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The following message was posted to: PharmPK
Dear All,
We have conducted a bioequivalence study (2-way crossover study under
fed conditions) on a modified release formulation of an antibiotic
drug, and the the 90% CIs for ratios of the log-transformed
parameters, Cmax, AUC0-t & AUC0-inf were within the standard
acceptable limits of 80% - 125%.
But the ratio of arithmetic means of Tmax (Tmax-test / Tmax-ref) was
found low. Though Tmax is not a parameter for determination of
bioequivalence, this present situation depicts that the test drug is
gettting absorbed faster than the reference product, though the
extent of bioavailability is not affected as shown by Cmax, and AUC
parameters.
Can this be justified from a clinical point of view , considering
that the clinical effectiveness of the drug is in the maintenance of
concentrations above the MIC, and that in actual clinical practice
this drug will not be required to be taken along with food.
V. Madhuri
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Dear Madhuri,
This is an interesting topic, especially since no data is presented,
which allows me to speculate on various aspects of the issue :-).
I am assuming that both formulations result in a prolonged apparent
half-life of the compound and since there does not seem to be any
differences in almost all of the parameters you have estimated, the
half-life is similar for the two formulations. This, to some extent
contradicts your statement that the absorption from the test formulation
is faster than the reference formulation. The reason is (if my
assumption above is true), that a faster absorption would mean a shorter
half-life since the apparent half-life you estimate is influenced by the
formulation and a faster absorption would mean shorter apparent
half-life. I guess what you meant is that the onset of absorption
happens earlier although the rate and extent are similar, as the two
formulations seem to have similar Cmax and AUC values.
So the real question is whether this earlier start of absorption is of
any clinical significance in terms of bacteria clearance. Personally, I
don't see any disadvantage with this but it is up to the clinician to
decide.
Now I have a question for you. I was just curious why you did a "2-way
crossover study under fed conditions" when you think that "in actual
clinical practice this drug will not be required to be taken along with
food"?
Toufigh Gordi
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The following message was posted to: PharmPK
Tmax is an order statistic you need to look at a Hodges-Lemann
distribution free approach of the difference in median Tmax.
thanks
mike
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I have a couple of questions:
(1) How "flat" are your concentrations around Tmax? With controlled
release
formulations, the plasma concentration-time curve will often show a
significant region of similar concentrations where absorption and
clearance
are nearly the same. This makes Tmax very sensitive (and, in my
opinion, not
very important).
(2) How are you defining Tmax - by the maximum sample value or from a
fitted
model that finds Tmax between samples?
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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