RE: [NMusers] Absorption

Dear,
I may be missing something here. If the data is dose proportional for
Cmax and AUC, why are you trying to fit a nonlinear model in ka and/or
F?
If you have much higher variability (higher CV%) at the higher doses,
then I would try using a different eta for the higher doses.
 
A saturable first pass model will mean a nonlinear (higher than expected
concentrations/exposures) at larger doses. If your data says that you do
not have higher than dose proportional Cmax and AUC, I don't see why you
would think there is a satruable first pass?
Malaz

 
 -----Original Message-----
From: owner-nmusers_at_globomaxnm.com [mailto:owner-nmusers_at_globomaxnm.com]
On Behalf Of Adithya Muralidharan
Sent: Tuesday, September 04, 2007 3:26 PM
To: justin.wilkins_at_novartis.com; nmusers_at_globomaxnm.com
Subject: Re: [NMusers] Absorption



        Dear Justin,
         
        I did look into dose normalized concentrations-time curve and i
do not see any nonlinearity in PK except for a couple of subjects who
appear to be outliers. I did try to run transit model with FOCE in NM6
but it runs for a long time and results in terminated message. I did
look into Rada's previous abstarct and tried to use it for single dose
but had no luck. I have around 8 observations in the absorption phase
and 6 in the elimination phase.I have mailed you the code i used for my
model
         
        Dear Malaz,
         
        Thanks for your tips, i did look into the dose linearity early
on the drug appears to be dose proportional on both AUC and Cmax. There
is definitely a shift in Tmax from 1 hour in lower doses to 6 hours in
higher doses but this drug has low solubility so i assumed that this was
inherent characteristic of the drug so i used a combination Zero-First
order model to address this issue but that was not good enough.
         
        At higher doses i have 3 subjects who have much higher
concentrations leading to Cmax unlike other subjects in the same dose
group. I tried to remove these three subjects to see whether they were
impacting the model but it appears that they have no effect on the
model.
         
        I tried fixing volume but even that doesnot answer the anomaly
of the model at higher doses.
         
        This drug is a 3A4 substrate so i am assuming that may be there
is a saturable first pass effect observed at higher doses. In trying to
address this i used a dose varying absorption model as
KA=KAMAX*DOSE/KA(50)+DOSE. when i run with this NONMEM returns to me the
same set of intial conditions in other words the same intial condition
value is returned as final estimate.
         
        Could anyone please advice on how to model saturable first pass
effect.
         
        Thanks to all
        Adithya
         


         
        On 9/4/07, justin.wilkins_at_novartis.com
<justin.wilkins_at_novartis.com > wrote:


                Dear Adithya,
                
                Your problem has attracted some good advice from the
list, but if you are still interested in trying out the transit model,
perhaps we could help, if you were able to furnish some more details
about what exactly went wrong with your implementation of it in NONMEM V
- posted code snippets and precise error messages would be of particular
use.
                
                It ought to be possible to make it work under NMV,
although the richer the data, the better, and NMV is known to be less
robust at working with differential equations than NMVI. Problems can
often be resolved with some minor tweaking, given sufficient information
in the data to support the model - how many observations per individual
are you working with, and how well covered is the absorption phase? You
might also try hard-coding the transit compartments, i.e. not estimating
the number as a model parameter, but fixing it to different values until
you find an optimum.
                
                You might also want to take a look at some previous work
on the subject, in which the method was established for single dosing:
                
                Savic R, Jonker DM, Kerbusch T, Karlsson MO. PAGE 13
(2004) Abstr 513 [ www.page-meeting.org/?abstract=513
<http://www.page-meeting.org/?abstract=513> ]
                
                Have you tried normalizing the concentrations by dose
and plotting them on the same axes? That should give you information
with respect to whether you have any dose-related nonlinearity - if the
curves for each dose levels are roughly superimposed, kinetics are
linear, and if not, the relative positions of the curves should provide
some useful clues about what is going on.
                
                Best regards
                Justin
                
Justin Wilkins
Novartis Pharma AG
PH346, MODELING & SIMULATION
CHBS, WSJ-027.1.084
Novartis Pharma AG
Lichtstrasse 35
CH-4056 Basel
Switzerland
Phone: +41 61 324 6549
Fax: +41 61 324 3039
Mobile: +41 76 561 0949
Email : justin.wilkins_at_novartis.com <mailto:justin.wilkins_at_novartis.com>





"Adithya Muralidharan" < adithya.kandadai_at_gmail.com
<mailto:adithya.kandadai_at_gmail.com> >
Sent by: owner-nmusers_at_globomaxnm.com

03.09.2007 19:10

To
nmusers_at_globomaxnm.com
cc
Subject
[NMusers] Absorption

                


                
                
                
                Dear nmusers,
                
                I am working on a rising single dose study, with 5
cohorts (10, 25,
                50, 100 and 200 mg dose groups). This is a oral drug.
There are a
                total of 45 subjects in the study, 9 subjects in each
cohort.
                
                The data fits well to a two compartment model, but at
higher doses 100
                and 200mg dose groups the concentrations leading to Cmax
is
                overpredicted significantly that the model seems to be
completely
                ineffecient in explaining the absorption phase at higher
doses.
                
                I have tried using a
                
                Mixture model assuming that there is a sub population
with a totally
                different absorption, this seemed to work but visual
predictive check
                failed.
                
                Used a cobination zero and first order absorption model
which couldn't
                fix the issue at higher doses
                
                Transit compartment model (A flexible approach to
modeling variable
                absorption in the context of repeated dosing:
illustrated with
                rifampicin, J. Wilkins, Page 2007). This approach did
not work with
                NONMEM V.
                
                i assumed that the drug at higher doses has saturable
absorption but
                even that does not help much.
                
                Can someone please comment on this.
                
                Thanks
                Adithya
                
                


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Received on Tue Sep 04 2007 - 16:40:35 EDT