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=9999 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
_______________________________________________________________________