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So, a faculty colleague of
mine was on a conference call yesterday that included attendees from a
well-known US regulatory agency, and the topic came up of when the drug
at issue reached steady state. His point (and mine), is that steady
state is defined as the point when the concentration at one point after
one dose in a regular regimen is the same as another. (Usually we
expect steady-state to occur after 4-5 T1/2, and can plan our
assessments based upon that. The point was made from the east that the
variability of these concentrations at specific time points at what is
thought to be steady state needed to be defined. When asked to suggest
a variability (CV), a value of 30% was given (!).
So my question to the group is, at what point is steady state defined?
For example, how much variability can exist in repeated nadir sample
concentrations and yet still allow the assertion that steady-state has
been reached?
(Another wild statement from the east was that the company he was
advising had to perform a full PK study to define T1/2 so that
steady-state could be defined as 7-8xT1/2.)
--
Paul R. Hutson, Pharm.D.
Associate Professor
UW School of Pharmacy
777 Highland Avenue
Madison WI 53705-2222
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The following message was posted to: PharmPK
Dear Dr. Hutson,
Please see the following review article on steady state assessment.
The AAPS Journal Vol 10, No.1 March 2008, Pages 141-147.
Maganti L et al.
Kind regards,
Raju
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Hi,
I think this discussion needs to clarify the difference between the
definition of a steady state in terms of pharmacokinetic theory and a
pragmatic test based on observations to show that the system appears to
be near enough to steady state that it is "good enough for government
work" .
I like the theoretical definition of steady state being when the amount
of drug entering the system is equal to the amount lost over some
interval of time. This implies regularity of dosing from one interval to
the next but dosing within the interval need not be identical e.g.
steady state over 24 h can be achieved by dosing by alternating dosing
of say every 12 h on one day and every 6 h on the next day (assuming
linear PK). This would be at PK steady state (over 24 h) but does not
meet the proposed definition of "the point when the concentration at one
point after one dose in a regular regimen is the same as another" (e.g.
comparing he conc at 3 h after any dose on successive days).
One should recognize that the theoretical definition is never truly
reached in practice because it takes an infinite amount of time to truly
reach a steady state. Tests of closeness to a "steady state" could be
based on a comparison of the area under the concentration time curve
(AUC) obtained from two presumed "steady state" intervals. (Note that I
use "steady state" to refer to a pragmatic "good enough for government
work" approximation to true steady state). What is "good enough for
government work" requires an answer from the government.
These AUCs could be obtained using observed concentrations and
non-compartmental methods or by integrating predicted concentrations
from a compartmental model. The compartmental model method does not rely
on making observations close to steady state because future
concentrations that might be close enough to test for "steady state" can
be predicted.
I teach that 4 half-lives is close enough for clinical work under the
assumption of a one compartment model. Defining "steady state" in terms
of half-lives for any other compartmental assumption has lots of
problems which is why I would prefer a pragmatic test based on AUC.
Nick
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The following message was posted to: PharmPK
Dear Raju:
Thank you for pointing out this classic study from Dr. Maganti at Merck. It assesses both
the AUC and trough methods of determining steady-state, and I am informed of methods I had
not previously encountered. Their paper presumes for argument that steady state is
achieved when 90% of steady state is achieved (roughly 3 half-lives). The AUC methods
appear hampered in part by the assumption of linearity. The individual trough methods are
favored in this article.
What surprises me, and prompted my initial inquiry, is that there does not appear to be a
formal criterion from the FDA with regard to steady-state. Not only when steady state is
reached (such as a certain percentage of asymptotic concentration, or 3 vs 5 terminal
half-lives), but what methodology should be used and what criteria for intra-subject
variability in trough concentrations, number of troughs tested, etc, and what confidence
interval should/must be established. Perhaps I am naiive from by academic setting with
respect to the flexibility granted by the agency in defining for a given case when steady
state is achieved.
I was too informal in my previous post, and welcome other insights from the group
regarding how they have proven to this or other regulatory agencies that steady-state has
been achieved.
Paul
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Paul
Whether or not the drug has reached a steady state is never a regulatory question. So
there is no reason for FDA or any agency to come up with that criterion. IMO, more
appropriate questions from the regulatory point of view are safety, efficacy, dosing in
special populations and adjusting for factors extrinsic to patients etc. as it relates to
exposures. So if the steady state question was brought from one of those viewpoints, you
might want to see if there are ways to answer the underlying question. If the desire is to
simply estimate t1/2 and empirically establish the steady state w/o any context, you can
reasonably argue against doing such an academic study or might find creative ways to
reasonably derive that information.
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