Dear Ann,
Change to ALAG4. Note that you could use ADVAN 5 or 7 for this model if you
specify all rate constants. These should be faster.
Best regards,
Mats
Mats Karlsson, PhD
Professor of Pharmacometrics
Dept of Pharmaceutical Biosciences
Uppsala University
Sweden
Postal address: Box 591, 751 24 Uppsala, Sweden
Phone +46 18 4714105
Fax + 46 18 4714003
From: owner-nmus...@globomaxnm.com [mailto:owner-nmus...@globomaxnm.com] On
Behalf Of Ann Rigby-Jones
Sent: Friday, August 06, 2010 11:46 AM
To: 'nmusers@globomaxnm.com'
Subject: [NMusers] ALAG with transit model
Dear NMUsers
I'm trying to evaluate a transit model in an attempt to better describe
early drug concentrations following intravenous injection (1 minute and 10
minute infusions) of a sedative-hypnotic drug. Additionally, I have
incorporated lag times to described the short delay between the infusion
pump being turned on and the drug emerging from the cannula. This time
delay differed between the 1min and 10 min infusion groups due to
differences in the pump flow rate.
When I model using a classic 3 or 4-compartment mamillary model, ALAG is
estimated and models minimise successfully. However, when I try to
incorporate transit compartments, ALAG is not estimated (THETAs remain as
the initial estimate). There must be something wrong with my control stream
but I'm struggling to spot the problem, grateful for any thoughts! I'm
using NONMEM7 and PLT Tools.
With thanks and all best wishes
Ann
$PROBLEM 3comp 3 transit advan9
$INPUT ID DOSE AMT RATE DUR TIME ORI DV EVID ART AGE WGT
$DATA PKcen12LN.csv IGNORE=#
$SUBROUTINES ADVAN9 TOL=3
$MODEL
;NCOMPS=9
COMP(CENTRAL, DEFOBS) ;1
COMP(PERIPH1) ;2
COMP(PERIPH2) ;3
COMP(TRANS1, DEFDOSE) ;4
COMP(TRANS2) ;5
COMP(TRANS3) ;6
;COMP(TRANS4) ;7
;COMP(TRANS5) ;8
;COMP(TRANS6) ;9
$PK
CL=THETA(1)*EXP(ETA(1))
Q2=THETA(2)*EXP(ETA(2))
Q3=THETA(3)*EXP(ETA(3))
V1=THETA(4)*EXP(ETA(4))
V2=THETA(5)*EXP(ETA(5))
V3=THETA(6)*EXP(ETA(6))
K10=CL/V1
K12=Q2/V1
K13=Q3/V1
K21=Q2/V2
K31=Q3/V3
IF (DUR.EQ.10) THEN
ALAG1=THETA(7)*EXP(ETA(7))
ELSE
ALAG1=THETA(8)*EXP(ETA(7))
ENDIF
KTR=THETA(9)*EXP(ETA(8))
S1=V1
$DES
;standard 3-comp model
;DADT(1)=A(2)*K21 + A(3)*K31 - A(1)*(K10+K12+K13)
;DADT(2)=A(1)*K12 - A(2)*K21
;DADT(3)=A(1)*K13 - A(3)*K31
;3 comp transit model
DADT(1)=A(6)*KTR + A(2)*K21 + A(3)*K31 - A(1)*(K10+K12+K13)
DADT(2)=A(1)*K12 - A(2)*K21
DADT(3)=A(1)*K13 - A(3)*K31
DADT(4)=-A(4)*KTR
DADT(5)=A(4)*KTR - A(5)*KTR
DADT(6)=A(5)*KTR - A(6)*KTR
;DADT(7)=A(6)*KTR - A(7)*KTR
;DADT(8)=A(7)*KTR - A(8)*KTR
;DADT(9)=A(8)*KTR - A(9)*KTR
$ERROR
W=1
IPRED= -2
IF (F.GT.0) IPRED=LOG(F)
Y=IPRED + ERR(1)
IRES=DV-IPRED
IWRES=IRES/W
$THETA (0, 563);CL
$THETA (0, 336);Q2
$THETA (0, 2640) ;Q3
$THETA (0, 2630) ;V1
$THETA (0, 41200) ;V2
$THETA (0, 27600) ;V3
$THETA (0.2167, 0.549,1) ;ALAG 10MIN
$THETA (0.00833, 0.101, 1) ;ALAG 1MIN
$THETA (0, 0.282) ;KTR
$OMEGA (0.0456) ; ETA CL
$OMEGA (1.37); ETA Q2
$OMEGA (0.133) ; ETA Q3
$OMEGA (0 FIX) ; ETA V1
$OMEGA (0.405) ; ETA V2
$OMEGA (0 FIX) ; ETA V3
$OMEGA (0. 2); ETA LAG SHARED
$OMEGA (0.33); ETA KTR
$SIGMA (0.570)
$ESTIMATION METHOD=1 PRINT=1 MAX= NOABORT SIG=3 ;POSTHOC INTER
MSFO=msfo.outputfile
$COVA
$TABLE ID EVID AMT TIME IPRED IRES
NOPRINT FILE=AllRecords.txt
$TABLE ID
CL Q2 Q3 V1 V2 V3
ETA1 ETA2 ETA3 ETA4 ETA5 ETA6 ETA7 ;ETA8
FIRSTONLY NOPRINT NOAPPEND FILE=FirstRecords.txt
__
Ann Rigby-Jones PhD MRSC
Research Fellow in Pharmacokinetics & Pharmacodynamics
Peninsula College of Medicine & Dentistry
N31, ITTC Phase 1
Tamar Science Park
1 Davy Road
Derriford
Plymouth
PL6 8BX
___
