Thank you Nick.
We see the advantage and disadvantages this approach clear and
understand the difference between the modeling and the curve fitting
exercise. On the other hand, out motto is to keep an open mind and to
keep trying. There are scenarios where the approach may work and where
it will not work. In any case, it is useful to study it and keep it in
the library even if it is classified as a rare case.
It is easier to provide critique than to suggest something
constructive. Lets phrase Leonid for doing the constructive part and
being innovative. Lets thank Robert for providing the algorithm!
Take care,
Pavel
On Thu, Jan 16, 2014 at 07:48 PM, Nick Holford wrote:
Pavel,
Unless your drug is an alkylating agent the use of AUC will always be
mechanistically wrong.
I hope you also considered the possibility of disease progression (i.e.
changing baseline) and also the possibility of changing C50 due to
potentiation or physiological changes.
Nick
On 17/01/2014 1:29 p.m., lgibian...@quantpharm.com
<mailto:lgibian...@quantpharm.com> wrote:
Hi Pavel,
You mentioned that the effect compartment did not help, and the model I
suggested is identical to the effect compartment. May be try something
like
transit compartment model:
DADT(2)=C-K0*A(2)
DADT(3)=K0*A(2)-K0*A(3)
...
DADT(X)=K0*A(X-1)-K0*A(X)
AUCapprox=A(2)+...+A(X)
This will prolong the shape of AUCapprox(t). It could be a bit simpler
and
smoother than tlag implementation
Leonid
Original email:
-----------------
From: Pavel Belo non...@optonline.net <mailto:non...@optonline.net>
Date: Thu, 16 Jan 2014 13:05:54 -0500 (EST)
To: lgibian...@quantpharm.com <mailto:lgibian...@quantpharm.com> ,
nmusers@globomaxnm.com <mailto:nmusers@globomaxnm.com>
Subject: RE: [NMusers] backward integration from t-a to t
Hello Leonid,
Thank you bein helpful. You got the main point. AUC is a better
predictor than concentration, but it has to disppear very slowly but
surely.
A potential challenge is biological meaning of this approach. It will
be necessary to explain it to the biologists, who ask question like "Why
do you use 2 compartment in PK model while human body has so many
compartments?".
We will see!
Thanks,
Pavel
On Wed, Jan 15, 2014 at 01:19 AM, lgibian...@quantpharm.com
<mailto:lgibian...@quantpharm.com> wrote:
Pavel,
I think one can use equation
DADT(2)=C-K0*A(2)
where C is the drug concentration. When K0=0, A2 is cumulative AUC.
When
k0>0, A2 would represent something like AUC for the interval prior to
the current
time
The length of the interval would be proportional to 1/K0 (and equal to
infinity when k0=0). Conceptually, K0 is the rate of "AUC elimination"
from the
system. PD then can be made dependent on A2, and the model would
select optimal
value of K0. One interesting case to understand the concept is when C
is constant.
Then A2=C/K0 while AUC over some interval TAU is AUC=C*TAU. So
roughly, A2 can
be interpreted as AUC over the interval of 1/K0. Leonid
Original email:
-----------------
From: Pavel Belo non...@optonline.net <mailto:non...@optonline.net>
Date: Tue, 14 Jan 2014 13:45:18 -0500 (EST)
To: robert.ba...@iconplc.com <mailto:robert.ba...@iconplc.com> ,
nmusers@globomaxnm.com <mailto:nmusers@globomaxnm.com>
Subject: [NMusers] backward integration from t-a to t
Dear Robert,
Ã,
Efficacy isÃ, frequently considered aÃ, function of AUC.Ã, (AUC is just
an integral. It is obvious how to calculate AUC any software which can
solve ODE.)Ã, A disadvantage of this model of efficacyÃ, is that the
effect is irreversable becauseÃ, AUC of concentration can only
increase;Ã, it cannot decrease.Ã, In many cases, a more meaningful model
is a model where AUC is calculated form time tÃ, -a to t (kind of
"moving average"), where t is timeÃ, in the system of differential
equations (variable T in NONMEM).Ã, Ã, There are 2 obvious ways to
calculate AUC(t-a, t).Ã, The first is to do backward integration, which
looks like a hard and resource consuming way for NONMEM.Ã, The second
one is to keep in memory AUC for all time pointsÃ, usedÃ, during theÃ,
integrationÃ, and calculate AUC(t-a,t) as AUC(t) - AUC(t-a), there
AUC(t-a) can be interpolated using two closest time points below and
above t-a.Ã,
Ã,
Is there a way toÃ, access AUC forÃ, the past time points (> integration
routine?Ã, It seems like an easyÃ, thing to do.Ã, Ã, Ã,
Ã,
Kind regards,
PavelÃ, Ã,
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Nick Holford, Professor Clinical Pharmacology
Dept Pharmacology & Clinical Pharmacology, Bldg 503 Room 302A
University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand
office:+64(9)923-6730 mobile:NZ +64(21)46 23 53
email: n.holf...@auckland.ac.nz <mailto:n.holf...@auckland.ac.nz>
http://holford.fmhs.auckland.ac.nz/
<http://holford.fmhs.auckland.ac.nz/>
Holford NHG. Disease progression and neuroscience. Journal of
Pharmacokinetics and Pharmacodynamics. 2013;40:369-76
http://link.springer.com/article/10.1007/s10928-013-9316-2
<http://link.springer.com/article/10.1007/s10928-013-9316-2>
Holford N, Heo Y-A, Anderson B. A pharmacokinetic standard for babies
and adults. J Pharm Sci. 2013:
http://onlinelibrary.wiley.com/doi/10.1002/jps.23574/abstract
<http://onlinelibrary.wiley.com/doi/10.1002/jps.23574/abstract>
Holford N. A time to event tutorial for pharmacometricians. CPT:PSP.
2013;2: http://www.nature.com/psp/journal/v2/n5/full/psp201318a.html
<http://www.nature.com/psp/journal/v2/n5/full/psp201318a.html>
Holford NHG. Clinical pharmacology = disease progression + drug action.
British Journal of Clinical Pharmacology. 2013:
http://onlinelibrary.wiley.com/doi/10.1111/bcp.12170/abstract
<http://onlinelibrary.wiley.com/doi/10.1111/bcp.12170/abstract>
