Re: Simultaneous drug and metabolite POPPK
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]