PO
IF(RTE.EQ.2) F1=THETA(2); IP

TVKA=THETA(3); GUT
IF(RTE.EQ.2) TVKA=THETA(4); IP
IF(RTE.EQ.3) TVKA=THETA(5); SQ PUMP

CL=THETA(6)*EXP(ETA(1)); CL
V=THETA(7)*EXP(ETA(2)); V
KA=TVKA;*EXP(ETA(3));
;IF(RTE.EQ.3) ALAG1=THETA(8)*EXP(ETA(4))

K=CL/V
T12=0.693/K
AUC=F1*AMT/CL
TMAX=(LOG(KA)-LOG(K))/(KA-K)
CMAX=(F1*AMT/V)*EXP(-K*TMAX)
CAVE=F1*AMT/(CL*24)

S2=V


$ERROR

IPRE = F
W1=F
   DEL = 0
   IF(IPRE.LT.0.001) DEL = 1
   IRES = DV-IPRE; NEGATIVE TREND IS OVERESTIMATING IPRED WRT DV
   IWRE = IRES/(W1+DEL)

Y=IPRE+EPS(1)
$THETA 0.642; F1PO
$THETA 1.267; F1IP

$THETA 0.472; KAGUT
$THETA 8.879; KAIP
$THETA 4.564; KASQ


$THETA 0.146; CL
$THETA 0.289; V
 
$OMEGA 0.313; ETACL
$OMEGA 0.964; EtTAV

$SIGMA 0.178; SIG1

$EST METH=1 INT NOABORT MAXEVAL=9999 POSTHOC

$TABLE ID TIME AUC AMT K KA CL V F1 RTE ETA1 ETA2
NOPRINT ONEHEADER FILE=CycloSim.fit

#AMT in micromoles,,,,,,,,,,
#TIME in hours,,,,,,,,,,
#DV in microMolar,,,,,,,,,,
#COMP: 1 for PO_ 2 for blood_3 for IP_4 for SC,,,,,,,,,,
#RTE: 1 for PO 2 for IP 3 for SQ Pump,,,,,,,,,,
#ID,TIME,AMT,RATE,ADDL,II,DUR,DV,COMP,RTE,EVID
1,0,0.608,.,.,.,.,.,1,1,1
1,0.1,.,.,.,.,.,1,2,1,0
1,0.2,.,.,.,.,.,1,2,1,0
1,0.3,.,.,.,.,.,1,2,1,0
1,0.4,.,.,.,.,.,1,2,1,0
1,0.5,.,.,.,.,.,1,2,1,0
1,0.6,.,.,.,.,.,1,2,1,0
1,0.7,.,.,.,.,.,1,2,1,0
1,0.8,.,.,.,.,.,1,2,1,0
1,0.9,.,.,.,.,.,1,2,1,0
1,1,.,.,.,.,.,1,2,1,0
1,1.2,.,.,.,.,.,1,2,1,0
1,1.4,.,.,.,.,.,1,2,1,0
1,1.6,.,.,.,.,.,1,2,1,0
1,1.8,.,.,.,.,.,1,2,1,0
1,2,.,.,.,.,.,1,2,1,0
1,2.2,.,.,.,.,.,1,2,1,0
1,2.4,.,.,.,.,.,1,2,1,0
1,2.6,.,.,.,.,.,1,2,1,0
1,2.8,.,.,.,.,.,1,2,1,0
1,3,.,.,.,.,.,1,2,1,0
1,4,.,.,.,.,.,1,2,1,0
1,5,.,.,.,.,.,1,2,1,0
1,6,.,.,.,.,.,1,2,1,0
1,7,.,.,.,.,.,1,2,1,0
1,8,.,.,.,.,.,1,2,1,0
1,9,.,.,.,.,.,1,2,1,0
1,10,.,.,.,.,.,1,2,1,0
1,11,.,.,.,.,.,1,2,1,0
1,12,.,.,.,.,.,1,2,1,0
1,13,.,.,.,.,.,1,2,1,0
1,14,.,.,.,.,.,1,2,1,0
1,15,.,.,.,.,.,1,2,1,0
1,16,.,.,.,.,.,1,2,1,0
1,17,.,.,.,.,.,1,2,1,0
1,18,.,.,.,.,.,1,2,1,0
1,19,.,,,,,1,2,1,0
1,20,.,.,.,.,.,1,2,1,0
1,21,.,.,.,.,.,1,2,1,0
1,22,.,.,.,.,.,1,2,1,0
1,23,.,.,.,.,.,1,2,1,0
1,24,.,.,.,.,.,1,2,1,0
1,25,.,.,.,.,.,1,2,1,0
1,26,.,.,.,.,.,1,2,1,0
1,27,.,.,.,.,.,1,2,1,0
1,28,.,.,.,.,.,1,2,1,0
1,29,.,.,.,.,.,1,2,1,0
1,30,.,.,.,.,.,1,2,1,0
1,31,.,.,.,.,.,1,2,1,0
1,32,.,.,.,.,.,1,2,1,0
1,33,.,.,.,.,.,1,2,1,0
1,34,.,.,.,.,.,1,2,1,0
1,35,.,.,.,.,.,1,2,1,0
1,36,.,.,.,.,.,1,2,1,0
1,37,.,.,.,.,.,1,2,1,0
1,38,.,.,.,.,.,1,2,1,0
1,39,.,.,.,.,.,1,2,1,0
1,40,.,.,.,.,.,1,2,1,0
1,41,.,.,.,.,.,1,2,1,0
1,42,.,.,.,.,.,1,2,1,0
1,43,.,.,.,.,.,1,2,1,0
1,44,.,.,.,.,.,1,2,1,0
1,45,.,.,.,.,.,1,2,1,0
1,46,.,.,.,.,.,1,2,1,0
1,47,.,.,.,.,.,1,2,1,0
1,48,.,.,.,.,.,1,2,1,0
--
Paul R. Hutson, Pharm.D.
Associate Professor
UW School of Pharmacy
777 Highland Avenue
Madison WI 53705-2222
Tel 608.263.2496
Fax 608.265.5421
Pager 608.265.7000, p7856

Received on Mon Jan 07 2008 - 02:43:55 EST