Non-zero peripheral drug amount
From: Paul Hutson <prhutson@pharmacy.wisc.edu>
Subject: Non-zero peripheral drug amount
Date: Tue, 02 Oct 2001 16:10:04 -0500
I am trying to determine if calculated tissue concentrations of topotecan affect had an impact upon response or toxicity.
I have set up a control stream (below) with $DES that is used to generate values for the peripheral compartment (A(2)). The run converges at reasonable parameters, but the table with output of A(2) has a non-zero amount of drug in the peripheral compartment at the beginning of the dose. The sampling is repeated 6 weeks later, and in this case the starting amount in A(2) is zero. I've added the first patient's data set. Does anyone see why A(2) at time =0 for the first infusion should be a non-zero number? I have tried using EVID = 3
$PROBLEM TOPOTECAN 20
; NONRENAL CL, V1, V2 f(DWGT)
$INPUT ID DATE=DROP TIME DV AMT RATE ADDL II WGT HT AGE SCR GEN EVID
$DATA TOPOXRT1.TXT IGNORE=C
$SUBROUTINE ADVAN6 TOL=3
$MODEL NCOMP=2 COMP=(CENTRAL,DEFDOS,DEFOBS) COMP=(PERIPH)
$PK
BSA=(HT*WGT/3600)**0.5; CALCULATES BSA
THT=(HT-152.4)/2.54; CALCS HT ABOVE 5FT (IN CM)
IBW=45 - 5*(GEN-1)+(2.3*THT); CALCS "IDEAL BODY WT" BY GENder (M=0; F=1)
DWGT=IBW
IF(IBW.GT.WGT) DWGT=WGT;
;USES ACTUAL WGT IF < IDEAL WGT
;CALCS CREATININE CLEARANCE
TAGE=140-AGE
CLCR=(TAGE*WGT*0.85**GEN)/(72*SCR); ESTIMATED CLCR BASED UPON ACTUAL WEIGHT
CCLCR=(TAGE*IBW*0.85**GEN)/(72*SCR); USING IBW RATHER THAN ACTUAL WT
;IF(LVL=1)
TVCLR=THETA(1)
CLR=TVCLR*EXP(ETA(1))*CLCR/100; RENAL, 100 TAKEN AS USUAL CLCR
TVCLNR=THETA(2)*DWGT
CLNR=TVCLNR*EXP(ETA(2)); NONRENAL
CL=CLR+CLNR
TVV1=THETA(3)*DWGT
V1=TVV1*EXP(ETA(3));
TVQ=THETA(4)
Q=TVQ*EXP(ETA(4));
TVV2=THETA(5)*DWGT
V2=TVV2*EXP(ETA(5))
K10=CL/V1
K12=Q/V1
K21=Q/V2
S1=V1
IF (ABS(ETA(1)).GT.10) EXIT 1 100
IF (ABS(ETA(2)).GT.10) EXIT 1 200
IF (ABS(ETA(3)).GT.10) EXIT 1 300
IF (ABS(ETA(4)).GT.10) EXIT 1 400
IF (ABS(ETA(5)).GT.10) EXIT 1 500
$ERROR
FX=0
IF (F.EQ.0) FX=1
W=F+FX
IPRED=F
IRES=DV-IPRED
IWRES=IRES/W
Y=IPRED+W*EPS(1)
$THETA (0.01,1,1000); CLRENAL
$THETA (0.0001,0.1,1000); CLNONRENAL
$THETA (0.001,1.5,1000); V1
$THETA (0.001,1.5,1000); Q
$THETA (0.001,50,1000); V2
$OMEGA 1 1 1 1 1
$SIGMA .25
$DES
DADT(1)=-(K10+K12)*A(1)+K21*A(2)
DADT(2)=K12*A(1)-K21*A(2)
X1=A(1); AMT IN CENTRAL COMPARTMENT
X2=A(2); AMT IN PERIPHERAL COMPT
$EST MAXEVAL=4000 POSTHOC NSIG=3 PRINT=10 METHOD=0 NOABORT
$COV
$TABLE ID TIME IPRED IWRES NOPRINT ONEHEADER FILE=sdtab20.txt
$TABLE ID CL V1 Q V2 X2 ETA1 ETA2 ETA3 ETA4
ETA5 NOPRINT ONEHEADER FILE=patab20.txt
$TABLE ID WGT HT BSA AGE CLCR CCLCR GEN NOPRINT ONEHEADER FILE=cotab20.txt
$TABLE ID TIME PRED X2 NOPRINT ONEHEADER FILE=AUCDATA20.TXT
Data file (abbreviated) TOPOXRT1.TXT
C ID,DATE,TIME,DV,AMT,RATE,ADDL,II,WT,HT,AGE,SCR,GEN,EVID
1,03/13/95,09:30,.,350,656.25,4,24,59.9,177.8,55,0.6,0,4
1,03/13/95,10:03,2.3,.,.,.,.,59.9,177.8,55,0.6,0,0
1,03/13/95,10:35,1.3,.,.,.,.,59.9,177.8,55,0.6,0,0
1,03/13/95,11:35,1.0,.,.,.,.,59.9,177.8,55,0.6,0,0
1,03/13/95,12:03,0.8,.,.,.,.,59.9,177.8,55,0.6,0,0
1,03/13/95,13:03,0.6,.,.,.,.,59.9,177.8,55,0.6,0,0
1,03/13/95,14:00,0.5,.,.,.,.,59.9,177.8,55,0.6,0,0
1,03/13/95,15:02,0.3,.,.,.,.,59.9,177.8,55,0.6,0,0
1,04/17/95,09:10,.,350,700,4,24,59.9,177.8,55,0.6,0,1
1,04/17/95,09:45,14.6,.,.,.,.,59.9,177.8,55,0.6,0,0
1,04/17/95,09:50,4.8,.,.,.,.,59.9,177.8,55,0.6,0,0
1,04/17/95,10:18,2.8,.,.,.,.,59.9,177.8,55,0.6,0,0
1,04/17/95,11:12,2.1,.,.,.,.,59.9,177.8,55,0.6,0,0
1,04/17/95,11:42,1.6,.,.,.,.,59.9,177.8,55,0.6,0,0
1,04/17/95,12:45,1.2,.,.,.,.,59.9,177.8,55,0.6,0,0
1,04/17/95,13:37,0.8,.,.,.,.,59.9,177.8,55,0.6,0,0
1,04/17/95,14:40,0.6,.,.,.,.,59.9,177.8,55,0.6,0,0
TABLE NO. 4 AUCTOPO20.TXT
ID TIME X2 DV PRED RES WRES
1.0000E+00 0.0000E+00 6.2590E+01 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00
1.0000E+00 5.5000E-01 9.0577E+01 2.3000E+00 8.3474E+00 -6.0474E+00 1.0209E+00
1.0000E+00 1.0800E+00 1.1248E+02 1.3000E+00 1.4657E+00 -1.6573E-01 8.7022E-01
1.0000E+00 2.0800E+00 7.7681E+01 1.0000E+00 6.5279E-01 3.4721E-01 7.4096E-01
1.0000E+00 2.5500E+00 6.4157E+01 8.0000E-01 5.9276E-01 2.0724E-01 8.5609E-01
1.0000E+00 3.5500E+00 4.2671E+01 6.0000E-01 4.9269E-01 1.0731E-01 6.8998E-01
1.0000E+00 4.5000E+00 2.8964E+01 5.0000E-01 4.1392E-01 8.6084E-02 3.5720E-01
1.0000E+00 5.5300E+00 1.9028E+01 3.0000E-01 3.4268E-01 -4.2681E-02 4.2396E-01
1.0000E+00 8.3967E+02 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00 0.0000E+00
Paul Hutson, Pharm.D.
Associate Professor (CHS)
UW School of Pharmacy
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