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Re: parent drug and metabolite

From: Nick Holford <n.holford>
Date: Mon, 05 Mar 2007 18:32:27 +1300

Leonid,

You are quite correct. (Zheng -- please accept my apologies). In haste I misread the equations:

DADT(2)=CL1*A(1)/V1+Q/V3*A(3)-Q/V2*A(2)-K20*A(2)
DADT(3)=Q/V2*A(2)-Q/V3*A(3)

It would be clearer to me if it was written:

DADT(1)=-CL1*A(1)/V1
DADT(2)=CL1*A(1)/V1+Q*A(3)/V3-Q*A(2)/V2-K20*A(2)
DADT(3)=Q*A(2)/V2-Q*A(3)/V3

or more efficiently and IMHO much more clearly:

C1=A(1)/V1
C2=A(2)/V2
C3=A(3)/V3
DADT(1)=-CL1*C1
DADT(2)=CL1*C1 + Q*(C3 - C2) - CL2*C2
DADT(3)=Q*(C2 - C3) ; reversible formation of metabolite 3

where CL2 is the elimination clearance of metabolite 2 (equivalent to K20*V2 in the original parameterization).

It now becomes obvious to me that it is assumed that metabolite 2 is formed reversibly from metabolite 2 and is eliminated by the reverse reaction back to metabolite 2.

Nick

Leonid Gibiansky wrote:
>
> I cannot see any problems with the equations, looks correct to me:
> K=CL1/V1
> DADT1=-K*A(1)
> S1=V1
>
> etc.
> Leonid
>
> Nick Holford wrote:
> > Sam,
> >
> > There is no problem with using CL1 in this code. This is not a reserved word and CL is not a required variable name when using $DES.
> >
> > I fixed the more obvious errors so that the following code will run with NM-TRAN. However, the equations for parent and metabolites dont make sense to me. It looks like Amounts are being multiplied by volumes when they should be divided in order to get concentration.
> >
> > Nick
> >
> > $PROBLEM Parent drug & active metabolite
> > ;Units: Time=mins,
> > ;Concentration=uM(umols/L), Amount=umols
> > ;Age=yrs, Weight=kg
> > $DATA AW2.CSV IGNORE=#
> > $INPUT ID TIME DV ANUM AMT SEX=DROP WT AGE CMT
> >
> > $SUBROUTINE ADVAN6 TRANS1 TOL=5
> > $MODEL
> > COMP=(PARENT) COMP=(METAB1) COMP=(METAB2)
> >
> > $PK
> > CL1=THETA(1)*EXP(ETA(1))
> > V1=THETA(2)*EXP(ETA(2))
> > K20=THETA(3)*EXP(ETA(3))
> > Q=THETA(4)*EXP(ETA(4))
> > V2=THETA(5)*EXP(ETA(5))
> > V3=THETA(6)*EXP(ETA(6))
> > S1=V1
> > S2=V2
> > K12=CL1/V1
> >
> > $DES
> > DADT(1)=-CL1*A(1)/V1
> > DADT(2)=CL1*A(1)/V1+Q/V3*A(3)-Q/V2*A(2)-K20*A(2)
> > DADT(3)=Q/V2*A(2)-Q/V3*A(3)
> >
> > $ERROR
> > W=F
> > IPRED=F
> > IRES=DV-IPRED
> > IWRES=IRES/W
> > P1=0
> > IF(CMT.EQ.1)P1=1
> > P2=0
> > IF(CMT.EQ.2)P2=1
> > Y1=W*(1+ERR(1))
> > Y2=W*(1+ERR(2))
> > Y=P1*Y1+P2*Y2
> >
> > $THETA
> > (0,,100000) ; CL1
> > (0,,100000) ; V1
> > (0,,100000) ; K20
> > (0,,100000) ; Q
> > (0,,100000) ; V2
> > (0,,100000) ; V3
> > $OMEGA
> > 0.1 ; PPV_CL1
> > 0.1 ; PPV_V1
> > 0.1 ; PPV_K20
> > 0.1 ; PPV_Q
> > 0.1 ; PPV_V2
> > 0.1 ; PPV_V3
> > $SIGMA
> > 0.1 ; RUV_P
> > 0.1 ; RUV_M
> >
> > ;$ESTIMATION MAXEVAL=9999 PRINT=5 POSTHOC
> > ;$COVARIANCE
> > $TABLE ID TIME DV ANUM AMT WT AGE CMT EVID MDV IPRED IWRES
> > NOPRINT ONEHEADER FILE=OUTAMIWR.FIT
> >
> >
> > Sam Liao wrote:
> >> Hi Zheng:
> >> It is complaining the CL1. You need to replace all CL1 with CL. But
> >> you have other problems in your $INPUT statement and the data set too.
> >>
> >> Sam
> >>> Dear All:
> >>>
> >>> why do I get following error message with the following code? Any
> >>> opinions regarding this problem and code will be highly appreciated.
> >>> Thank you very much for your consideration and help. I am modeling
> >>> parent drug and active metabolite at the same time with this code.
> >>>
> >>>
> >>> AN ERROR WAS FOUND IN THE CONTROL STATEMENTS.
> >>>
> >>> AN ERROR WAS FOUND ON LINE 13 AT THE APPROXIMATE POSITION NOTED:
> >>> CL1=THETA(1)*EXP(ETA(1))
> >>> X
> >>> THE CHARACTERS IN ERROR ARE:
> >>> 202 FORTRAN SYNTAX IS INCORRECT OR INAPPROPRIATE IN THIS CONTEXT.
> >>> 4
> >>>
> >>>
> >>> $PROBLEM Parent drug & active metabolite ;Units: Time=mins,
> >>> Concentration=uM(umols/L), Amount=umols
> >>> ;Age=yrs, Weight=kg
> >>> $DATA AW2.CSV IGNORE=C $INPUT ID TIME DV ANUM AMT SEX WT AGE CMT EVID MDV
> >>>
> >>> $SUBROUTINE ADVAN6 TRANS1 TOL=5
> >>> $MODEL
> >>> COMP=(PARENT) COMP=(METAB1) COMP=(METAB2)
> >>>
> >>> $PK
> >>> CL1=THETA(1)*EXP(ETA(1))
> >>> V1=THETA(2)*EXP(ETA(2))
> >>> K20=THETA(3)*EXP(ETA(3))
> >>> Q=THETA(4)*EXP(ETA(4))
> >>> V2=THETA(5)*EXP(ETA(5))
> >>> V3=THETA(6)*EXP(ETA(6))
> >>> S1=V1
> >>> S2=V2
> >>> K12=CL1/V1
> >>>
> >>> $DES
> >>> DADT(1)=-CL1*A(1)/V1
> >>> DADT(2)=CL1*A(1)/V1+Q/V3*A(3)-Q/V2*A(2)-K20*A(2)
> >>> DADT(3)=Q/V2*A(2)-Q/V3*A(3)
> >>>
> >>> $ERROR
> >>> W=F
> >>> IPRED=F
> >>> IRES=DV-IPRED
> >>> IWRES=IRES/W
> >>> P1=0
> >>> IF(CMT.EQ.1)P1=1
> >>> P2=0
> >>> IF(CMT.EQ.2)P2=1
> >>> Y1=W*(1+ERR(1))
> >>> Y2=W*(1+ERR(2))
> >>> Y=P1*Y1+P2*Y2
> >>>
> >>> $THETA
> >>> (0,,0.1000E+07)
> >>> (0,,0.1000E+07)
> >>> (0,,0.1000E+07)
> >>> (0,,0.1000E+07)
> >>> (0,,0.1000E+07)
> >>> (0,,0.1000E+07)
> >>> (0,,0.1000E+07)
> >>> (0,,0.1000E+07)
> >>> $OMEGA
> >>> (0,,0.1000E+07)
> >>> (0,,0.1000E+07)
> >>> (0,,0.1000E+07)
> >>> (0,,0.1000E+07)
> >>> (0,,0.1000E+07)
> >>> (0,,0.1000E+07)
> >>> (0,,0.1000E+07)
> >>> $SIGMA
> >>> (0,,0.1000E+07)
> >>> (0,,0.1000E+07)
> >>>
> >>> $ESTIMATION MAXEVAL=9999 PRINT=5 POSTHOC
> >>>
> >>> $COVARIANCE
> >>>
> >>> $TABLE ID TIME DV ANUM AMT SEX WT AGE CMT EVID MDV IPRED IWRES
> >>> NOPRINT ONEHEADER FILE=OUTAMIWR.FIT
> >>>
> >>> ID Time DV Anum AMT Gender WT Age CMT
> >>> 1 0 0 1 3371.43 F 110.23 44 1
> >>> 1 1 187 1 0 F 110.23 44 1
> >>> 1 1 14.24 1 0 F 110.23 44 2
> >>> 1 5 85.55 1 0 F 110.23 44 1
> >>> 1 5 28.49 1 0 F 110.23 44 2
> >>> 1 15 12.1 1 0 F 110.23 44 1
> >>> 1 15 13.43 1 0 F 110.23 44 2
> >>> 1 30 1.03 1 0 F 110.23 44 1
> >>> 1 30 3.25 1 0 F 110.23 44 2
> >>> 1 45 1.19 1 0 F 110.23 44 2
> >>> 1 60 0.83 1 0 F 110.23 44 2
> >>> 1 120 0.4 1 0 F 110.23 44 2
> >>> 1 180 0.35 1 0 F 110.23 44 2
> >>> 1 240 0.13 1 0 F 110.23 44 2
> >>>
> >>> Zheng
> >>>
> >>>
> >>>
> >>>
> >>>
> >
> > --
> > Nick Holford, Dept Pharmacology & Clinical Pharmacology
> > University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand
> > email:n.holford
> > http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
> >
> >

--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand
email:n.holford
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
Received on Mon Mar 05 2007 - 00:32:27 EST

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