Dear all,
I'm now developing a simple PBPK structural model in NONMEM. The input to the
PBPK model was a i.m. injection, and the only output was the renal excretion.
Because the drug was a long acting formulation, so I try to model the
absorption into a fast phase and a slow phase. Now, here comes the problem. I
don't know how to get DOSE into the model. Here is the control stream file:
$PROB WBPBPK POPULATION MODEL$INPUT ID TIME CONC=DV AMT WT EVID CMT$DATA
...\PBPK.TXT IGNORE=#$SUBROUTINES ADVAN6 TOL=3$MODELCOMP = (LIV) ; 1 - LIVER
COMPARTMENTCOMP = (KID) ; 2 - KIDNEY COMPARTMENTCOMP = (MUS) ; 3 - MUSCLE
COMPARTMENTCOMP = (INJ) ; 4 - INJECTIONSITE COMPARTMENT RECEIVING DOSECOMP =
(VEN) ; 5 - VENOUS COMPARTMENTCOMP = (OUT) ; 6 - KIDNEY EXCRETION
COMPARTMENT$PK; ------------------------ TWO ABSORBTION
PHASE-------------------- ;PHSF = 0.714 ; FAST PHASE ABSORPTION FRACTIONPHSS =
0.286 ; SLOW PHASE ABSORPTION FRACTIONKF = 0.032334 ; FAST PHASE ABSORPTION
ABSORPTION RATEKS = 0.00835 ; SLOW PHASE ABSORPTION ABSORPTION RATE;
------------------------- BLOOD FLOWS (Q,L/HR) -------------------- ;QVEN =
2.049*WT ;L/H/KG;QLIV =QVEN*0.3053*(WT/25) ;L/H/KG;QKID =QVEN*0.1398*(WT/25)
;L/H/KG;QMUS =QVEN*0.2524*(WT/25) ;L/H/KG;QINJ = QVEN*0.2524*(0.5/WT/25)
;L/H/KG;;----------------------------TISSUE VOLUMES
(V,L)----------------------;VLIV
=0.0294*WT ;KG;VKID =0.004*WT ;KG;VMUS =0.4007*WT ;KG;VINJ =0.5 ;KG;VVEN
=0.06*WT ;KG;;----------------------------PARTITION
COEFFICIENTS-------------------;PLIV = EXP(THETA(2))PKID = EXP(THETA(3))PMUS =
EXP(THETA(4));---------------------KIDNEY
EXCRETION-------------------;TVEXCR=EXP(THETA(1))EXCR=TVEXCR*EXP(ETA(1))$DES;--------------------COMPARTMENT
CONCENTRATIONS-------------------;C1 = A(1)/VLIVC2 = A(2)/VKIDC3 = A(3)/VMUSC4
= A(4)/VINJC5 =
A(5)/VVENDADT(1)=QLIV*(C5-C1/PLIV)DADT(2)=(QKID*(C5-C2/PKID)-C2*EXCR)DADT(3)=QMUS*(C5-C3/PMUS)DADT(4)=(QINJ*(C5-C4/PMUS))DADT(5)=(QLIV*C1/PLIV+QKID*C2/PKID+QMUS*C3/PMUS+QINJ*C4/PMUS-QVEN*C5)DADT(6)=EXCR$ERRORY=A(3)/VMUS+EPS(1);------------------------------INITIAL
ESTIMATES--------------------------------;$THETA(0,0.5) ;
1-EXCR$THETA(0,1.82,10) ; 2-PLIV$THETA(0,6.46,10) ;
3-PKID$THETA(0,0.486) ; 4-PMUS$OMEGA(0.5) ; 1-EXCR$SIGMA(1) ;
1-ERROR$EST PRINT=5
MAX=9990 POSTHOC SIGDIG=3 METHOD=1$COV MATRIX=R$TABLE ID TIME CONC WT AMT
NOPRINT ONEHEADER FILE=PBPK.FIT
Can anyone give some hint?Thanks in advance!
Ke, Fang
PBPK structural model in NONMEM!
In NONMEM help, you can find information about CMT and I think NONMEM is
using the same logic as SADAPT and PDX-MC-PEM.
CMT specifies the number of the compartment into which the dose is
introduced. Then based on that, when you construct your data set, if
the dose is given in the fourth compartment, you just put cmt=4 at the
time the dosing event occurs and evid must be set to 1 (may be not
necessary with NONMEM but a must in the other programs). If you have
only one single bolus dose, I guess you could use also the initial
condition option available since NONMEM6 (in $PK for example, a dose of
1000 in compartment 4 could be defined by writing A_0(4)= 1000 ) but it
is easier to just input the dose in the data set as it would work for
both single, multiple doses and also dosing through infusion (The you
use both the DOSE and the RATE DATA ITEMS).
Using the data set
ID TIME DOSE RATE EVID CMT
1 0 1000 0 1 4
Would put a dose of 1000 units in the fourth compartment (fourth
differential equation).
Best Regards;
Serge Guzy; Ph.D
President, CEO, POP_PHARM
Quoted reply history
From: [email protected] [mailto:[email protected]]
On Behalf Of ke fang
Sent: Saturday, December 12, 2009 10:28 PM
To: nonmem usersgroup
Subject: [NMusers] PBPK structural model in NONMEM!
Dear all,
I'm now developing a simple PBPK structural model in NONMEM. The input
to the PBPK model was a i.m. injection, and the only output was the
renal excretion.. Because the drug was a long acting formulation, so I
try to model the absorption into a fast phase and a slow phase. Now,
here comes the problem. I don't know how to get DOSE into the model.
Here is the control stream file:
$PROB WBPBPK POPULATION MODEL
$INPUT ID TIME CONC=DV AMT WT EVID CMT
$DATA ..\PBPK.TXT IGNORE=#
$SUBROUTINES ADVAN6 TOL=3
$MODEL
COMP = (LIV) ; 1 - LIVER COMPARTMENT
COMP = (KID) ; 2 - KIDNEY COMPARTMENT
COMP = (MUS) ; 3 - MUSCLE COMPARTMENT
COMP = (INJ) ; 4 - INJECTIONSITE COMPARTMENT RECEIVING DOSE
COMP = (VEN) ; 5 - VENOUS COMPARTMENT
COMP = (OUT) ; 6 - KIDNEY EXCRETION COMPARTMENT
$PK
; ------------------------ TWO ABSORBTION PHASE-------------------- ;
PHSF = 0.714 ; FAST PHASE ABSORPTION FRACTION
PHSS = 0.286 ; SLOW PHASE ABSORPTION FRACTION
KF = 0.032334 ; FAST PHASE ABSORPTION ABSORPTION RATE
KS = 0.00835 ; SLOW PHASE ABSORPTION ABSORPTION RATE
; ------------------------- BLOOD FLOWS (Q,L/HR) -------------------- ;
QVEN = 2.049*WT ;L/H/KG;
QLIV =QVEN*0.3053*(WT/25) ;L/H/KG;
QKID =QVEN*0.1398*(WT/25) ;L/H/KG;
QMUS =QVEN*0.2524*(WT/25) ;L/H/KG;
QINJ = QVEN*0.2524*(0.5/WT/25) ;L/H/KG;
;----------------------------TISSUE VOLUMES (V,L)----------------------;
VLIV =0.0294*WT ;KG;
VKID =0.004*WT ;KG;
VMUS =0.4007*WT ;KG;
VINJ =0.5 ;KG;
VVEN =0.06*WT ;KG;
;----------------------------PARTITION COEFFICIENTS-------------------;
PLIV = EXP(THETA(2))
PKID = EXP(THETA(3))
PMUS = EXP(THETA(4))
;---------------------KIDNEY EXCRETION-------------------;
TVEXCR=EXP(THETA(1))
EXCR=TVEXCR*EXP(ETA(1))
$DES
;--------------------COMPARTMENT CONCENTRATIONS-------------------;
C1 = A(1)/VLIV
C2 = A(2)/VKID
C3 = A(3)/VMUS
C4 = A(4)/VINJ
C5 = A(5)/VVEN
DADT(1)=QLIV*(C5-C1/PLIV)
DADT(2)=(QKID*(C5-C2/PKID)-C2*EXCR)
DADT(3)=QMUS*(C5-C3/PMUS)
DADT(4)=(QINJ*(C5-C4/PMUS))
DADT(5)=(QLIV*C1/PLIV+QKID*C2/PKID+QMUS*C3/PMUS+QINJ*C4/PMUS-QVEN*C5)
DADT(6)=EXCR
$ERROR
Y=A(3)/VMUS+EPS(1)
;------------------------------INITIAL
ESTIMATES--------------------------------;
$THETA(0,0.5) ; 1-EXCR
$THETA(0,1.82,10) ; 2-PLIV
$THETA(0,6.46,10) ; 3-PKID
$THETA(0,0.486) ; 4-PMUS
$OMEGA(0.5) ; 1-EXCR
$SIGMA(1) ; 1-ERROR
$EST PRINT=5 MAX=9990 POSTHOC SIGDIG=3 METHOD=1
$COV MATRIX=R
$TABLE ID TIME CONC WT AMT NOPRINT ONEHEADER FILE=PBPK.FIT
Can anyone give some hint?
Thanks in advance!
Ke, Fang
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Dear Ka
To me one of main issues here is the identifiability of partition
coefficients because you don't have any observations to uniquely estimate
these parameters and there is not an observable relationship between renal
excretion and partition coefficients either. In such cases incorporation of
prior knowledge may be helpful, see:
Langdon G, Gueorguieva I, Aarons L and Karlsson M (2007) Linking preclinical
and clinical whole-body physiologically based pharmacokinetic models with
prior distributions in NONMEM. Eur J Clin Pharmacol 63:485-498.
( http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=C
itation&list_uids=17345074 &db=PubMed&dopt=Citation&list_uids=17345074).
I noticed you have normalised weight to 25, are you subjects children?
Please note that if this is the case then body composition and blood flow to
organs change by age and weight; however you haven't considered eta for
partition coefficients. Renal function is a big player for your drug and you
may also need considering maturation of renal function in children:
Rhodin MM, Anderson BJ, Peters AM, Coulthard MG, Wilkins B, Cole M, Chatelut
E, Grubb A, Veal GJ, Keir MJ and Holford NH (2009) Human renal function
maturation: a quantitative description using weight and postmenstrual age.
Pediatr Nephrol 24:67-76.
( http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=C
itation&list_uids=18846389 &db=PubMed&dopt=Citation&list_uids=18846389).
In addition to incorporation of physiological knowledge into your model if
you have any physicochemical or in vitro data you can still use such
information. Your case as well as Paul Hutson case (Duration of Absorption
Time From Depot (Gut) as Covariate posted on Friday) are good examples of
joining bottom-up and top-down approaches, see:
http://www.pkuk.org.uk/ContentImages/MasoudJamei.pdf.
Regards
Masoud
Quoted reply history
From: [email protected] [mailto:[email protected]] On
Behalf Of ke fang
Sent: 13 December 2009 06:28
To: nonmem usersgroup
Subject: [NMusers] PBPK structural model in NONMEM!
Dear all,
I'm now developing a simple PBPK structural model in NONMEM. The input to
the PBPK model was a i.m. injection, and the only output was the renal
excretion.. Because the drug was a long acting formulation, so I try to
model the absorption into a fast phase and a slow phase. Now, here comes the
problem. I don't know how to get DOSE into the model. Here is the control
stream file:
$PROB WBPBPK POPULATION MODEL
$INPUT ID TIME CONC=DV AMT WT EVID CMT
$DATA ..\PBPK.TXT IGNORE=#
$SUBROUTINES ADVAN6 TOL=3
$MODEL
COMP = (LIV) ; 1 - LIVER COMPARTMENT
COMP = (KID) ; 2 - KIDNEY COMPARTMENT
COMP = (MUS) ; 3 - MUSCLE COMPARTMENT
COMP = (INJ) ; 4 - INJECTIONSITE COMPARTMENT RECEIVING DOSE
COMP = (VEN) ; 5 - VENOUS COMPARTMENT
COMP = (OUT) ; 6 - KIDNEY EXCRETION COMPARTMENT
$PK
; ------------------------ TWO ABSORBTION PHASE-------------------- ;
PHSF = 0.714 ; FAST PHASE ABSORPTION FRACTION
PHSS = 0.286 ; SLOW PHASE ABSORPTION FRACTION
KF = 0.032334 ; FAST PHASE ABSORPTION ABSORPTION RATE
KS = 0.00835 ; SLOW PHASE ABSORPTION ABSORPTION RATE
; ------------------------- BLOOD FLOWS (Q,L/HR) -------------------- ;
QVEN = 2.049*WT ;L/H/KG;
QLIV =QVEN*0.3053*(WT/25) ;L/H/KG;
QKID =QVEN*0.1398*(WT/25) ;L/H/KG;
QMUS =QVEN*0.2524*(WT/25) ;L/H/KG;
QINJ = QVEN*0.2524*(0.5/WT/25) ;L/H/KG;
;----------------------------TISSUE VOLUMES (V,L)----------------------;
VLIV =0.0294*WT ;KG;
VKID =0.004*WT ;KG;
VMUS =0.4007*WT ;KG;
VINJ =0.5 ;KG;
VVEN =0.06*WT ;KG;
;----------------------------PARTITION COEFFICIENTS-------------------;
PLIV = EXP(THETA(2))
PKID = EXP(THETA(3))
PMUS = EXP(THETA(4))
;---------------------KIDNEY EXCRETION-------------------;
TVEXCR=EXP(THETA(1))
EXCR=TVEXCR*EXP(ETA(1))
$DES
;--------------------COMPARTMENT CONCENTRATIONS-------------------;
C1 = A(1)/VLIV
C2 = A(2)/VKID
C3 = A(3)/VMUS
C4 = A(4)/VINJ
C5 = A(5)/VVEN
DADT(1)=QLIV*(C5-C1/PLIV)
DADT(2)=(QKID*(C5-C2/PKID)-C2*EXCR)
DADT(3)=QMUS*(C5-C3/PMUS)
DADT(4)=(QINJ*(C5-C4/PMUS))
DADT(5)=(QLIV*C1/PLIV+QKID*C2/PKID+QMUS*C3/PMUS+QINJ*C4/PMUS-QVEN*C5)
DADT(6)=EXCR
$ERROR
Y=A(3)/VMUS+EPS(1)
;------------------------------INITIAL
ESTIMATES--------------------------------;
$THETA(0,0.5) ; 1-EXCR
$THETA(0,1.82,10) ; 2-PLIV
$THETA(0,6.46,10) ; 3-PKID
$THETA(0,0.486) ; 4-PMUS
$OMEGA(0.5) ; 1-EXCR
$SIGMA(1) ; 1-ERROR
$EST PRINT=5 MAX=9990 POSTHOC SIGDIG=3 METHOD=1
$COV MATRIX=R
$TABLE ID TIME CONC WT AMT NOPRINT ONEHEADER FILE=PBPK.FIT
Can anyone give some hint?
Thanks in advance!
Ke, Fang
Dear Ke
To me one of main issues here is the identifiability of partition
coefficients because you don’t have any observations to uniquely estimate
these parameters and there is not an observable relationship between renal
excretion and partition coefficients either. In such cases incorporation of
prior knowledge may be helpful, see:
Langdon G, Gueorguieva I, Aarons L and Karlsson M (2007) Linking preclinical
and clinical whole-body physiologically based pharmacokinetic models with
prior distributions in NONMEM. Eur J Clin Pharmacol 63:485-498. (
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17345074
).
I noticed you have normalised weight to 25, are you subjects children?
Please note that if this is the case then body composition and blood flow to
organs change by age and weight; however you haven’t considered eta for
partition coefficients. Renal function is a big player for your drug and you
may also need considering maturation of renal function in children:
Rhodin MM, Anderson BJ, Peters AM, Coulthard MG, Wilkins B, Cole M, Chatelut
E, Grubb A, Veal GJ, Keir MJ and Holford NH (2009) Human renal function
maturation: a quantitative description using weight and postmenstrual age.
Pediatr Nephrol 24:67-76. (
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18846389).
In addition to incorporation of physiological knowledge into your model if
you have any physicochemical or in vitro data you can still use such
information. Your case as well as Paul Hutson case (Duration of Absorption
Time From Depot (Gut) as Covariate posted on Friday) are good examples of
joining bottom-up and top-down approaches, see:
http://www.pkuk.org.uk/ContentImages/MasoudJamei.pdf.
Regards
Masoud
Quoted reply history
2009/12/13 ke fang <[email protected]>
> Dear all,
>
> I'm now developing a simple PBPK structural model in NONMEM. The input to
> the PBPK model was a i.m. injection, and the only output was the renal
> excretion.. Because the drug was a long acting formulation, so I try to
> model the absorption into a fast phase and a slow phase. Now, here comes the
> problem. I don't know how to get DOSE into the model. Here is the control
> stream file:
>
> $PROB WBPBPK POPULATION MODEL
> $INPUT ID TIME CONC=DV AMT WT EVID CMT
> $DATA ..\PBPK.TXT IGNORE=#
> $SUBROUTINES ADVAN6 TOL=3
> $MODEL
> COMP = (LIV) ; 1 - LIVER COMPARTMENT
> COMP = (KID) ; 2 - KIDNEY COMPARTMENT
> COMP = (MUS) ; 3 - MUSCLE COMPARTMENT
> COMP = (INJ) ; 4 - INJECTIONSITE COMPARTMENT RECEIVING DOSE
> COMP = (VEN) ; 5 - VENOUS COMPARTMENT
> COMP = (OUT) ; 6 - KIDNEY EXCRETION COMPARTMENT
> $PK
> ; ------------------------ TWO ABSORBTION PHASE-------------------- ;
> PHSF = 0.714 ; FAST PHASE ABSORPTION FRACTION
> PHSS = 0.286 ; SLOW PHASE ABSORPTION FRACTION
> KF = 0.032334 ; FAST PHASE ABSORPTION ABSORPTION RATE
> KS = 0.00835 ; SLOW PHASE ABSORPTION ABSORPTION RATE
> ; ------------------------- BLOOD FLOWS (Q,L/HR) -------------------- ;
> QVEN = 2.049*WT ;L/H/KG;
> QLIV =QVEN*0.3053*(WT/25) ;L/H/KG;
> QKID =QVEN*0.1398*(WT/25) ;L/H/KG;
> QMUS =QVEN*0.2524*(WT/25) ;L/H/KG;
> QINJ = QVEN*0.2524*(0.5/WT/25) ;L/H/KG;
> ;----------------------------TISSUE VOLUMES (V,L)----------------------;
> VLIV =0.0294*WT ;KG;
> VKID =0.004*WT ;KG;
> VMUS =0.4007*WT ;KG;
> VINJ =0.5 ;KG;
> VVEN =0.06*WT ;KG;
> ;----------------------------PARTITION COEFFICIENTS-------------------;
> PLIV = EXP(THETA(2))
> PKID = EXP(THETA(3))
> PMUS = EXP(THETA(4))
> ;---------------------KIDNEY EXCRETION-------------------;
> TVEXCR=EXP(THETA(1))
> EXCR=TVEXCR*EXP(ETA(1))
> $DES
> ;--------------------COMPARTMENT CONCENTRATIONS-------------------;
> C1 = A(1)/VLIV
> C2 = A(2)/VKID
> C3 = A(3)/VMUS
> C4 = A(4)/VINJ
> C5 = A(5)/VVEN
> DADT(1)=QLIV*(C5-C1/PLIV)
> DADT(2)=(QKID*(C5-C2/PKID)-C2*EXCR)
> DADT(3)=QMUS*(C5-C3/PMUS)
> DADT(4)=(QINJ*(C5-C4/PMUS))
> DADT(5)=(QLIV*C1/PLIV+QKID*C2/PKID+QMUS*C3/PMUS+QINJ*C4/PMUS-QVEN*C5)
> DADT(6)=EXCR
> $ERROR
> Y=A(3)/VMUS+EPS(1)
> ;------------------------------INITIAL
> ESTIMATES--------------------------------;
> $THETA(0,0.5) ; 1-EXCR
> $THETA(0,1.82,10) ; 2-PLIV
> $THETA(0,6.46,10) ; 3-PKID
> $THETA(0,0.486) ; 4-PMUS
> $OMEGA(0.5) ; 1-EXCR
> $SIGMA(1) ; 1-ERROR
> $EST PRINT=5 MAX=9990 POSTHOC SIGDIG=3 METHOD=1
> $COV MATRIX=R
> $TABLE ID TIME CONC WT AMT NOPRINT ONEHEADER FILE=PBPK.FIT
>
> Can anyone give some hint?
> Thanks in advance!
>
> Ke, Fang
>
>
Dear Masoud and Guzy,
Thanks for your comments, and sorry for my late reply.
I recode my control stream file and data file, but i'm not quite sure if it
is appropriate. Please correct me if i was wrong! Thanks in advance!
Here is the control stream.
$PROB WBPBPK POPULATION MODEL
$INPUT ID TIME CONC=DV AMT WT EVID CMT MDV
$DATA ..\PBPK.TXT IGNORE=#
$SUBROUTINES ADVAN8 TOL=3
$MODEL
COMP = (LIV,NODOSE) ; 1 - LIVER COMPARTMENT
COMP = (KID,DEFOBS,NODOSE) ; 2 - KIDNEY COMPARTMENT
COMP = (MUS,NODOSE) ; 3 - MUSCLE COMPARTMENT
COMP = (INJ,NODOSE) ; 4 - INJECTIONSITE COMPARTMENT RECEIVING DOSE
COMP = (VEN,NODOSE) ; 5 - VENOUS COMPARTMENT
COMP = (OUT,NODOSE) ; 6 - KIDNEY EXCRETION COMPARTMENT
COMP = (PHSF) ; 7 - FAST PHASE
COMP = (PHSS) ; 8 - SLOW PHASE
COMP = (OTH,NODOSE) ; 9 - OTHER TISSUE
$PK
"FIRST
" COMMON /PRCOMG/ IDUM1,IDUM2,IMAX
" INTEGER IDUM1,IDUM2,IMAX
" IMAX=100000
; ------------------------ TWO ABSORBTION PHASE-------------------- ;
KF = 0.32334 ; FAST PHASE ABSORPTION RATE
KS = 0.0835 ; SLOW PHASE ABSORPTION RATE
; ------------------------- BLOOD FLOWS (Q,L/HR) -------------------- ;
QVEN = 0.25*WT**0.75 ;L/H/KG;
QLIV =QVEN*0.3053;L/H/KG;
QKID =QVEN*0.1398;L/H/KG;
QMUS =QVEN*0.2524 ;L/H/KG;
QINJ = QVEN*0.2524*(0.5/WT) ;L/H/KG;
QOTH=QVEN-QLIV-QKID-QMUS-QINJ
;----------------------------TISSUE VOLUMES (V,L)----------------------;
VLIV =0.0294*WT ;KG;
VKID =0.004*WT ;KG;
VMUS =0.4007*WT ;KG;
VINJ =0.5 ;KG;
VVEN =0.06*WT ;KG;
VOTH=WT-VLIV-VKID-VMUS-VINJ-VVEN
;----------------------------PARTITION COEFFICIENTS-------------------;
PLIV = 1.94
PKID = 2.38
PMUS = 1.11
POTH = 0.05
;---------------------KIDNEY EXCRETION-------------------;
EXCR=(THETA(1))*EXP(ETA(1))
;PLIV=THETA(2)*EXP(ETA(2))
;PKID=THETA(3)*EXP(ETA(3))
;PMUS=THETA(4)*EXP(ETA(4))
;POTH=THETA(5)*EXP(ETA(5))
$DES
;--------------------COMPARTMENT CONCENTRATIONS-------------------;
C1 = A(1)/VLIV ; CONCENTRATION IN LIVER
C2 = A(2)/VKID ; CONCENTRATION IN KIDNEY
C3 = A(3)/VMUS ; CONCENTRATION IN MUSCLE
C4 = A(4)/VINJ ; CONCENTRATION IN INJECTION SITE
C5 = A(5)/VVEN ; CONCENTRATION IN VENOUS
C9 = A(9)/VOTH ; CONCENTRATION IN OTHER TISSUE
DADT(1)=QLIV*(C5-C1/PLIV)
DADT(2)=(QKID*(C5-C2/PKID)-A(2)*EXCR)
DADT(3)=QMUS*(C5-C3/PMUS)
DADT(4)=(KF*A(7)+KS*A(8)+QINJ*(C5-C4/PMUS))
DADT(5)=(QLIV*C1/PLIV+QKID*C2/PKID+QMUS*C3/PMUS+QINJ*C4/PMUS-QVEN*C5)
DADT(6)=EXCR*A(2)
DADT(7)=-KF*A(7)
DADT(8)=-KS*A(8)
DADT(9)=QOTH*(C5-C9/POTH)
$ERROR
Y=A(2)/VKID+EPS(1)
;------------------------INITIAL ESTIMATES------------------------------;
$THETA(0.01,7.12) ; 1-EXCR
;$THETA(1,5.01) ; 2-PLIV
;$THETA(1,3.77) ; 3-PKID
;$THETA(0.2,0.758) ; 4-PMUS
;$THETA(0,0.0889) ; 5-POTH
$OMEGA(0.09) ; 1-EXCR
;$OMEGA(0.09)
;$OMEGA(0.09)
;$OMEGA(0.09)
;$OMEGA(0.09)
;$OMEGA(0.09)
$SIGMA(1) ; 1-ERROR
$EST PRINT=5 MAX=9990 POSTHOC SIGDIG=7 METHOD=0
$COV MATRIX=R
$TABLE ID TIME CONC WT AMT NOPRINT ONEHEADER FILE=PBPK.FIT
Here is part of data file.
#ID TIME CONC AMT WT EVID CMT MDV
1 0 0 492.66 22.3 1 7 1
1 0 0 197.34 22.3 1 8 1
1 24 52.462 0 22.3 0 2 0
2 0 0 492.66 22.4 1 7 1
2 0 0 197.34 22.4 1 8 1
2 72 7.704 0 22.4 0 2 0
Ke, Fang