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Dear all,
I am wondering if its OK to use the following equation to calculate =
Accumulation
Index?
Dose-adjusted AUC(0-t) on day n / Dose-adjusted AUC(0-t) on day 1,
if different doses were used on day n (PK sampling after n days). As =
typically
we would use the same dose to investigate the accumulation of a =
compound. Any
thoughts on this would be greatly appreciated.
Thanks
--=20
Xinting Wang=
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Xinting,
The calculation you proposed would be numerically accurate, but there would be a
few things you might need to consider before taking that accumulation index
value as definitive.
1. Is the PK dose proportional across the dose range? If not, then using
dose-normalized values would be inaccurate.
2. Did you reach steady-state? When did you switch doses? If it is early, then
you probably reached steady-state. If it was late, you may still be accumulating
drug.
You can read more about accumulation on my blog
(http://blog.learnpkpd.com/2012/11/20/accumulation-what-it-means-and-how
-to-calculate-it/).
Good luck,
Nathan Teuscher
--
Nathan S. Teuscher, PhD
Founder, PK/PD Associates
www.learnpkpd.com
blog.learnpkpd.com
nathan.at.learnpkpd.com
Twitter: www.twitter.com/learnpkpd
Facebook: www.facebook.com/LearnPKPD
YouTube Channel: www.youtube.com/learnpkpd
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The following message was posted to: PharmPK
Dear Xinting,
I think in principle yes, but the problem with that aproach is that there are
two processes that take place between Day 1 and Day n, e.g. multiple dosing and
a change in dose and both may affect accumulation.
Multiple dosing could affect the PK ( induction for instance or reduced
absorption), but you could also have PK parameters that are not proportional to
the dose-increase. You would definitely also have to look at trough
concentrations, i.e., was steady state reached and was it maintained.
One way of checking is doing a simulation using your Day 1 data and thus
calcualte what to expect if your compound behaves as it theoretically should.
Kind regards,
Frieda
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This is fine only if you know that your PK parameters do not change with
dose in
the dose range you are working in. Even if dose-linearity is ok, if the
doses
are drastically different and there is a possibility of PK changing with
repeat
dosing due to effects on metabolism, etc., you take a risk in this
interpretation since different dose levels may have differential effects
on the
body and therefore, accumulation.
Kelly Byrnes-Blake, PhD
Northwest PK Solutions, LLC
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Xinting,
If you know the dose regimen and confirmed it has already reached steady
state
(ss) following the multiple dosing, then the Accumulation Index should be
estimated as:
AUC(tau,ss)/AUC(tau,day1) but not using AUC0-t for comparison. Strictly
speaking, AUCtau indicated AUCtau at steady state but people just simply
used
AUC(tau,day1) to express the AUC(0-dosing interval on day 1). If you have not
yet confirmed the achievement of steady state after N doses, the result
from
same equation only indicate the Accumulation following multiple dose with the
regimen after N dose or Day N (if the dosing interval is 24 hours).
Dose-adjusted AUC used not to apply for Accumulation Index but to investigate
linear PK following superposition rule, i.e., single dose PK predicated
PK after
multiple dosing.
By the way, steady state can be confirmed using statistical estimate but
not
simple visual inspection.
The best reference is from Rowland and Tozer's "Clinical Pharmacokinetics -
Concept and Application" (the new edition is available - the 4th ed).
Hope this helps.
Zhao Wang
Consultant Scientist
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The following message was posted to: PharmPK
I would suggest that Nathan's response is all that's required to assess
extent of accumulation in plasma with different doses, i.e.
considerations
of (i) dose proportionality and (ii) attainment of steady state.
The observed extent of accumulation will then reflect the elimination
half-life relative to the dosing interval and any other potential
non-linear
processes e.g. induction or changes in absorption.
I would propose fitting a linear kinetic model to ALL the data to test
for
linearity (rather than fitting to single dose and simulating the
repeat-dose
profile).
Regards,
Charlie
KinetAssist Ltd.
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