From: Paul Hutson <prhutson@pharmacy.wisc.edu>
Subject: Averaged peripheral concentration
Date: Fri, 24 Aug 2001 13:20:51 -0500
I am analyzing the PK of topotecan in the context of concurrent radiation
treatment wherein the effect of the XRT is irreversible and possibly
concentration dependent. I am trying to compare the effect (tox and
efficacy) of the XRT as a function of the concentration of the drug in
either of the central and peripheral compartments. Although AUC is
downplayed in the thread 99feb042000.html on the NONMEM repository, the
average amount (AUC*V2/(TIMExrt-stop - TIMExrt-start)) of topotecan in the
peripheral compartment during radiation is a rational variable to evaluate
(says me). As the control stream below indicates, I am using $DES In
addition to fitting general poppk for an antineoplastic drug. The
generation and tabulation of amount A(2) in the peripheral
compartment with subsequent trapezoidal summation in a spreadsheet is
doable, but not very elegant. If included in a NONMEM control stream, does
this require the use of a (3 x N) array for Time, PeripheralAmt, and
cumulative AUC? Suggestions are welcome; haven't had to use arrays much
before. Thanks.
Paul
$PROBLEM TOPOTECAN FINAL 2 CHECKOUT
$INPUT ID DATE=DROP TIME DV AMT RATE ADDL II WGT HT AGE SCR UVOL CMT
WEEK PT ETHY LEVL GEN EVID
$DATA TOPOXRT.TXT IGNORE=C
$SUBROUTINE ADVAN6 TRANS1 TOL=5
$MODEL NPAR=5 NCOMP=3 COMP=(CENTRAL,DEFDOS,DEFOBS) COMP=(PERIPH) COMP=(OUT)
; COMP 3 REFLECTS URINE COLLECTION
$PK
;CALCULATES BSA
BSA=(HT*WGT/3600)**0.5
;CALCS HT ABOVE 5FT (IN CM)
THT=(HT-152.4)/2.54
;CALCS IDEAL BODY WEIGHT BY GENder
;Males = 0; Female = 1
IBW=45 - 5*(GEN-1)+(2.3*THT)
DWGT=IBW
;USES ACTUAL WGT IF < IDEAL WGT
IF(IBW.GT.WGT) DWGT=WGT
;CALCS CREATININE CLEARANCE
TAGE=140-AGE
CLCR=(TAGE*IBW*0.85**GEN)/(72*SCR)
KREN=THETA(1)*CLCR/100; K10-RENAL, 100 TAKEN AS USUAL CLCR
KNREN=THETA(2); K10-NONRENAL
K12=THETA(3); K12
K21=THETA(4); K21
K10=KREN+KNREN
TVV1=THETA(5);*BSA
V1=TVV1*EXP(ETA(1))
CLREN=KREN*V1*EXP(ETA(2))
CLNREN=KNREN*V1*EXP(ETA(3))
CL=CLREN+CLNREN
TVQ=K12*V1;*BSA
Q=TVQ*EXP(ETA(4))
TVV2=(K12/K21)/V1;*BSA
V2=TVV2*EXP(ETA(5))
S1=V1
TEOI=TIME-RATE/AMT; REPORTS TIME SINCE END OF INFUSION
IF (TEOI.LT.0) TEOI=0
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
$DES
DADT(1)=-(K10+K12)*A(1)+K21*A(2)
DADT(2)=K12*A(1)-K21*A(2)
A1=A(1); AMT IN CENTRAL COMPARTMENT
A2=A(2); AMT IN PERIPHERAL COMPT
$ERROR
FX=0
IF (F.EQ.0) FX=1
W=F+FX
IPRED=F
IRES=DV-IPRED
IWRES=IRES/W
IF (CMT.EQ.1) Y=IPRED+W*ERR(1); CENTRAL (SAMPLED) CMPT
IF (CMT.EQ.2) Y=IPRED+W*ERR(2); PERIPHERAL CMPT
IF (CMT.EQ.3) Y=IPRED+W*ERR(3); URINE
$THETA (0.01,1,1000); KREN
$THETA (0.01,1,1000); KNONREN
$THETA (0.01,1.5,1000); K12
$THETA (0.01,1.5,1000); K21
$THETA (0.1,50,1000); V1
$OMEGA 1 1 1 1 1
$SIGMA .25 .25 .25
;$EST MAXEVAL=4000 NSIG=3 PRINT=10 METHOD=0 NOABORT
;$EST MAXEVAL=4000 NSIG=3 PRINT=10 METHOD=1 NOABORT
;$COV
$TABLE ID TIME IPRED IWRES NOPRINT ONEHEADER FILE=sdtab2
$TABLE ID CL V1 Q V2 TEOI A2 ETA1 ETA2 ETA3 ETA4 ETA5 NOPRINT ONEHEADER
FILE=patab2
Paul Hutson, Pharm.D.
Associate Professor (CHS)
UW School of Pharmacy
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