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

Dear Paul,

 

When using $SIM only, the AUC will be estimated based on the simulated
parameter values including the ETA's. With PRED or if you do $SIM+$EST
(without POSTHOC), the AUC will be based on parameters with ETA set to zero.

 

Best regards,

Mats

 


Mats Karlsson, PhD
Professor of Pharmacometrics
Div. of Pharmacokinetics and Drug Therapy
Dept. of Pharmaceutical Biosciences
Faculty of Pharmacy
Uppsala University
Box 591
SE-751 24 Uppsala
Sweden
phone +46 18 471 4105
fax +46 18 471 4003
mats.karlsson_at_farmbio.uu.se

  _____


From: owner-nmusers_at_globomaxnm.com [mailto:owner-nmusers_at_globomaxnm.com] On
Behalf Of Paul Hutson
Sent: Monday, January 07, 2008 07:00
To: NMUSERS_at_GLOBOMAXNM.COM
Subject: [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 - 02:01:40 EST