Marcus,
In the case of first-order elimination of 5FU you can make an assumption
of a constant fraction of total 5FU clearance describing the formation
of its metabolite. But a constant fraction is not compatible with a
mixed order process for formation of a metabolite. As the 5FU conc rises
the fraction will decrease because the mixed order clearance to
metabolite will decrease while the 5FU clearance by a first-order other
process (not to the metabolite) will remain unchanged.
You have to consider estimating another parameter (CLOTHER) describing
the other clearance (not to the metabolite) or fixing CLOTHER to zero
which assumes all of the parent is converted to metabolite. See NM-TRAN
code below.
I prefer to refer to the model predictions by meaningful names rather
than use NONMEM's default and essentially meaningless name F. In the
code below different names are used for parent and metabolite concs in
the $DES and $ERROR blocks because NONMEM does not allow a variable to
be created in $DES with the same name as one being created in $ERROR. I
like to prefix the $ERROR name with 'D' when I refer to the same
quantity in $DES.
Best wishes,
Nick
$PK
VP = THETA(1) ; volume of parent
CLOTHER =THETA(2) ; clearance of parent by first-order other process
VMAX =THETA(3) ; Vmax of parent to metabolite mixed order process
KM =THETA(4) ; Km of parent to metabolite mixed order process
VM = THETA(5) ; volume of metabolite
CLM =THETA(6) ; clearance of metabolite
$DES
DCP =A(1)/VP ; parent i.e. 5FU
DCM =A(2)/VM ; metabolite i.e. 5FU-H2
CLP2M =VMAX/(KM+DCP) ; clearance from parent to metabolite
DADT(1) = - (CLP2M + CLOTHER) *DCP
DADT(2) = CLP2M*DCP - CLM*DCM
$ERROR
CP =A(1)/VP ; This is the same as DCP in the $DES block
CM =A(2)/VM ; This is the same as DCM in the $DES block
IF (CMT.EQ.1) THEN
Y=LOG(CP) + EPS(1)
ENDIF
IF (CMT.EQ.2) THEN
Y=LOG(CM) + EPS(2)
ENDIF
On 18/05/2012 11:23 p.m., markus joerger wrote:
dear Community,
I am modeling 5FU --> 5FU-H2, that is potentially saturable. The
linear model runs smoothly, with a fixed proportion of 85% of the
parent going to the metabolite. I wonder how the coding should be if I
introduce saturable metabolism from 5FU to 5FU-H2. This model does not
minimize. Should the coding for saturable metabolism (again with a 85%
proportion going from 5FU to 5FU-H2) look like: ?
V1=THETA(1)*EXP(ETA(1))
VM=THETA(2)*EXP(ETA(2))
KM=THETA(3)*EXP(ETA(3))
CL2=THETA(4)*EXP(ETA(4))
V2=THETA(5)*EXP(ETA(5))
S1=V1/1000
S2=V2/1000
FM=0.85
K20=CL2/V2
$DES
C1=A(1)/S1
C2=A(2)/S2
DADT(1)=-C1*VM/(KM+C1)
DADT(2)=C1*FM*VM/(KM+C1)-K20*A(2)
LINEAR MODEL:
------------------------------------------------------------------------------------------------------------------------------------
$INPUT C=DROP ID OCC TIME AMT RATE DV CMT MDV EVID AGE SEX HEP OXA
IRI BEV WT BSA ECOG A496G DPD4 DPD5 CCL
$DATA 08088_6.CSV IGNORE=C
$SUBROUTINES ADVAN5
$MODEL COMP=(CENTRAL, DEFDOSE)
COMP=(5FUH2)
$ABBREVIATED DERIV2=NOCOMMON
$PK
FLAG1=0
FLAG2=0
IF(OCC.EQ.1) FLAG1=1
IF(OCC.EQ.2) FLAG2=2
TVCL1=THETA(1)*THETA(5)**SEX
CL1=TVCL1*EXP(ETA(1)+FLAG1*ETA(2)+FLAG2*ETA(3))
V1=THETA(2)*EXP(ETA(4))
TVCL2=THETA(3)*THETA(6)**SEX
CL2=TVCL2*EXP(ETA(5))
V2=THETA(4)*EXP(ETA(6))
S1=V1/1000
S2=V2/1000
FM=0.85
K10=(1-FM)*CL1/V1
K12=FM*CL1/V1
K20=CL2/V2
$ERROR CALLFL=0
IPRE=-3
IF(F.GT.0) IPRE=LOG(F)
PROP=0
IF(CMT.EQ.1)PROP=EPS(1)
IF(CMT.EQ.2)PROP=EPS(2)
Y=LOG(F)+PROP
W=LOG(F)
IRES=DV-IPRE
IWRES=IRES/W
$THETA
(0, 152) ;CL1
(0, 43.3) ;V1
(0, 144) ;CL2
(0, 122) ;V2
(0,1) ;SEX > CL-5FU
(0,1) ;SEX > CL-5FU-H2
$OMEGA
0.04 ;IIV CL1
$OMEGA BLOCK(1)
0.004 ;IOV OCC1; CL-5FU
$OMEGA BLOCK(1) SAME ;IOV OCC2; CL-5FU
$OMEGA
0.04 ;IIV V1
0.04 ;IIV CL2
0.04 ;IIV V2
$SIGMA
0.329 ;EPS COMP1
0.136 ;EPS COMP2
--
Markus Joerger MD PhD
Associate Professor
Medical Oncology&Clinical Pharmacology
Cantonal Hospital
9007 St. Gallen
Switzerland
[email protected] <mailto:[email protected]>
[email protected] <mailto:[email protected]>
Phone: +41-765591070
Fax: +41-714946325
--
Nick Holford, Professor Clinical Pharmacology
First World Conference on Pharmacometrics, 5-7 September 2012
Seoul, Korea http://www.go-wcop.org
Dept Pharmacology& Clinical Pharmacology, Bldg 505 Room 202D
University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand
tel:+64(9)923-6730 fax:+64(9)373-7090 mobile:+64(21)46 23 53
email: [email protected]
http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford
