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FW: Revisit parameterization question

From: Tsai, Kuenhi <kuenhi_tsai>
Date: Tue, 16 Sep 2008 15:51:29 -0400

Nick,

Thank you SO much for your help. I read your discussion on this issue in
2001. Your and Steve Dullful's helpful reply confirmed me that I should
redo my models now using TRANS4! And I need to think and learn about
other issues (F1, protein binding,..) you mentioned in your email.

One question... Although I believe CL and V is correlated to weight, the
correlation (using MONOMIX) between V1 and weight is < 0.2. Should I
still incorporate weight as a covariate into V1? Also my CL has higher
correlation to height instead weight (0.35 vs. 0.2), shall I use height
instead of weight as a covariate for CL? Do I stick too much on
algebraic results?

I am running models by both NONMEM and MONOLIX. Even I use the same
models (perhaps, since I am not sure whether MONOLIX automatically
incorporates all correlations of thetas in estimation), I get the
different results of estimation. Did you have any experiences on this
issue? Marc gave me some suggestions. I haven't done so yet, but like
to hear your comments.

Thank you very much again for your help.

All the best

Kuenhi

-----Original Message-----
From: Nick Holford [mailto:n.holford
Sent: Monday, September 15, 2008 3:40 PM
To: Tsai, Kuenhi
Subject: Re: [NMusers] Revisit parameterization question

Kuenhi,

Parameterisation is important for intepretation and for estimation and
should be distinguished from the algebraic convenience of performing
some calculation.

Interpretation of parameters is more useful when the parameters can be
related to physiological or pharmacological mechanisms. Parameters
estimated in this way can have their variability explained better by
other covariates e.g. renal function will change clearance of renally
cleared drugs but there is no physiological entity resembling a rate
constant so parameterisation in terms of a rate constants will always
require an empirical application of renal function.

Differences in estimation can sometimes be observed with different
parameterisations because of the dependence on numerical issues related
to such matters as derivatives. But this is only a challenge for better
computer hardware and software and not of fundamental importance.

So my bottom line preference is to parameterise in terms of quantities
that can be mapped to some mechanistic or physical reality. This means
using volumes and clearances for distribution and mass transfer
kinetics.

Note also that one of the most important mechanistic causes for
correlation between CL and V is weight. You should include weight on all

CL, V1, Q and V2 because there is no sensible reason to believe they do
not increase with weight. After that you might add an ETA to F1 in order

to capture other correlations due to between subject variability in
bioavailability and protein binding. I would definitely use TRANS4
always in preference to TRANS1.

Nick


Tsai, Kuenhi wrote:
> Dear All,
>
> I am working on a data set that the estimates become quite different
> under different model assumptions (such as fixed or not fixed ka,
> different block structure) using ADVAN4 TRANS1. One suggests me that
I
> should use TRANS4 to avoid the problem of the high correlations among
> ka, Cl, V, k, and k12. When I reviewed the previous NM user
discussion
> in "reparameterization", the highest "scored" discussion occurred in
> 2001. I am wondering whether there are any updated discussion and
> references on this topic. Any of your help are greatly appreciated.
>
> All the best
>
> Kuenhi Tsai
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--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
n.holford
http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford

Notice: This e-mail message, together with any attachments, contains
information of Merck & Co., Inc. (One Merck Drive, Whitehouse Station,
New Jersey, USA 08889), and/or its affiliates (which may be known
outside the United States as Merck Frosst, Merck Sharp & Dohme or
MSD and in Japan, as Banyu - direct contact information for affiliates is
available at http://www.merck.com/contact/contacts.html) that may be
confidential, proprietary copyrighted and/or legally privileged. It is
intended solely for the use of the individual or entity named on this
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Received on Tue Sep 16 2008 - 15:51:29 EDT

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