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Hi everyone,
I would like to ask a question. If a drug in development causes
reduction in AUC and Cmax by 50% when taken with a standard breakfast or
with a high-fat meal, what kind of questions would one want to ask and
how does one interact and make sense of this data clinically? The said
dose is supposed to produce intermediate exposure and double the dose is
supposed to produce exposure with maximal efficacy according to modeling
data. Is it reasonable for a sponsor to say that this is not a
'meaningful' thing? Many thanks.
Kind regards.
MIA
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Clinically it determines whether the patient should take the medication at
the same time during the day (breakfast vs dinner). If the change in PK
parameters is dramatic with the meal type then it would also bring the
suggestion of taking the medication with the same type of meal (fat,
carbohydrate, etc).
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Mia,
You have a food effect, where likely absorption from the gut is reduced due to fat in meal.
Dan Combs
Combs Consulting Service
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Mia
Just to add to Dan's comment that relates to intestinal absorption.
Delayed gastric emptying due to the meal also reduces Cmax. That alone
increases the first pass effect when hepatic extraction rate is
constant, so you get a reduced AUC which is independent of fat in the
meal.
Andrew Sutton
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Dear MIA
Dan is right in stating that you have a food effect, in fact reducing the
exposure by 50% is a significant food effect and is something that would
probably go in the label, if the drug reaches the market. It is not
something that can be ignored as being "not meaningful." Also, in your email
you say that the maximum efficacy is projected to be at twice the exposure.
Food would drop the exposure level down the dose response curve and it may
be better to state that the drug should be given in the absence of food and
perform all future studies in the fasted state. Other factors to consider
are: variability in exposure in fed and fasted states; safety profile if
Tmax lengthened and Cmax reduced; steepness of dose response curve.
Brian
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Dear MIA
Food contains multiple substances and these substances may affect absorption of drug may
be due chelation or change in ionization of the drug in different pH or possibly pgp etc.
may be involved.
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Andrew and Mia
Since about 70% of the time a decrease in AUC is found for BDDCS Class 3
poorly metabolized drugs, hepatic first pass effect would not be the
driving force. It's more likely an effect on decreasing solubility,
making the drug less available for absorption or potentially an
inhibition of uptake transporters. Mia--What is the mechanism of
elimination of the drug, metabolism or renal/biliary excretion of
unchanged drug?
Les
Leslie Z. Benet, Ph.D.
Professor
Department of Bioengineering & Therapeutic Sciences
Schools of Pharmacy & Medicine
University of California San Francisco
533 Parnassus Avenue, Room U-68
San Francisco, CA 94143-0912
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Dear all,
In rats, absorption was about 80%. The drug was primarily eliminated by
renal (40%), biliary (20%) and intestinal excretion of parent compound.
A minor component of elimination was metabolism (25%), followed by
excretion of metabolites into bile, urine and feces.
2. So far the drug has only been tested in healthy volunteers. Will
testing in patients be likely to change anything with regards to the AUC
reduction?
Thanks.
MIA
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