Dear NMusers,
I have plasma concentration versus time data for a drug and its active
metabolite. I would like to simulataneously fit this drug and its metabolite
using NONMEM to obtain estimates of prameters and associated variability for
both drug and its active metabolite. I am sure guys have done this nicely in
past. I was wondering if someone can share a control stream and sample data
for my guidance.
Thanks
_______________
Vijay V Upreti
PhD Candidate
Pharmacokinetics-Biopharmaceutics Laboratory
Dept. of Pharmaceutical Sciences
University of Maryland, School of Pharmacy
Rm S509, 20 Penn St., Baltimore, MD 21201
Voice: 410.706.7388; Fax: 410.706.5017
Simultaneous drug and metabolite POPPK
Dear Vijai,
An example of a model fitted to log-transformed plasma concentrations of a
parent drug and its active metabolite (cf. extended model in European Journal
of Clinical Pharmacology 2002;58(4) Suppl:S1-S67.):
Program code:
$PROBLEM Parent drug & active metabolite
$INPUT ID AMT TIME RATE EVID CMT DV
$DATA XXXXX.prn IGNORE=#
$SUBROUTINES ADVAN5
$MODEL
COMP=(DEFOBS1); central compartment of parent drug
COMP=(PERIPH1); peripheral compartment of parent drug
COMP=(PERIPH2); peripheral compartment of parent drug
COMP=(DEFOBS2); central compartment of metabolite
COMP=(PERIPH3); peripheral compartment of parent drug
COMP=(PERIPH4); peripheral compartment of parent drug
COMP=(PERIPH5); compartment of intermediary metabolites between parent drug
and active metabolite
$PK
;----------------------------------------------------------------------------
;BASIC PK OF PARENT DRUG (observations after two intravenous infusions given 12
h apart)
;----------------------------------------------------------------------------
K10=THETA(1)*(1+ETA(1))
K12=THETA(2)*(1+ETA(2))
K21=THETA(3)*(1+ETA(3))
K13=THETA(4)*(1+ETA(4))
K31=THETA(5)*(1+ETA(5))
;----------------------------------------------------------------------------
;BASIC PK OF ACTIVE METABOLITE (observations after two intravenous infusions
given 12 h apart or after two intravenous infusions of the parent drug given 12
h apart)
;----------------------------------------------------------------------------
K40=THETA(6)*(1+ETA(6))
K45=THETA(7)*(1+ETA(7))
K54=THETA(8)*(1+ETA(8))
K46=THETA(9)*(1+ETA(9))
K64=THETA(10)*(1+ETA(10))
;----------------------------------------------------------------------------
;VOLUMES OF DISTRIBUTION
;----------------------------------------------------------------------------
S1 =THETA(11)*(1+ETA(11))
S4 =THETA(11)*(1+ETA(11)); joint estimate for parent drug and active metabolite
;----------------------------------------------------------------------------
;SYSTEMIC GENERATION OF ACTIVE METABOLITE
;----------------------------------------------------------------------------
K74=THETA(12)*(1+ETA(12)); transformation of intermediary to active metabolite
K17=THETA(13)*(1+ETA(13)); transformation of parent drug to intermediary
metabolite
;----------------------------------------------------------------------------
$ERROR
IF (EVID.EQ.0.AND.F.GT.0) THEN
IPRED=LOG(F)
ELSE
IPRED=LOG(F+1)
ENDIF
IRES=DV-IPRED
IWRES=IRES
X1=0
X2=0
IF(CMT.EQ.1)X1=1; flag for parent drug observation(CMT=1)
IF(CMT.EQ.4)X2=1; flag for active metabolite observation(CMT=4)
Y=IPRED+X1*EPS(1)+X2*EPS(2)
.....
Data file XXXX.prn, first subject
# ID AMT TIME RATE EVID CMT DV
1 2214 0 27675 4 1 XXX
1 . 0.08 . 0 1 XXX
1 . 0.25 . 0 1 XXX
1 . 0.5 . 0 1 XXX
1 . 0.999 . 0 1 XXX
1 . 0.999 . 0 4 YYY
1 2208 1 27600 1 1 .
1 . 1.08 . 0 1 XXX
1 . 1.08 . 0 4 YYY
1 . 1.25 . 0 1 XXX
1 . 1.25 . 0 4 YYY
1 . 1.5 . 0 1 XXX
1 . 1.5 . 0 4 YYY
1 . 2 . 0 1 XXX
1 . 2 . 0 4 YYY
1 . 2.5 . 0 1 XXX
1 . 2.5 . 0 4 YYY
1 . 3 . 0 1 XXX
1 . 3 . 0 4 YYY
1 . 4 . 0 1 XXX
1 . 4 . 0 4 YYY
1 . 6 . 0 4 YYY
1 . 8 . 0 1 XXX
1 . 8 . 0 4 YYY
1 . 9 . 0 4 YYY
1 . 12 . 0 4 YYY
1 . 15 . 0 1 XXX
1 . 15 . 0 4 YYY
1 . 21 . 0 4 YYY
1 . 43 . 0 4 YYY
1 756 0 9450 4 4 .
1 . 0.08 . 0 4 YYY
1 . 0.25 . 0 4 YYY
1 . 0.5 . 0 4 YYY
1 . 0.999 . 0 4 YYY
1 762 1 9525 1 4 .
1 . 1.08 . 0 4 YYY
1 . 1.25 . 0 4 YYY
1 . 1.5 . 0 4 YYY
1 . 2 . 0 4 YYY
1 . 2.5 . 0 4 YYY
1 . 3 . 0 4 YYY
1 . 4 . 0 4 YYY
1 . 8 . 0 4 YYY
1 . 15 . 0 4 YYY
1 . 21 . 0 4 YYY
1 . 31 . 0 4 YYY
/ Johan
> Johan Rosenborg
> Senior Pharmacokineticist, Clinical Pharmacology
> Medical Science Sweden
> AstraZeneca R&D Lund
> SE-221 87 Lund, Sweden
Tel: +46 46 33 65 99
Quoted reply history
-----Original Message-----
From: [EMAIL PROTECTED]
[mailto:[EMAIL PROTECTED] Behalf Of Vijay V. Upreti
Sent: 12 februari 2007 19:20
To: [email protected]
Subject: [NMusers] Simultaneous drug and metabolite POPPK
Dear NMusers,
I have plasma concentration versus time data for a drug and its active
metabolite. I would like to simulataneously fit this drug and its metabolite
using NONMEM to obtain estimates of prameters and associated variability for
both drug and its active metabolite. I am sure guys have done this nicely in
past. I was wondering if someone can share a control stream and sample data
for my guidance.
Thanks
_______________
Vijay V Upreti
PhD Candidate
Pharmacokinetics-Biopharmaceutics Laboratory
Dept. of Pharmaceutical Sciences
University of Maryland, School of Pharmacy
Rm S509, 20 Penn St., Baltimore, MD 21201
Voice: 410.706.7388; Fax: 410.706.5017
Hello
This is a code + data example for an IV infusion,
PARENT = 1 = cpt1
METAB = 2 = cpt2
Regards
Saik
Saïk URIEN, MD, PhD
Directeur de Recherche, INSERM
Service de Pharmacologie
Centre René Huguenin
35 rue Dailly
F92210 St Cloud
Tel. 01 4711 1684
Fax 01 4711 1617
email : [EMAIL PROTECTED]
$PROB R IV INFUS
$INPUT ID TIME AMT RATE DV CMT MDV
$DATA DATA125.csv
$SUBROUTINE ADVAN6 TOL=3
$MODEL
COMP=(PARENT)
COMP=(METAB)
$PK
V1=THETA(1)*EXP(ETA(1))
CL=THETA(2)*EXP(ETA(2))
P12=THETA(3)*EXP(ETA(3))
K20=THETA(4)*EXP(ETA(4))
S1=V
KEL =CL/V
K12 =P12*KEL
K10 =KEL - K12
V2 = 1
$DES
DADT(1) = -(K10+K12)*A(1)
DADT(2) = K12*A(1) - K20*A(2)
$ERROR
C1=A(1)/V1
C2=A(2)/V2
IPRED = C1
IF (CMT.EQ.2) IPRED=C2
Y=C1*(1+EPS(1))+EPS(2)
IF (CMT.EQ.2) Y=C2*(1+EPS(3))+EPS(4)
$THETA (0,5);V
$THETA (0,10);CL
$THETA (0,.005,1);f12
$THETA (0,.01);K20
$OMEGA 0.4;oV
$OMEGA 0.4;oCL
$OMEGA 0.1;of12
$OMEGA 0.1;oK20
$SIGMA .4;sPp
$SIGMA 1;sPa
$SIGMA .4;sMp
$SIGMA .1;sMa
$EST METHOD=1 INTERACTION MAXEVAL=4500 PRINT=10 POSTHOC
$COV
$TABLE ID TIME CMT NOPRINT FILE=r
DATA CORRESPONDING TO THE CODE ABOVE
#ID TIME AMT RATE DV CMT MDV
1101 0 433.36 216.68 0 1 1
1101 1 0 0 11.84 1 0
1101 1 0 0 0.44 2 0
1101 2 0 0 41.17 1 0
1101 2 0 0 1.05 2 0
1101 2.08 0 0 21.08 1 0
1101 2.08 0 0 0.91 2 0
1101 2.25 0 0 11.78 1 0
1101 2.25 0 0 0.82 2 0
1101 2.5 0 0 6.38 1 0
1101 2.5 0 0 0.6 2 0
1101 3 0 0 1.48 1 0
1101 3 0 0 0.26 2 0
1101 4 0 0 0.17 1 0
1101 4 0 0 0.06 2 0
1101 6 0 0 0.02 1 0
1102 0 1132.65 566.32 0 1 1
1102 1 0 0 33.49 1 0
1102 1 0 0 1.17 2 0
1102 2 0 0 38.02 1 0
1102 2 0 0 1.65 2 0
1102 2.08 0 0 45.7 1 0
1102 2.08 0 0 1.77 2 0
1102 2.25 0 0 46.49 1 0
1102 2.25 0 0 3.22 2 0
1102 2.5 0 0 40.18 1 0
1102 2.5 0 0 1.82 2 0
1102 3 0 0 13.41 1 0
1102 3 0 0 1.22 2 0
1102 4 0 0 2.7 1 0
1102 4 0 0 0.46 2 0
1102 6 0 0 0.12 1 0
1102 6 0 0 0.09 2 0
-----Message d'origine-----
Quoted reply history
De : [EMAIL PROTECTED]
[mailto:[EMAIL PROTECTED] la part de Vijay V. Upreti
Envoyé : lundi 12 février 2007 19:20
À : [email protected]
Objet : [NMusers] Simultaneous drug and metabolite POPPK
Dear NMusers,
I have plasma concentration versus time data for a drug and its active
metabolite. I would like to simulataneously fit this drug and its metabolite
using NONMEM to obtain estimates of prameters and associated variability for
both drug and its active metabolite. I am sure guys have done this nicely in
past. I was wondering if someone can share a control stream and sample data
for my guidance.
Thanks
_______________
Vijay V Upreti
PhD Candidate
Pharmacokinetics-Biopharmaceutics Laboratory
Dept. of Pharmaceutical Sciences
University of Maryland, School of Pharmacy
Rm S509, 20 Penn St., Baltimore, MD 21201
Voice: 410.706.7388; Fax: 410.706.5017
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I have a question for those who submitted these two examples - Did you
transform the data into micromolar quantities? It is not clear from the
examples. I have not done much parent/metabolite modeling (just lucky I
guess) but it seems to me that one would have to work in molar units for
these models to be valid. Can someone comment on this?
Mike
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
Michael J. Fossler, Pharm. D., Ph. D., F.C.P.
Director
Clinical Pharmacokinetics, Modeling & Simulation
GlaxoSmithKline
(610) 270 - 4797
FAX: (610) 270-5962
Cell: (443) 350-1194
[EMAIL PROTECTED]
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
I think the easiest and least confusing way is to transform all concentrations
into molar units in your data sets at the beginning when you model parent and
metabolites simultaneously. However, there are other options to go around this
issue. For example, you can also incorporate molecular weights into your model
if you have to use weight concentrations in your data set for some reason.
Alan
Quoted reply history
-----Original Message-----
From: [EMAIL PROTECTED] [mailto:[EMAIL PROTECTED] Behalf Of [EMAIL PROTECTED]
Sent: Tuesday, February 13, 2007 9:02 AM
To: Nmusers (E-mail); [EMAIL PROTECTED]
Subject: RE: [NMusers] Simultaneous drug and metabolite POPPK
I have a question for those who submitted these two examples - Did you
transform the data into micromolar quantities? It is not clear from the
examples. I have not done much parent/metabolite modeling (just lucky I guess)
but it seems to me that one would have to work in molar units for these models
to be valid. Can someone comment on this?
Mike
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
Michael J. Fossler, Pharm. D., Ph. D., F.C.P.
Director
Clinical Pharmacokinetics, Modeling & Simulation
GlaxoSmithKline
(610) 270 - 4797
FAX: (610) 270-5962
Cell: (443) 350-1194
[EMAIL PROTECTED]
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
Dear Vijai,
This topic has been discussed intensively in the past.
A quick search can find you this:
http://huxley.phor.com/nonmem/nm/98jul021999.html
For more complete results, search
http://www.phor.com/nonmem/sitesearch/index.html
Best regards, Liping
Rosenborg, Johan wrote:
>Erratum: intravenous infusions were given 1 h apart (not 12 h) in the
example below - sorry!/ Johan
>
>
>
>>Johan Rosenborg
>>Senior Pharmacokineticist, Clinical Pharmacology
>>Medical Science Sweden
>>AstraZeneca R&D Lund
>>SE-221 87 Lund, Sweden
>>
>>
> Tel: +46 46 33 65 99
>
>
Quoted reply history
>-----Original Message-----
>From: Rosenborg, Johan
>Sent: 13 februari 2007 10:11
>To: [email protected]
>Subject: RE: [NMusers] Simultaneous drug and metabolite POPPK
>
>
>Dear Vijai,
>
>An example of a model fitted to log-transformed plasma concentrations
of a parent drug and its active metabolite (cf. extended model in
European Journal of Clinical Pharmacology 2002;58(4) Suppl:S1-S67.):
>
>Program code:
>
>$PROBLEM Parent drug & active metabolite
>$INPUT ID AMT TIME RATE EVID CMT DV
>$DATA XXXXX.prn IGNORE=#
>$SUBROUTINES ADVAN5
>$MODEL
> COMP=(DEFOBS1); central compartment of parent drug
> COMP=(PERIPH1); peripheral compartment of parent drug
> COMP=(PERIPH2); peripheral compartment of parent drug
> COMP=(DEFOBS2); central compartment of metabolite
> COMP=(PERIPH3); peripheral compartment of parent drug
> COMP=(PERIPH4); peripheral compartment of parent drug
> COMP=(PERIPH5); compartment of intermediary metabolites between
parent drug and active metabolite
>$PK
>;----------------------------------------------------------------------
------
>;BASIC PK OF PARENT DRUG (observations after two intravenous infusions
given 12 h apart)
>;----------------------------------------------------------------------
------
> K10=THETA(1)*(1+ETA(1))
> K12=THETA(2)*(1+ETA(2))
> K21=THETA(3)*(1+ETA(3))
> K13=THETA(4)*(1+ETA(4))
> K31=THETA(5)*(1+ETA(5))
>;----------------------------------------------------------------------
------
>;BASIC PK OF ACTIVE METABOLITE (observations after two intravenous
infusions given 12 h apart or after two intravenous infusions of the
parent drug given 12 h apart)
>;----------------------------------------------------------------------
------
> K40=THETA(6)*(1+ETA(6))
> K45=THETA(7)*(1+ETA(7))
> K54=THETA(8)*(1+ETA(8))
> K46=THETA(9)*(1+ETA(9))
> K64=THETA(10)*(1+ETA(10))
>;----------------------------------------------------------------------
------
>;VOLUMES OF DISTRIBUTION
>;----------------------------------------------------------------------
------
> S1 =THETA(11)*(1+ETA(11))
> S4 =THETA(11)*(1+ETA(11)); joint estimate for parent drug and active
metabolite
>;----------------------------------------------------------------------
------
>;SYSTEMIC GENERATION OF ACTIVE METABOLITE
>;----------------------------------------------------------------------
------
> K74=THETA(12)*(1+ETA(12)); transformation of intermediary to active
metabolite
> K17=THETA(13)*(1+ETA(13)); transformation of parent drug to
intermediary metabolite
>;----------------------------------------------------------------------
------
>$ERROR
> IF (EVID.EQ.0.AND.F.GT.0) THEN
> IPRED=LOG(F)
> ELSE
> IPRED=LOG(F+1)
> ENDIF
> IRES=DV-IPRED
> IWRES=IRES
>X1=0
>X2=0
>IF(CMT.EQ.1)X1=1; flag for parent drug observation(CMT=1)
>IF(CMT.EQ.4)X2=1; flag for active metabolite observation(CMT=4)
> Y=IPRED+X1*EPS(1)+X2*EPS(2)
>.....
>
>Data file XXXX.prn, first subject
># ID AMT TIME RATE EVID CMT DV
> 1 2214 0 27675 4 1 XXX
> 1 . 0.08 . 0 1 XXX
> 1 . 0.25 . 0 1 XXX
> 1 . 0.5 . 0 1 XXX
> 1 . 0.999 . 0 1 XXX
> 1 . 0.999 . 0 4 YYY
> 1 2208 1 27600 1 1 .
> 1 . 1.08 . 0 1 XXX
> 1 . 1.08 . 0 4 YYY
> 1 . 1.25 . 0 1 XXX
> 1 . 1.25 . 0 4 YYY
> 1 . 1.5 . 0 1 XXX
> 1 . 1.5 . 0 4 YYY
> 1 . 2 . 0 1 XXX
> 1 . 2 . 0 4 YYY
> 1 . 2.5 . 0 1 XXX
> 1 . 2.5 . 0 4 YYY
> 1 . 3 . 0 1 XXX
> 1 . 3 . 0 4 YYY
> 1 . 4 . 0 1 XXX
> 1 . 4 . 0 4 YYY
> 1 . 6 . 0 4 YYY
> 1 . 8 . 0 1 XXX
> 1 . 8 . 0 4 YYY
> 1 . 9 . 0 4 YYY
> 1 . 12 . 0 4 YYY
> 1 . 15 . 0 1 XXX
> 1 . 15 . 0 4 YYY
> 1 . 21 . 0 4 YYY
> 1 . 43 . 0 4 YYY
> 1 756 0 9450 4 4 .
> 1 . 0.08 . 0 4 YYY
> 1 . 0.25 . 0 4 YYY
> 1 . 0.5 . 0 4 YYY
> 1 . 0.999 . 0 4 YYY
> 1 762 1 9525 1 4 .
> 1 . 1.08 . 0 4 YYY
> 1 . 1.25 . 0 4 YYY
> 1 . 1.5 . 0 4 YYY
> 1 . 2 . 0 4 YYY
> 1 . 2.5 . 0 4 YYY
> 1 . 3 . 0 4 YYY
> 1 . 4 . 0 4 YYY
> 1 . 8 . 0 4 YYY
> 1 . 15 . 0 4 YYY
> 1 . 21 . 0 4 YYY
> 1 . 31 . 0 4 YYY
>
>/ Johan
>
>
>
>>Johan Rosenborg
>>Senior Pharmacokineticist, Clinical Pharmacology
>>Medical Science Sweden
>>AstraZeneca R&D Lund
>>SE-221 87 Lund, Sweden
>>
>>
> Tel: +46 46 33 65 99
>
>
>-----Original Message-----
>From: [EMAIL PROTECTED]
>[mailto:[EMAIL PROTECTED] Behalf Of Vijay V. Upreti
>Sent: 12 februari 2007 19:20
>To: [email protected]
>Subject: [NMusers] Simultaneous drug and metabolite POPPK
>
>
>Dear NMusers,
>
>I have plasma concentration versus time data for a drug and its active
>metabolite. I would like to simulataneously fit this drug and its
metabolite
>using NONMEM to obtain estimates of prameters and associated
variability for
>both drug and its active metabolite. I am sure guys have done this
nicely in
>past. I was wondering if someone can share a control stream and sample
data
>for my guidance.
>
>
>
>Thanks
>
>_______________
>Vijay V Upreti
>PhD Candidate
>Pharmacokinetics-Biopharmaceutics Laboratory
>Dept. of Pharmaceutical Sciences
>University of Maryland, School of Pharmacy
>Rm S509, 20 Penn St., Baltimore, MD 21201
>Voice: 410.706.7388; Fax: 410.706.5017
>
>
>
--
Liping (CD) Zhang, PhD
Strategic Modeling and Simulation
Clinical Discovery
Bristol-Myers Squibb Co.
PO Box 4000 - Mail Stop: D14-06
Princeton, NJ 08543-4000
Location: D1.452
Phone: 609-252-6604
Fax: 609-252-7821
Email: [EMAIL PROTECTED]
Dear Vijai,
This topic has been discussed intensively in the past.
A quick search can find you this:
http://huxley.phor.com/nonmem/nm/98jul021999.html
For more complete results, search
http://www.phor.com/nonmem/sitesearch/index.html
Best regards, Liping
Rosenborg, Johan wrote:
Erratum: intravenous infusions were given 1 h apart (not 12 h) in the example below - sorry!/ Johan
Johan Rosenborg
Senior Pharmacokineticist, Clinical Pharmacology
Medical Science Sweden
AstraZeneca R&D Lund
SE-221 87 Lund, Sweden
Tel: +46 46 33 65 99
-----Original Message-----
From: Rosenborg, Johan
Sent: 13 februari 2007 10:11
To: [email protected]
Subject: RE: [NMusers] Simultaneous drug and metabolite POPPK
Dear Vijai,
An example of a model fitted to log-transformed plasma concentrations of a parent drug and its active metabolite (cf. extended model in European Journal of Clinical Pharmacology 2002;58(4) Suppl:S1-S67.):
Program code:
$PROBLEM Parent drug & active metabolite
$INPUT ID AMT TIME RATE EVID CMT DV
$DATA XXXXX.prn IGNORE=#
$SUBROUTINES ADVAN5
$MODEL
COMP=(DEFOBS1); central compartment of parent drug
COMP=(PERIPH1); peripheral compartment of parent drug
COMP=(PERIPH2); peripheral compartment of parent drug
COMP=(DEFOBS2); central compartment of metabolite
COMP=(PERIPH3); peripheral compartment of parent drug
COMP=(PERIPH4); peripheral compartment of parent drug
COMP=(PERIPH5); compartment of intermediary metabolites between parent drug and active metabolite
$PK
;----------------------------------------------------------------------------
;BASIC PK OF PARENT DRUG (observations after two intravenous infusions given 12 h apart)
;----------------------------------------------------------------------------
K10=THETA(1)*(1+ETA(1))
K12=THETA(2)*(1+ETA(2))
K21=THETA(3)*(1+ETA(3))
K13=THETA(4)*(1+ETA(4))
K31=THETA(5)*(1+ETA(5))
;----------------------------------------------------------------------------
;BASIC PK OF ACTIVE METABOLITE (observations after two intravenous infusions given 12 h apart or after two intravenous infusions of the parent drug given 12 h apart)
;----------------------------------------------------------------------------
K40=THETA(6)*(1+ETA(6))
K45=THETA(7)*(1+ETA(7))
K54=THETA(8)*(1+ETA(8))
K46=THETA(9)*(1+ETA(9))
K64=THETA(10)*(1+ETA(10))
;----------------------------------------------------------------------------
;VOLUMES OF DISTRIBUTION
;----------------------------------------------------------------------------
S1 =THETA(11)*(1+ETA(11))
S4 =THETA(11)*(1+ETA(11)); joint estimate for parent drug and active metabolite
;----------------------------------------------------------------------------
;SYSTEMIC GENERATION OF ACTIVE METABOLITE
;----------------------------------------------------------------------------
K74=THETA(12)*(1+ETA(12)); transformation of intermediary to active metabolite
K17=THETA(13)*(1+ETA(13)); transformation of parent drug to intermediary metabolite
;----------------------------------------------------------------------------
$ERROR
IF (EVID.EQ.0.AND.F.GT.0) THEN
IPRED=LOG(F)
ELSE
IPRED=LOG(F+1)
ENDIF
IRES=DV-IPRED
IWRES=IRES
X1=0
X2=0
IF(CMT.EQ.1)X1=1; flag for parent drug observation(CMT=1)
IF(CMT.EQ.4)X2=1; flag for active metabolite observation(CMT=4)
Y=IPRED+X1*EPS(1)+X2*EPS(2)
.....
Data file XXXX.prn, first subject
# ID AMT TIME RATE EVID CMT DV
1 2214 0 27675 4 1 XXX
1 . 0.08 . 0 1 XXX
1 . 0.25 . 0 1 XXX
1 . 0.5 . 0 1 XXX
1 . 0.999 . 0 1 XXX
1 . 0.999 . 0 4 YYY
1 2208 1 27600 1 1 .
1 . 1.08 . 0 1 XXX
1 . 1.08 . 0 4 YYY
1 . 1.25 . 0 1 XXX
1 . 1.25 . 0 4 YYY
1 . 1.5 . 0 1 XXX
1 . 1.5 . 0 4 YYY
1 . 2 . 0 1 XXX
1 . 2 . 0 4 YYY
1 . 2.5 . 0 1 XXX
1 . 2.5 . 0 4 YYY
1 . 3 . 0 1 XXX
1 . 3 . 0 4 YYY
1 . 4 . 0 1 XXX
1 . 4 . 0 4 YYY
1 . 6 . 0 4 YYY
1 . 8 . 0 1 XXX
1 . 8 . 0 4 YYY
1 . 9 . 0 4 YYY
1 . 12 . 0 4 YYY
1 . 15 . 0 1 XXX
1 . 15 . 0 4 YYY
1 . 21 . 0 4 YYY
1 . 43 . 0 4 YYY
1 756 0 9450 4 4 .
1 . 0.08 . 0 4 YYY
1 . 0.25 . 0 4 YYY
1 . 0.5 . 0 4 YYY
1 . 0.999 . 0 4 YYY
1 762 1 9525 1 4 .
1 . 1.08 . 0 4 YYY
1 . 1.25 . 0 4 YYY
1 . 1.5 . 0 4 YYY
1 . 2 . 0 4 YYY
1 . 2.5 . 0 4 YYY
1 . 3 . 0 4 YYY
1 . 4 . 0 4 YYY
1 . 8 . 0 4 YYY
1 . 15 . 0 4 YYY
1 . 21 . 0 4 YYY
1 . 31 . 0 4 YYY
/ Johan
Johan Rosenborg
Senior Pharmacokineticist, Clinical Pharmacology
Medical Science Sweden
AstraZeneca R&D Lund
SE-221 87 Lund, Sweden
Tel: +46 46 33 65 99
-----Original Message-----
From: [EMAIL PROTECTED]
[ mailto:[EMAIL PROTECTED] ]On Behalf Of Vijay V. Upreti
Sent: 12 februari 2007 19:20
To: [email protected]
Subject: [NMusers] Simultaneous drug and metabolite POPPK
Dear NMusers,
I have plasma concentration versus time data for a drug and its active
metabolite. I would like to simulataneously fit this drug and its metabolite
using NONMEM to obtain estimates of prameters and associated variability for
both drug and its active metabolite. I am sure guys have done this nicely in
past. I was wondering if someone can share a control stream and sample data
for my guidance.
Thanks
_______________
Vijay V Upreti
PhD Candidate
Pharmacokinetics-Biopharmaceutics Laboratory
Dept. of Pharmaceutical Sciences
University of Maryland, School of Pharmacy
Rm S509, 20 Penn St., Baltimore, MD 21201
Voice: 410.706.7388; Fax: 410.706.5017
--
Liping (CD) Zhang, PhD
Strategic Modeling and Simulation
Clinical Discovery
Bristol-Myers Squibb Co.
PO Box 4000 – Mail Stop: D14-06
Princeton, NJ 08543-4000
Location: D1.452
Phone: 609-252-6604
Fax: 609-252-7821
Email: [EMAIL PROTECTED]
Mike,
This depends on the purpose of the modeling and the information
available. Usually, we only have Parent and Met concentration data after
oral administration, therefore, we can't estimate the true disposition
parameters. We can get CL/F and V/F for parent, but we can get nothing
more than apparent Production rate constant and Elimination rate
constant for Met. In this case, converting the data to micromolar unit
or not is not critical.
e.g.
Let's begin from the differential equation below:
DADT(3)=KMP(iv)*A(2)-KME*A(3)
Eq 1
where A(2) is the amount of parent (mg), A(3) is the amount of
metabolite (mg). KmP is the production rate of the metabolite.
Because the distribution volume of Met (V3) is unobtainable (no IV data
of Met), we have to convert dA/dt to dC/dt and divide both sides of Eq 1
by V3 as follows:
DADT(3)/V3=KMP(iv)*A(2)/V3-KME*A(3)/V3
Eq 2
In NONMEM, we coded this as follows:
DADT(3)=KMP *A(2)/V2-KME*A(3)
Eq 3
Please note that DADT(3) in Eq 3, actually, is dC3/dt (a rate of
concentration instead of amount), and KMP in Eq 3 = KMP(iv) x V2/V3 in
Eq 1. In other words, KMP is a composite parameter of both volumn ratio
and molecular weight ratio.
If there are IV data for both parent and metabolite after
administrations of parent and metabolite seperately, the true
disposition parameters can be estimated for both. By converting the
concentration unit to molar, we can estimate formation fraction of
parent to metabolite.
Jun Shi
Clinical Pharmacology and Drug Dynamics
Forest Research Institute
Rm18-35
Harborside Financial Center-Plaza V
Jersey City, NJ 07311
Tel: 201-427-8044
Fax: 201-427-8498
Email: [EMAIL PROTECTED]
-----Original Message-----
Quoted reply history
From: [EMAIL PROTECTED]
[mailto:[EMAIL PROTECTED] On Behalf Of
[EMAIL PROTECTED]
Sent: Tuesday, February 13, 2007 9:02 AM
To: Nmusers (E-mail); [EMAIL PROTECTED]
Subject: RE: [NMusers] Simultaneous drug and metabolite POPPK
I have a question for those who submitted these two examples -
Did you transform the data into micromolar quantities? It is not clear
from the examples. I have not done much parent/metabolite modeling (just
lucky I guess) but it seems to me that one would have to work in molar
units for these models to be valid. Can someone comment on this?
Mike
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
Michael J. Fossler, Pharm. D., Ph. D., F.C.P.
Director
Clinical Pharmacokinetics, Modeling & Simulation
GlaxoSmithKline
(610) 270 - 4797
FAX: (610) 270-5962
Cell: (443) 350-1194
[EMAIL PROTECTED]
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
Alternatively, you can express the metabolites in microgram-equivalents of
the parent
Quoted reply history
-----Original Message-----
From: [EMAIL PROTECTED] [mailto:[EMAIL PROTECTED] On
Behalf Of [EMAIL PROTECTED]
Sent: Tuesday, February 13, 2007 15:02
To: Nmusers (E-mail); [EMAIL PROTECTED]
Subject: RE: [NMusers] Simultaneous drug and metabolite POPPK
I have a question for those who submitted these two examples - Did you
transform the data into micromolar quantities? It is not clear from the
examples. I have not done much parent/metabolite modeling (just lucky I
guess) but it seems to me that one would have to work in molar units for
these models to be valid. Can someone comment on this?
Mike
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
Michael J. Fossler, Pharm. D., Ph. D., F.C.P.
Director
Clinical Pharmacokinetics, Modeling & Simulation
GlaxoSmithKline
(610) 270 - 4797
FAX: (610) 270-5962
Cell: (443) 350-1194
[EMAIL PROTECTED]
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
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I just performed this kind of population analysis (with pdx-MC-PEM , not
NONMEM) and there was no problem. In fact I never changed the units that
were in ng/ml for both the drug parent and 7 metabolites. I think (I can
be wrong of course) that the model parameters take care of everything
automatically. The model parameters will have the units that include the
conversion needed (from ng to nanmoles).
Serge Guzy
President, CEO; POP-PHARM, Inc.
_____
Quoted reply history
From: [EMAIL PROTECTED] [mailto:[EMAIL PROTECTED]
On Behalf Of Xiao, Alan
Sent: Tuesday, February 13, 2007 6:49 AM
To: [EMAIL PROTECTED]; Nmusers (E-mail);
[EMAIL PROTECTED]
Subject: RE: [NMusers] Simultaneous drug and metabolite POPPK
I think the easiest and least confusing way is to transform all
concentrations into molar units in your data sets at the beginning when
you model parent and metabolites simultaneously. However, there are
other options to go around this issue. For example, you can also
incorporate molecular weights into your model if you have to use weight
concentrations in your data set for some reason.
Alan
-----Original Message-----
From: [EMAIL PROTECTED]
[mailto:[EMAIL PROTECTED] Behalf Of
[EMAIL PROTECTED]
Sent: Tuesday, February 13, 2007 9:02 AM
To: Nmusers (E-mail); [EMAIL PROTECTED]
Subject: RE: [NMusers] Simultaneous drug and metabolite POPPK
I have a question for those who submitted these two examples -
Did you transform the data into micromolar quantities? It is not clear
from the examples. I have not done much parent/metabolite modeling (just
lucky I guess) but it seems to me that one would have to work in molar
units for these models to be valid. Can someone comment on this?
Mike
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
Michael J. Fossler, Pharm. D., Ph. D., F.C.P.
Director
Clinical Pharmacokinetics, Modeling & Simulation
GlaxoSmithKline
(610) 270 - 4797
FAX: (610) 270-5962
Cell: (443) 350-1194
[EMAIL PROTECTED]
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
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The information contained in this email message may contain confidential or
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views of XOMA.
Alan,
I am afraid that you didnt read my code carefully enough. Actually, Eqs 1-3
are talking about the SAME thing, ie, metabolite rate. I started out with the
full data, i.e., with IV info available (Eq1), then, tried to illustrate the
issue when IV data is not available (Eq2) and finally, show how this can be
coded in NONMEM in view of the constraint in order to fit the data (Eq3).
All I tried to say is that there are many other identifiability issues can NOT
be addressed with this type of data by modeling (i.e., model P and Met when
only P is administrated, and more than one metabs are formed). Given this fact,
conversion to molar unit becomes less critical (although it is a good
practice). One should be always cautious when interpret the parameter obtained
on its physiological meaning (even if you have concerted to molar unit).
Jun
Quoted reply history
-----Original Message-----
From: Xiao, Alan [mailto:[EMAIL PROTECTED]
Sent: Tue 2/13/2007 5:22 PM
To: Shi, Jun; [EMAIL PROTECTED]; Nmusers (E-mail); [EMAIL PROTECTED]
Subject: RE: [NMusers] Simultaneous drug and metabolite POPPK
Hmm,
I wonder how you write the mass balance equation for the parent and how to
define parameter KMP. If you use the same term KMP(iv)*A(2) in both equations
for the parent [DADT(2)=...-KMP(iv)*A(2)] and the metabolite (DADT(3)=...],
then this same term have different physical meaning in two equations if weight
concentrations are used. I think you don't want to use the same term to
represent two different things (and two different quantities) in your mass
balance equations although you may still get fitting perfect.
In addition, for simultaneously modeling parent/metabolite data, yes, if you
don't have iv data for metabolite, you can not get a unique set of parameter
estimates for metabolites because of overparameterization. However, if you have
prior information about metabolic ratios, you can fix that into your model,
such as Kel_met_parent / Kel_tot_parent=R (e.g. 0.5), where Kel_met_parent is
elimination rate constant of the parent through metabolism of interest and
Kel_tot_parent is the total elimination rate constant of the parent, so R is
called metabolic ratio. Once this ratio is available, volume of distribution
for metabolites are estimable if data is informative.
They might be other options to handle the issue as well.
Alan
-----Original Message-----
From: [EMAIL PROTECTED] [mailto:[EMAIL PROTECTED] Behalf Of Shi, Jun
Sent: Tuesday, February 13, 2007 10:50 AM
To: [EMAIL PROTECTED]; Nmusers (E-mail); [EMAIL PROTECTED]
Subject: RE: [NMusers] Simultaneous drug and metabolite POPPK
Mike,
This depends on the purpose of the modeling and the information available.
Usually, we only have Parent and Met concentration data after oral
administration, therefore, we can't estimate the true disposition parameters.
We can get CL/F and V/F for parent, but we can get nothing more than apparent
Production rate constant and Elimination rate constant for Met. In this case,
converting the data to micromolar unit or not is not critical.
e.g.
Let's begin from the differential equation below:
DADT(3)=KMP(iv)*A(2)-KME*A(3)
Eq 1
where A(2) is the amount of parent (mg), A(3) is the amount of metabolite (mg).
KmP is the production rate of the metabolite.
Because the distribution volume of Met (V3) is unobtainable (no IV data of
Met), we have to convert dA/dt to dC/dt and divide both sides of Eq 1 by V3 as
follows:
DADT(3)/V3=KMP(iv)*A(2)/V3-KME*A(3)/V3 Eq 2
In NONMEM, we coded this as follows:
DADT(3)=KMP *A(2)/V2-KME*A(3)
Eq 3
Please note that DADT(3) in Eq 3, actually, is dC3/dt (a rate of concentration
instead of amount), and KMP in Eq 3 = KMP(iv) x V2/V3 in Eq 1. In other words,
KMP is a composite parameter of both volumn ratio and molecular weight ratio.
If there are IV data for both parent and metabolite after administrations of
parent and metabolite seperately, the true disposition parameters can be
estimated for both. By converting the concentration unit to molar, we can
estimate formation fraction of parent to metabolite.
Jun Shi
Clinical Pharmacology and Drug Dynamics
Forest Research Institute
Rm18-35
Harborside Financial Center-Plaza V
Jersey City, NJ 07311
Tel: 201-427-8044
Fax: 201-427-8498
Email: [EMAIL PROTECTED]
-----Original Message-----
From: [EMAIL PROTECTED] [mailto:[EMAIL PROTECTED] On Behalf Of [EMAIL PROTECTED]
Sent: Tuesday, February 13, 2007 9:02 AM
To: Nmusers (E-mail); [EMAIL PROTECTED]
Subject: RE: [NMusers] Simultaneous drug and metabolite POPPK
I have a question for those who submitted these two examples - Did you
transform the data into micromolar quantities? It is not clear from the
examples. I have not done much parent/metabolite modeling (just lucky I guess)
but it seems to me that one would have to work in molar units for these models
to be valid. Can someone comment on this?
Mike
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
Michael J. Fossler, Pharm. D., Ph. D., F.C.P.
Director
Clinical Pharmacokinetics, Modeling & Simulation
GlaxoSmithKline
(610) 270 - 4797
FAX: (610) 270-5962
Cell: (443) 350-1194
[EMAIL PROTECTED]
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
I think this is the central point ( and the reason I brought it up): you
may have a very good fit to the data, but the parameters could be
completely meaningless. Although occasionally that may not matter, I
would worry about the validity of any extrapolation I did with a model
whose parameters did not have a biological meaning. If we did not care
about the biology, we could just fits splines to the data and take the
rest of the day off...
Mike
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
Michael J. Fossler, Pharm. D., Ph. D., F.C.P.
Director
Clinical Pharmacokinetics, Modeling & Simulation
GlaxoSmithKline
(610) 270 - 4797
FAX: (610) 270-5962
Cell: (443) 350-1194
[EMAIL PROTECTED]
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
"Shi, Jun" <[EMAIL PROTECTED]>
Sent by: [EMAIL PROTECTED]
14-Feb-2007 12:18
To
"Xiao, Alan" <[EMAIL PROTECTED]>, [EMAIL PROTECTED],
"Nmusers (E-mail)" <[email protected]>, [EMAIL PROTECTED]
cc
"Shi, Jun" <[EMAIL PROTECTED]>
Subject
RE: [NMusers] Simultaneous drug and metabolite POPPK
Alan,
Let's make sure what we agree and what we don't agree. Frankly, I am not
clear where we disagree (until I saw your poster).
O.K., let's do conversion of concentration of P and Mets to molar unit
(this makes chemical sense ? we agreed), and fix Vd of met to be 1 (this
is the trick in coding, but couldn?t resolve the fundamental issue of
lacking of info?we agreed).
What we may have talked differently is the definition of KMP, which is not
the K12 in your poster. In the model I am referring to, KMP is
?disconnected? from any of k for parent. In the real world, parent does
not only form one metab, metab does not always behave in formation rate
being the rate limiting, and metab does not always sequentially formed
from one to another? Your model appeared to simply some of the real world
issues ? it is fine when your data gives the justifications.
As we both know there are many unidentifiable factors in modeling P and
Metab simultaneously (F, Fm, Vd?), I hope that you could agree with me
that one should always be cautious when interpret parameter obtained from
such a model (i.e., modeling P and Met after oral administration of P) on
its physiological meaning. The key issue to me here, is that whether the
model offers good predictivity and under what underlying conditions.
Jun
Quoted reply history
-----Original Message-----
From: Xiao, Alan [mailto:[EMAIL PROTECTED]
Sent: Wed 2/14/2007 9:31 AM
To: Shi, Jun; [EMAIL PROTECTED]; Nmusers (E-mail);
[EMAIL PROTECTED]
Subject: RE: [NMusers] Simultaneous drug and metabolite POPPK
I know your Equs 1-3 are talking the SAME thing since they are all about
the metabolite. But my question is the physical meaning of the term in the
equation for the parent (which you did not show) and in the equation for
the metabolite. After a closer look to your equations below, I have a
question related to the fundamental science - chemistry. That is, your KMP
term in the mass balance differential equations for the metabolite refers
to the mass (production) rate of the metabolite. The same term in the
equation for the parent refers to the mass (elimination) rate of the
parent (to the metabolite). Unless the metabolite and the parent have
exactly the same molecular weight (MW), these two mass rates that this
same term refers to are different. That's the fundamental chemistry behind
the discussion about whether or not concentrations should be in molar
units. Or you have to use molecular weight to correct the parameter
estimates after modeling if you have to use weight concentration units as
Serge mentioned in another email. Based on the equations below, I think
you'll have to re-define/interpret your parameter in a way different from
what is normally taught in class.
By the way, in equation 3 below, it is equivalent to fix V3=1, which I
don't think can really resolve the overparameterization problem. The
following poster in the 2002 ASCPT meeting might be able to help a little
on this. Also, can you give the steps to derive how volume ratios become a
part of KMP?
Thanks,
Alan
-----Original Message-----
From: Shi, Jun [mailto:[EMAIL PROTECTED]
Sent: Tuesday, February 13, 2007 8:09 PM
To: Xiao, Alan; [EMAIL PROTECTED]; Nmusers (E-mail);
[EMAIL PROTECTED]
Subject: RE: [NMusers] Simultaneous drug and metabolite POPPK
Alan,
I am afraid that you didn't read my code carefully enough. Actually, Eqs
1-3 are talking about the SAME thing, ie, metabolite rate. I started out
with the full data, i.e., with IV info available (Eq1), then, tried to
illustrate the issue when IV data is not available (Eq2) and finally, show
how this can be coded in NONMEM in view of the constraint in order to fit
the data (Eq3).
All I tried to say is that there are many other identifiability issues can
NOT be addressed with this type of data by modeling (i.e., model P and Met
when only P is administrated, and more than one metabs are formed). Given
this fact, conversion to molar unit becomes less critical (although it is
a good practice). One should be always cautious when interpret the
parameter obtained on its physiological meaning (even if you have
concerted to molar unit).
Jun
-----Original Message-----
From: Xiao, Alan [ mailto:[EMAIL PROTECTED]
Sent: Tue 2/13/2007 5:22 PM
To: Shi, Jun; [EMAIL PROTECTED]; Nmusers (E-mail);
[EMAIL PROTECTED]
Subject: RE: [NMusers] Simultaneous drug and metabolite POPPK
Hmm,
I wonder how you write the mass balance equation for the parent and how to
define parameter KMP. If you use the same term KMP(iv)*A(2) in both
equations for the parent [DADT(2)=...-KMP(iv)*A(2)] and the metabolite
(DADT(3)=...], then this same term have different physical meaning in two
equations if weight concentrations are used. I think you don't want to use
the same term to represent two different things (and two different
quantities) in your mass balance equations although you may still get
fitting perfect.
In addition, for simultaneously modeling parent/metabolite data, yes, if
you don't have iv data for metabolite, you can not get a unique set of
parameter estimates for metabolites because of overparameterization.
However, if you have prior information about metabolic ratios, you can fix
that into your model, such as Kel_met_parent / Kel_tot_parent=R (e.g.
0.5), where Kel_met_parent is elimination rate constant of the parent
through metabolism of interest and Kel_tot_parent is the total elimination
rate constant of the parent, so R is called metabolic ratio. Once this
ratio is available, volume of distribution for metabolites are estimable
if data is informative.
They might be other options to handle the issue as well.
Alan
-----Original Message-----
From: [EMAIL PROTECTED] [ mailto:[EMAIL PROTECTED]
]On Behalf Of Shi, Jun
Sent: Tuesday, February 13, 2007 10:50 AM
To: [EMAIL PROTECTED]; Nmusers (E-mail);
[EMAIL PROTECTED]
Subject: RE: [NMusers] Simultaneous drug and metabolite POPPK
Mike,
This depends on the purpose of the modeling and the information available.
Usually, we only have Parent and Met concentration data after oral
administration, therefore, we can't estimate the true disposition
parameters. We can get CL/F and V/F for parent, but we can get nothing
more than apparent Production rate constant and Elimination rate constant
for Met. In this case, converting the data to micromolar unit or not is
not critical.
e.g.
Let's begin from the differential equation below:
DADT(3)=KMP(iv)*A(2)-KME*A(3) Eq 1
where A(2) is the amount of parent (mg), A(3) is the amount of metabolite
(mg). KmP is the production rate of the metabolite.
Because the distribution volume of Met (V3) is unobtainable (no IV data of
Met), we have to convert dA/dt to dC/dt and divide both sides of Eq 1 by
V3 as follows:
DADT(3)/V3=KMP(iv)*A(2)/V3-KME*A(3)/V3 Eq 2
In NONMEM, we coded this as follows:
DADT(3)=KMP *A(2)/V2-KME*A(3) Eq 3
Please note that DADT(3) in Eq 3, actually, is dC3/dt (a rate of
concentration instead of amount), and KMP in Eq 3 = KMP(iv) x V2/V3 in Eq
1. In other words, KMP is a composite parameter of both volumn ratio and
molecular weight ratio.
If there are IV data for both parent and metabolite after administrations
of parent and metabolite seperately, the true disposition parameters can
be estimated for both. By converting the concentration unit to molar, we
can estimate formation fraction of parent to metabolite.
Jun Shi
Clinical Pharmacology and Drug Dynamics
Forest Research Institute
Rm18-35
Harborside Financial Center-Plaza V
Jersey City, NJ 07311
Tel: 201-427-8044
Fax: 201-427-8498
Email: [EMAIL PROTECTED]
-----Original Message-----
From: [EMAIL PROTECTED] [ mailto:[EMAIL PROTECTED]
On Behalf Of [EMAIL PROTECTED]
Sent: Tuesday, February 13, 2007 9:02 AM
To: Nmusers (E-mail); [EMAIL PROTECTED]
Subject: RE: [NMusers] Simultaneous drug and metabolite POPPK
I have a question for those who submitted these two examples - Did you
transform the data into micromolar quantities? It is not clear from the
examples. I have not done much parent/metabolite modeling (just lucky I
guess) but it seems to me that one would have to work in molar units for
these models to be valid. Can someone comment on this?
Mike
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
Michael J. Fossler, Pharm. D., Ph. D., F.C.P.
Director
Clinical Pharmacokinetics, Modeling & Simulation
GlaxoSmithKline
(610) 270 - 4797
FAX: (610) 270-5962
Cell: (443) 350-1194
[EMAIL PROTECTED]
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
I think we are actually along the same line overall. What we got into below are
some technical trivials, although very fundamental. For the model used in the
poster, it is simplified, trying to show what's the problem and how it could be
handled rather than intending to mimic all possibilities in reality, as you can
understand.
Alan
Quoted reply history
-----Original Message-----
From: Shi, Jun [mailto:[EMAIL PROTECTED]
Sent: Wednesday, February 14, 2007 12:19 PM
To: Xiao, Alan; [EMAIL PROTECTED]; Nmusers (E-mail); [EMAIL PROTECTED]
Cc: Shi, Jun
Subject: RE: [NMusers] Simultaneous drug and metabolite POPPK
Alan,
Let's make sure what we agree and what we don't agree. Frankly, I am not clear
where we disagree (until I saw your poster).
O.K., let's do conversion of concentration of P and Mets to molar unit (this
makes chemical sense - we agreed), and fix Vd of met to be 1 (this is the trick
in coding, but couldn't resolve the fundamental issue of lacking of info-we
agreed).
What we may have talked differently is the definition of KMP, which is not the
K12 in your poster. In the model I am referring to, KMP is "disconnected" from
any of k for parent. In the real world, parent does not only form one metab,
metab does not always behave in formation rate being the rate limiting, and
metab does not always sequentially formed from one to another... Your model
appeared to simply some of the real world issues - it is fine when your data
gives the justifications.
As we both know there are many unidentifiable factors in modeling P and Metab
simultaneously (F, Fm, Vd...), I hope that you could agree with me that one
should always be cautious when interpret parameter obtained from such a model
(i.e., modeling P and Met after oral administration of P) on its physiological
meaning. The key issue to me here, is that whether the model offers good
predictivity and under what underlying conditions.
Jun
-----Original Message-----
From: Xiao, Alan [ mailto:[EMAIL PROTECTED]
Sent: Wed 2/14/2007 9:31 AM
To: Shi, Jun; [EMAIL PROTECTED]; Nmusers (E-mail); [EMAIL PROTECTED]
Subject: RE: [NMusers] Simultaneous drug and metabolite POPPK
I know your Equs 1-3 are talking the SAME thing since they are all about the
metabolite. But my question is the physical meaning of the term in the equation
for the parent (which you did not show) and in the equation for the metabolite.
After a closer look to your equations below, I have a question related to the
fundamental science - chemistry. That is, your KMP term in the mass balance
differential equations for the metabolite refers to the mass (production) rate
of the metabolite. The same term in the equation for the parent refers to the
mass (elimination) rate of the parent (to the metabolite). Unless the
metabolite and the parent have exactly the same molecular weight (MW), these
two mass rates that this same term refers to are different. That's the
fundamental chemistry behind the discussion about whether or not concentrations
should be in molar units. Or you have to use molecular weight to correct the
parameter estimates after modeling if you have to use weight concentration
units as Serge mentioned in another email. Based on the equations below, I
think you'll have to re-define/interpret your parameter in a way different from
what is normally taught in class.
By the way, in equation 3 below, it is equivalent to fix V3=1, which I don't
think can really resolve the overparameterization problem. The following poster
in the 2002 ASCPT meeting might be able to help a little on this. Also, can you
give the steps to derive how volume ratios become a part of KMP?
Thanks,
Alan
-----Original Message-----
From: Shi, Jun [ mailto:[EMAIL PROTECTED]
Sent: Tuesday, February 13, 2007 8:09 PM
To: Xiao, Alan; [EMAIL PROTECTED]; Nmusers (E-mail); [EMAIL PROTECTED]
Subject: RE: [NMusers] Simultaneous drug and metabolite POPPK
Alan,
I am afraid that you didn't read my code carefully enough. Actually, Eqs 1-3
are talking about the SAME thing, ie, metabolite rate. I started out with the
full data, i.e., with IV info available (Eq1), then, tried to illustrate the
issue when IV data is not available (Eq2) and finally, show how this can be
coded in NONMEM in view of the constraint in order to fit the data (Eq3).
All I tried to say is that there are many other identifiability issues can NOT
be addressed with this type of data by modeling (i.e., model P and Met when
only P is administrated, and more than one metabs are formed). Given this fact,
conversion to molar unit becomes less critical (although it is a good
practice). One should be always cautious when interpret the parameter obtained
on its physiological meaning (even if you have concerted to molar unit).
Jun
-----Original Message-----
From: Xiao, Alan [ mailto:[EMAIL PROTECTED]
Sent: Tue 2/13/2007 5:22 PM
To: Shi, Jun; [EMAIL PROTECTED]; Nmusers (E-mail); [EMAIL PROTECTED]
Subject: RE: [NMusers] Simultaneous drug and metabolite POPPK
Hmm,
I wonder how you write the mass balance equation for the parent and how to
define parameter KMP. If you use the same term KMP(iv)*A(2) in both equations
for the parent [DADT(2)=...-KMP(iv)*A(2)] and the metabolite (DADT(3)=...],
then this same term have different physical meaning in two equations if weight
concentrations are used. I think you don't want to use the same term to
represent two different things (and two different quantities) in your mass
balance equations although you may still get fitting perfect.
In addition, for simultaneously modeling parent/metabolite data, yes, if you
don't have iv data for metabolite, you can not get a unique set of parameter
estimates for metabolites because of overparameterization. However, if you have
prior information about metabolic ratios, you can fix that into your model,
such as Kel_met_parent / Kel_tot_parent=R (e.g. 0.5), where Kel_met_parent is
elimination rate constant of the parent through metabolism of interest and
Kel_tot_parent is the total elimination rate constant of the parent, so R is
called metabolic ratio. Once this ratio is available, volume of distribution
for metabolites are estimable if data is informative.
They might be other options to handle the issue as well.
Alan
-----Original Message-----
From: [EMAIL PROTECTED] [ mailto:[EMAIL PROTECTED] Behalf Of Shi, Jun
Sent: Tuesday, February 13, 2007 10:50 AM
To: [EMAIL PROTECTED]; Nmusers (E-mail); [EMAIL PROTECTED]
Subject: RE: [NMusers] Simultaneous drug and metabolite POPPK
Mike,
This depends on the purpose of the modeling and the information available.
Usually, we only have Parent and Met concentration data after oral
administration, therefore, we can't estimate the true disposition parameters.
We can get CL/F and V/F for parent, but we can get nothing more than apparent
Production rate constant and Elimination rate constant for Met. In this case,
converting the data to micromolar unit or not is not critical.
e.g.
Let's begin from the differential equation below:
DADT(3)=KMP(iv)*A(2)-KME*A(3)
Eq 1
where A(2) is the amount of parent (mg), A(3) is the amount of metabolite (mg).
KmP is the production rate of the metabolite.
Because the distribution volume of Met (V3) is unobtainable (no IV data of
Met), we have to convert dA/dt to dC/dt and divide both sides of Eq 1 by V3 as
follows:
DADT(3)/V3=KMP(iv)*A(2)/V3-KME*A(3)/V3 Eq 2
In NONMEM, we coded this as follows:
DADT(3)=KMP *A(2)/V2-KME*A(3)
Eq 3
Please note that DADT(3) in Eq 3, actually, is dC3/dt (a rate of concentration
instead of amount), and KMP in Eq 3 = KMP(iv) x V2/V3 in Eq 1. In other words,
KMP is a composite parameter of both volumn ratio and molecular weight ratio.
If there are IV data for both parent and metabolite after administrations of
parent and metabolite seperately, the true disposition parameters can be
estimated for both. By converting the concentration unit to molar, we can
estimate formation fraction of parent to metabolite.
Jun Shi
Clinical Pharmacology and Drug Dynamics
Forest Research Institute
Rm18-35
Harborside Financial Center-Plaza V
Jersey City, NJ 07311
Tel: 201-427-8044
Fax: 201-427-8498
Email: [EMAIL PROTECTED]
-----Original Message-----
From: [EMAIL PROTECTED] [ mailto:[EMAIL PROTECTED] On Behalf Of [EMAIL
PROTECTED]
Sent: Tuesday, February 13, 2007 9:02 AM
To: Nmusers (E-mail); [EMAIL PROTECTED]
Subject: RE: [NMusers] Simultaneous drug and metabolite POPPK
I have a question for those who submitted these two examples - Did you
transform the data into micromolar quantities? It is not clear from the
examples. I have not done much parent/metabolite modeling (just lucky I guess)
but it seems to me that one would have to work in molar units for these models
to be valid. Can someone comment on this?
Mike
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
Michael J. Fossler, Pharm. D., Ph. D., F.C.P.
Director
Clinical Pharmacokinetics, Modeling & Simulation
GlaxoSmithKline
(610) 270 - 4797
FAX: (610) 270-5962
Cell: (443) 350-1194
[EMAIL PROTECTED]
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