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Dear Group,
I have a question about determine the dose linearity.
At least how many doses is needed to be able to claim in the dose range? Ideally, the AUC of every dose needs to be determined. But because I am doing the experiment in mouse and have limited amount of drug. Shall I only measure Cmax of each dose, if the Cmax increase linearly with dose, then I can conclude the dose linearity? Could anybody provide some reference doing the same thing?
Thanks,
Norman
-
Norman Zhou NSEC fellow, The Ohio State University College of Pharmacy
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The following message was posted to: PharmPK
Norman,
You said:
"Ideally, the AUC of every dose needs to be determined. But because I am
doing the experiment in mouse and have limited amount of drug. Shall I only
measure Cmax of each dose, if the Cmax increase linearly with dose, then I
can conclude the dose linearity? Could anybody provide some reference doing
the same thing?"
You don't say whether your doses are iv or po. A common misconception is
that the highest data point taken in a plasma concentration-time data set is
Cmax. Because it would be highly serendipitous if a sample could actually be
taken exactly at the time of Cmax (even for an iv dose, but especially so
for oral doses), a safe assumption is that Cmax is always higher than the
highest observation. A properly fitted PK model (if sufficient data points
are available) will provide the best estimate of the actual Cmax.
Best regards,
Walt
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (NASDAQ: SLP)
42505 10th Street West
Lancaster, CA 93534-7059
U.S.A.
http://www.simulations-plus.com
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Hi Walt,
Thanks for pointing out that I have missing the dosing route. We are actually working on a controlled released drug formulation for i.m. injection. That's why there is an absorption phase.
I agree with you that the actual Cmax may be no less than the measured Cmax. I wonder if it is valuable to compare the measured Cmax between different doses, and to draw any conclusion about the linearity based on Cmax.
Thanks,
Norman
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The following message was posted to: PharmPK
Norman wrote:
> "I agree with you (Walt) that the actual Cmax may be no less than the measured Cmax. I wonder if it is valuable to compare the
> measured >Cmax between different doses, and to draw any conclusion about the linearity based on Cmax."
I also agree that this is a considerable area of doubt so my question
is whether anyone has done the experiment that this suggests; namely,
to measure the difference between the real and observed Cmax in these
slow-release IM formulation conditions in a second study. I presume it
would be done by the second study concentrating sampling around the
estimated tmax calculated from the first study. However, I would
expect considerable inter-subject and even within-subject, inter-dose
variation which might render the information gained not much more
informative than the original.
This thought leads me to ask the modellers if this situation has been
modelled with different group variances so as to calculate group sizes
and feasibility of the second study producing useful information (that is reliable predictions of Cmax and tmax that would help
clinicians, especially when there is a strong relationship between
concentration and effect, as for antibiotics). If that produces
criteria for variances that could be compared with those actually
found in the first study, and the test formulation meets them, would
we now recommend that the second experiment should be done?
Andrew
[When I saw the original post I was tempted to comment that a single Cmax was useless but now I'm not sure. If the absorption and elimination were uncomplicated (e.g. first order - sorry Walt) you might expect C values at any particular time to give relative information about F. Thus, for good sensitivity one might pick a common time, close to an estimated (or know average) tmax and determine a C'max' for each animal. Of course variation in model and model parameters would lead to determination error but a larger number of animals may help. Of course, this may defeat the proposed advantage of one sampling time and the smaller number (of small) animals. As Andrew asks, I wonder if anyone has looked at this through simulations (Andrew's focus is different but the use of simulation is similar) - db]
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Andrew and David,
I'm certainly no expert when it comes to i.m. dosing, but I have a mental
picture is one of someone injecting different animals whose bodies are not
identical, and the person(s?) doing it trying to be consistent with respect
to angle and depth of needle penetration into the muscle, rate of injecting
the dose (affecting the pressure that would be built up within the site of
injection, which might affect absorption?), etc. Depending on the controlled
release technology and the physiology of the animal, the release rate and
disposition of the drug from a controlled release dosage form would vary as
well. Perhaps the variability is no worse than it would be for oral doses
among multiple animals. Can anyone enlighten those of us who lack experience
in this area?
I agree that first order absorption can be an adequate model (though wrong,
like all models) in some instances, but how would one determine whether this
is one of them? Even if "first order", if either absorption rate or
clearance is rapid, small differences in sampling parameters and analytical
variances might require a large number of animals in order to obtain enough
power to draw any conclusions about dose linearity. So it appears the
tradeoff might be between number of samples per animal and number of animals
- i.e., take enough samples to calculate AUC, or use enough animals to use
concentration at a fixed sampling time.
Best regards,
Walt
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (NASDAQ: SLP)
42505 10th Street West
Lancaster, CA 93534-7059
U.S.A.
http://www.simulations-plus.com
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With respect to the discussions on dose linearity (proportionality) and the uncertainty of reliably estimating Cmax, I can make a comment based on analysis of a large sample of toxicokinetic and Phase I studies (in the order of 10-20 studies per year, over the last 20 years). My experience is that the assessment of dose proportionality based on AUC is represented reasonably well by Cmax; i.e. Cmax generally reflects conclusions on dose proportionality estimated from AUC values. The assessment of dose proportionality was based on the power model as recommended by Gough K, et al. Drug Inform. J. 1995; 29 1039-1048.
So, although Cmax may be unreliably estimated, it's usually as good as AUC to assess dose proportionality.
Charlie Brindley
KinetAssist Limited
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