Dear Yuan,
it is good to hear that the article was useful. The model was completely
identifiable the way I wrote it. The reason for this was that I had very
dense concentration-time data in the same individual after single as well
as repeated dosing, and just by visual inspection of the profiles you
could see the change in the terminal slope. There was not good reason to
assume that this was due to a change in volume of distribution, so it had
to be clearance. The inhibition compartment is not a physiological
compartment but an empiric approach to describe the changes. However, the
physiologic explanation for the inhibition is given in the article.
The inhibition compartment is just an ordinary effect compartment. A2
corresponds to the amount of drug in the central compartment, so A2/V2 is
a concentration. And if concentration is coming in, then concentration is
also going out (i.e. A4 is a concentration).
If you have any questions, please feel free to give me a call. Also, if
you want to read more, you might want to have a look at my dissertation:
http://sundoc.bibliothek.uni-halle.de/diss-online/07/07H049/prom.pdf
or as a book: Dr. Plock, Nele: Pharmacokinetics of Antiinfectives in the
Treatment of Serious Grampositive Infections - Linezolid and Vancomycin
(ISBN 978-3-86553-218-3, Wiku, Germany, 2007)
Best regards
Nele
_________________________
Dr. Nele Plock
Bayer Schering Pharma AG
Drug Metabolism & Pharmacokinetics
Development Pharmacokinetics
Scientific Expert Development Pharmacokinetics
D- 13342 Berlin
Phone : +49-30-468 15146
Fax: +49-30-468 95146
[EMAIL PROTECTED]
http://www.bayerscheringpharma.de
Vorstand: Arthur J. Higgins, Vorsitzender | Werner Baumann, Andreas Busch,
Ulrich Köstlin, Kemal Malik, Gunnar Riemann
Vorsitzender des Aufsichtsrats: Werner Wenning
Sitz der Gesellschaft: Berlin | Eintragung: Amtsgericht Charlottenburg 93
HRB 283
"Yuyan Jin" <[EMAIL PROTECTED]>
Gesendet von: [EMAIL PROTECTED]
06.06.2008 05:57
An
"Murad Melhem" <[EMAIL PROTECTED]>
Kopie
[email protected]
Thema
Re: [NMusers] enzyme auto inhibition PK model
Thanks Murad,
I read the article you suggested tonight. this is the first paper I read
so far modeled enzyme auto-inhibition and it is really useful. it is also
nice to see that the article differentiate the inhibitable CL and
non-inhibitable Cl. but I am wondering if these two CL could be accurately
estimated without corresponding metabolites data? also, I still could not
figure out what the inhibition component refers to physiologically?
and why def equation for the auto-inhibition comparment was written as:
dA4/dt=Kic*( A2 / V2-A4)
isn't unit of A2 and A4 the same?
Can anyone give me some hint?
Sincerely,
Yuyan
Quoted reply history
On 6/5/08, Murad Melhem <[EMAIL PROTECTED]> wrote:
Hi Yuyan,
Mechanistic models incorporating an auto-inhibition component would be
more desirable. However, you may be able to describe the PK data of your
compound empirically by adding an additional inhibition compartment.
Depending on the concentration in this empirical compartment, systemic CL
from the central compartment is inhibited. Over time, you can allow the CL
to take values between 0 and 100% of the original value estimated for the
time of the first administration.
A good reference for such an empirical approach is:
Plock N, Buerger C, Joukhadar C, Kljucar S, Kloft C. Does linezolid
inhibit its own metabolism? Population pharmacokinetics as a tool to
explain the observed nonlinearity in both healthy volunteers and septic
patients. Drug Metab Dispos. 2007 Oct;35(10):1816-23.
I hope this helps.
Murad Melhem, PhD
Assistant Director PK/PD
Cognigen Corporation
Buffalo, NY
On Thu, Jun 5, 2008 at 5:06 PM, Yuyan Jin <[EMAIL PROTECTED]> wrote:
Hi Dear Nonmem user,
I am trying to model the kinetics of a compound that exhibits enzyme
auto-inhibition.I have found some previously suggested literature by
nonmem users, but all of them were auto-induction cases. Does anyone know
any enzyme auto-inhibition PK model paper published ?
Thanks so much!
Sincerely,
Yuyan Jin
Graduate student
University of Pittsburgh
--
Yuyan Jin