[NMusers] AUC Calculation in Simulation with and without EST

From: Paul Hutson <prhutson_at_pharmacy.wisc.edu>
Date: Sun, 06 Jan 2008 23:59:33 -0600

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
Received on Mon Jan 07 2008 - 00:59:33 EST