RE: Modeling Cmin and Tmin
Dear Friederike,
Below are an example of code for obtaining Cmax and Tmax for a simple PK
model (I know there are analytical solutions for this, it is only intended
as a simple example of a general approach). This can easily be manipulated
to instead obtain Cmin and Tmin with another kind of model (contact me again
if you run into any problems with that). This solution is based on the
addition of two compartments (compartment 3 and 4 in the example) and a
COMRES variable (COM(1)). One important thing to consider is that the
example code only works if the model predicts a single peak (or in your case
a single trough). If the model/design predicts several Cmax (or in your case
Cmin) the code needs to be extended to account for that (requires additional
compartments and COMRES variables). Temporary Cmax and Tmax (Cmin and Tmin)
estimates are outputted in a table file and the individual estimates should
be read for the last row of each individual. A good advise can be to add a
dummy row (EVID = 2) for each individual at a time well past the last
observation for any individual in the dataset and use that for read out.
$ABBREVIATED COMRES=1
$SUBS ADVAN6 TOL=5
$DES
DADT(1) = -KA*A(1) ; Amount in depot compartment
DADT(2) = KA*A(1)-KE*A(2) ; Amount in central compartment
X = KA*A(1)-KE*A(2) ; Derivative for the amount in central
compartment
COM(1)=0
IF(X.GT.0) COM(1)=1 ; A2 increasing
IF(X.EQ.0) COM(1)=2 ; A2 maximum
IF(X.LT.0) COM(1)=3 ; A2 decreasing
IF(COM(1).LT.3)THEN ; Time to Cmax
DADT(3) = 1
ELSE
DADT(3) = 0
ENDIF
IF(COM(1).LT.3)THEN ; Maximum A2
DADT(4) = X
ELSE
DADT(4) = 0
ENDIF
$ERROR
TMAX = A(3)
CMAX = A(4)/V ; Amount divided by the central volume of
distribution => Cmax
$TABLE ID TIME TMAX CMAX ONEHEADER NOPRINT FILE=mytab
; The individual CMAX and TMAX is found on the last row for each individual
in mytab
Kind regards,
Martin Bergstrand
-----------------------------------------------
Pharmacometrics Research Group,
Department of Pharmaceutical Biosciences,
Uppsala University
-----------------------------------------------
<mailto:[email protected]> [email protected]
-----------------------------------------------
Quoted reply history
From: [email protected] [mailto:[email protected]] On
Behalf Of Friederike Kanefendt
Sent: Wednesday, April 06, 2011 3:05 PM
To: Joachim Grevel; [email protected]
Subject: AW: [NMusers] Modeling Cmin and Tmin
Dear Joachim,
thank you for your explanations. My plan was not to determine the typical
value or distribution for this parameters (as THETA or ETA) but to determine
the minimum biomarker concentration for each ID with the appropriate time
for further correlation studies with outcome etc. I tried to use NONMEM to
determine Cmin while individual parameters/profiles are estimated. I read
something in NMusers about Cmax and thought that this is maybe also possible
for Cmin and Tmin
http://www.cognigencorp.com/nonmem/current/2008-January/0733.html
http://www.cognigencorp.com/nonmem/current/2008-January/0733.html
http://www.cognigencorp.com/nonmem/current/2007-December/0716.html
If this is not possible I would try this using simulations and R
Thanks
King regards, Friederike
Von: [email protected] [mailto:[email protected]] Im
Auftrag von Joachim Grevel
Gesendet: Mittwoch, 6. April 2011 11:49
An: Friederike Kanefendt; [email protected]
Betreff: RE: [NMusers] Modeling Cmin and Tmin
Dear Friederike,
Please, step back for one minute and try to understand what you want to find
out: You are applying a nonlinear mixed-effects modelling program to obtain
parameter values for your model. All parameters in your model are random
variables. Some have a mean of zero (ETAs, EPSs) some should have a mean <>
0 (THETAs). Your results are not point estimates but distributions.
Therefore you should approach the question of Cmin and Tmin through
simulation and report the confidence interval (or other stats) for your
parameters of interest. Thus construct a simulation data set with dense
time points around the expected Tmin, and run
$SIMULATION (240311) ONLYSIMULATION SUBPROBLEMS=1000
$TABLE ID TIME ...... NOHEADER NOAPPEND NOPRINT FILE=xxxx.tab
with all your final parameter estimates as initial values in your control
file. Then analyse your 100 (or 1000) simulated data files with R or SAS and
report the distribution of the Cmin and Tmin you found.
Please, come back with more questions in case I have confused you,
Joachim
Joachim Grevel, PhD
Scientific Director
BAST Inc Limited
BioCity Nottingham
Pennyfoot Street
Nottingham, NG1 1GF
Tel: +44 (0)115 8120497
From: [email protected] [mailto:[email protected]] On
Behalf Of Friederike Kanefendt
Sent: 06 April 2011 09:56
To: [email protected]
Subject: [NMusers] Modeling Cmin and Tmin
Dear NMUser,
I am a beginner in NONMEM and I have a question regarding modeling Cmin and
Tmin.
I have data of a biomarker which decreases after drug intake and I want to
determine the minimum change from baseline (Cmin) as well as the
corresponding time (Tmin). I tried different models but the estimated values
for these parameters are not plausible or always zero.
Has someone experience with this or any idea to solve this problem?
Thanks a lot
Best regards
Friederike
Attached I send you a part of my code:
$SUBROUTINE ADVAN6 TOL=3
...
$DES
...
DADT(5) = KIN*INH-KOUT*A(5) ; Biomarker CMT
IF(TIME.EQ.0) THEN
CMIN = BASE ; Baseline conc also
estimated by NM
TMIN=0
ENDIF
CC=A(5)
IF(CC.LT.CMIN) THEN
CMIN= CC
TMIN= T
ENDIF
REL = CMIN/BASE ; change relative to baseline
...
$ESTIMATION SIG=2 PRINT=1 METHOD=1 INTER MAXEVAL=0 NOABORT
Friederike Kanefendt
Pharmacist, PhD-Student
University of Bonn
-Clinical Pharmacy-
An der Immenburg 4
D-53121 Bonn
Phone: +49 (0)228 73-5781
Fax: +49(0) 228 73-9757
[email protected]