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Dear All
I would like your comments on the issue of reporting
non-compartmental half-life of a compound exhibiting nonlinear
(Michaelis-Menten clearance) PK for regulatory/labelling purposes. I
understand the scientific issues associated with reporting a half-life
in
this case. But how do you satisfy development team/marketing/clinical
needs
for a half-life to hang their hat on? Alternative methods of reporting
parameters in this case and the pros and cons of the method you follow
are
most welcome.
Thank you.
Balaji Agoram, Ph.D.
Research Scientist, PKDM
MS 30E-0-B, TO, CA 91320
(805) 447 4035 (phone)
(805) 375 6416 (fax)
[Does the pseudo first order half-life (from low dose) work with a BIG
warning that it will change at higher doses? - db]
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Dear Balaj,
I guess it is time for you to take advantage of this example and make
your colleagues realize that non-compartmental analysis is only a tool
to help you decide how to go forward with the analysis of the data and
choosing the right (compartmental) model. I have had a similar, if not
identical, issue where people were asking for "a" half-life. By doing a
compartmental analysis, incorporating a non-linear elimination, and
several rounds of discussions, people started to realize the value of
compartmental modeling. Such approach is especially needed in a
situation where non-linear kinetic prevails since non-compartmental
analysis does not allow for predicting different doses (and thereby
concentrations). And what is the use of an analysis (in this case NCA)
that describes what you have but cannot predict what would happen if the
conditions were changed? To my understanding, the whole purpose of
understanding the pharmacokinetic properties of a drug is to use that
information in predicting the system behavior under different
conditions. It is also a good example of how "useful" the term half-life
is.
If people still insist on NCA and want a half-life, you may give them
the right answer by asking for the concentration level they have in
mind, simulate the curve based on your compartmental analysis, and give
them the value of the half-life at that particular concentration level.
The trick is to make people understand that the half-life might change
depending on the concentration level. Of course, you don't need to tell
them how you estimated the half-life value :-).
Toufigh Gordi
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Agoram,
"Agoram, Balaji" wrote:
> Dear All
> I would like your comments on the issue of reporting
> non-compartmental half-life of a compound exhibiting nonlinear
> (Michaelis-Menten clearance) PK for regulatory/labelling purposes. I
> understand the scientific issues associated with reporting a half-life
> in this case. But how do you satisfy development
team/marketing/clinical
> needs for a half-life to hang their hat on? Alternative methods of
reporting
> parameters in this case and the pros and cons of the method you follow
> are most welcome.
Your question might be answered if you could explain why development
team/marketing/clinical need to hang their hats on the wrong peg? What
are the development /marketing/clinical imperatives that require a
half-life when a half-life may be inappropriate?
Another approach might be to understand the magnitude of the error in
assuming a first-order approximation to this mixed order process. What
is the target concentration for the drug and what is the Km? What is
the apparent half-life at the upper and lower ends of the usual dosing
rate?
Nick
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
email:n.holford.at.auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
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Balaji
If we take a definition of half-life as time for the
concentration to reduce by a factor of 2, a compartmental
analysis should yield a table or curve showing t1/2 v.
concentration in a range with transition from linear to
saturated kinetics.
The marketing team could work with a point estimate such as
the median of this range or the range itself, together with
some estimate of statistical uncertainty.
Immanuel Freedman, PhD., MIEEE
(619) 884-1347
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Hello Balaji,
I think Toufigh and Nick hit the nail on the head - the real question is
why these people think they need a single half-life. What purpose is it
serving for them? If you can answer that, then perhaps there is some
other kind of information they could be provided that would serve the
purpose.
In my cynicism, I suspect they want a simple number for marketing and
sales to provide to (some? many?) physicians who have little or no true
understanding of pharmacokinetics.
I know that you are quite expert at nonlinear kinetics (after all, you
did the majority of the programming on the nonlinear Metabolism and
Transporter Module in GastroPlus when you were at Simulations Plus!). I
share your frustration with those who want to apply NCA to everything,
whether it is suitable or not.
Walt
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (AMEX: SLP)
1220 W. Avenue J
Lancaster, CA 93534-2902
U.S.A.
http://www.simulations-plus.com
Phone: (661) 723-7723
FAX: (661) 723-5524
E-mail: walt.at.simulations-plus.com
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Balaji,
Many drugs (e.g. digoxin) have one or even several initial distribution
half-lives (e-g- t_half_alpha of 3 h), followed by a terminal
elimination
half-life (e.g. t_half_beta of 36 h). Couldn't you simply take the
lowest
value of the log-concentration time slope at the peak concentration
after
the highest labelled dose, and the terminal slope of the first-order
phase,
ant then just express : "due to saturable metabolism, the apparent
half-life decreases from an initial value of X h to a terminal value of
Y h
after a single dose..." ? (but warn your development/marketing/clinical
team not to use any of those half-lives to predict the degree of
accumulation !)
Thierry
Dear Balaji,Back to the Top
Constant clearance is one of the conditions to be met if you want to use
NCA. Otherwise, you will have to use a compartmental approach.
Jose Antonio Allue Ph.D.
Mass Spectrometry Laboratory
Metabolism & Pharmacokinetics Service
Research & Development Department
IPSEN-PHARMA S.A. Laboratories
Ipsen Group
Ctra. Laurea Miro 395
Sant Feliu de Llobregat, Barcelona, Spain
Telf.: 936858100
e-mail:jose-antonio.allue.aaa.ipsen.com
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Dear Balaji,
Check out the labeling for Paxil. The metabolism via CYP2D6 is
saturable so non-linear kinetics are in effect at higher doses.
Susan
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