Dear All
I'm trying to evaluate a transit model approach in an attempt to better
describe early drug concentrations following intravenous injection (1 minute
and 10 minute infusions) of a sedative-hypnotic drug. However, every
minimisation attempt is terminated due to rounding errors (E=134). I've tried
the usual strategies to overcome this e.g using final estimates of a terminated
run as initial estimates for the next, changing number of sig dig requested,
changing from a diagonal omega to a block omega, but nothing has been
successful.
I'd be very grateful for any suggestions of what I might try next :) Standard
3-comp and 4-comp mamillary models minise successful with these data, but so
far no luck with any of the transit models, I have tried model with 1 to 6
transit compartments. An example control stream is shown below. I'm using
NONMEM 7 with Intel Fortran.
With thanks and all best wishes
Ann
$PROBLEM 3comp 2 transit
$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
S1=V1
IF (DUR.EQ.10) THEN
ALAG4=THETA(7)*EXP(ETA(7))
ELSE
ALAG4=THETA(8)*EXP(ETA(8))
ENDIF
KTR=THETA(9)*EXP(ETA(9))
$DES
;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
DADT(1)=A(5)*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, 725) ;CL
$THETA (0, 238) ;Q2
$THETA (0, 2920) ;Q3
$THETA (0, 311) ;V1
$THETA (0, 38700) ;V2
$THETA (0, 39500) ;V3
$THETA (0.2167, 0.522,1) ;ALAG 10MIN
$THETA (0.00833, 0.122, 1) ;ALAG 1MIN
$THETA (0, 0.720) ;KTR
$OMEGA BLOCK(6)
0.0959 ; ETA CL
0.00804 0.0211 ; ETA Q2
0.00631 0.00143 0.166 ; ETA Q3
-0.00506 0.00121 -0.0635 0.0491 ; ETA V1
0.00293 -0.00746 0.00708 -0.00315 0.0328 ; ETA V2
0.00836 0.00688 0.00144 -0.00497 0.00741 0.153 ; ETA V3
$OMEGA 0.217 ; ETA ALAG 10
$OMEGA 0.4 ; ETA ALAG 1
$OMEGA 0.0171 ; ETA KTR
;$OMEGA (0.0686) ; ETA CL
;$OMEGA (0.01) ; ETA Q2
;$OMEGA (0.0251) ; ETA Q3
;$OMEGA (0 FIX) ; ETA V1
;$OMEGA (0.0328) ; ETA V2
;$OMEGA (0 FIX) ; ETA V3
;$OMEGA (0.170) ; ETA ALAG10
;$OMEGA (1.37) ; ETA ALAG1
;$OMEGA (0.00409) ; ETA KTR
$SIGMA (0.0944)
$ESTIMATION METHOD=1 PRINT=1 MAX=9999 NOABORT SIG=3 ;POSTHOC INTER
MSFO=msfo.outputfile
;$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
_______________________________________________________________________
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
Tel: +44 (0) 1752 432014
_______________________________________________________________________
