AUC Calculation in Simulation with and without EST
Dear Paul and NM users,
having recently benefitted from your kind input it is time that I also
provide some of the little sense I still have:
When Paul calculates the AUC with just one simulation without estimation,
he calculates the AUC with one possible set of parameters (here just CL).
That estimate could indeed be vastly different from the population mean
which is used to calculate PRED in the TABLE: AUC based on simulated CL
and AUC based on PRED disagree.
When he runs an estimation after the simulation, clearance will be
estimated based also on the initial population values given in the $THETA
records ansd based on the simulated data, and PRED will be different from
the PRED listed in the TABLE when there was no estimation: AUC based on
indiv parameters and AUC based on PRED agree.
You all think about that. I could be wrong as it is Monday morning, quite
early.
Joachim
__________________________________________
Joachim GREVEL, Ph.D.
MERCK SERONO International S.A.
Exploratory Medicine
1202 Geneva
Tel: +41.22.414.4751
Fax: +41.22.414.3059
Email: [EMAIL PROTECTED]
Paul wrote:
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
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