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The following message was posted to: PharmPK
Stefan,
As far as attenuating, I'm not so sure, but it certainly can amplify
differences.
Greater metabolism means lower bioavailability, which in turn means
an X%
change in total bioavailability is a bigger fraction than if
bioavailability
is higher. In the extreme, trying to match a reference that is 100%
bioavailable is much easier than trying to match one that is 1%
bioavailable.
Gut wall metabolism and transporters can create difficulties
demonstrating
bioequivalence when the enzyme or transporters are not uniformly
distributed
along the gut wall (3A4, 2D6, PepT1, Bile acid carrier, etc.).
Different in
vivo release rates will result in different concentrations in the
regions of
high expression, in turn resulting in modifying bioavailability.
To add to the difficulty, polymorphism can cause significant variance
among
subjects for some enzymes and transporters, requiring more subjects to
achieve sufficient power for a BE study.
Our GastroPlus(tm) software simulates all of the complex interactions
among
these phenomena. Its Virtual Trials capability can help customers to
avoid
conducting bioequivalence studies that would have failed when such
mechanisms are involved, and to select the number of subjects needed to
provide an acceptable probability of success.
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.-a-.simulations-plus.com
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