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The following message was posted to: PharmPK
Dear Forum
The correspondence on the amount of water to give volunteers in BE
studies
makes me wonder how far we should go in controlling the conditions of BE
studies since the more we do that the further we get away from
"reality".
For example, the amount of water drunk by the subjects is probably only
likely to make a measurable difference by affecting the rate that the
test
drug leaves the stomach, so why don't we reduce the variation in
gastric
emptying by giving a prokinetic drug? (obviously one that does not
vitiate
the assay). That is not a large step on from all the other controls
we now
use.
On the other hand we might give the drug with a non-absorbable gel
like agar
that retards emptying but which does not function as food.
Supposing we did both so as to get the range?
If we remove this source of variation, what are we left with? What
others
could we remove and would the results help us design better
formulations?
Andrew Sutton,
Guildford Clinical Pharmacology Ltd.
The Technology Centre, Occam Road
Guildford, Surrey, UK. GU2 7YG
Tel: +44 (0)1483 455375. Direct: 688303
URL: www.gcpl.co.uk
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Dear Andrew,
We should discriminate between the exploratory pharmacokinetic
studies and bioequivalence studies.
In the previous case, one wants to understand as much as possible
about all the processes that will define the pharmacokinetic
behaviour of the drug and later the formulation: the full ADME.
In these experiments the pharmacokinetic of the drug is studied on
different sub-populations (e.g. impaired hepatic or renal function,
healthy volunteers, different age group, etc.) or when administered
with other drugs, food, antacid products, etc.
In bioequivalence studies one is interested in the absorption phase
only and more specifically how differences in the drug-product
formulation may affect the absorption of the drug. The study is
concentrated on the 'A', since it is assumed that the 'DME' will be
the same. Once the drug is in solution, in the blood, the
distribution, metabolisation and elimination should be exactly the
same irrespective the formulation that it comes from. This is fully
true in the case of immediate-release formulations.
Since bioequivalence studies are focused in determining with the
highest precision and accuracy possible the difference in the drug
absorption from different formulations any additional source of
variability that may "cloud" the results is undesirable. Hence a very
high degree of control of the population, environment, GI tract
status, physical exercise, etc. between the periods of the study (the
most common design is the cross-over). Consequently, the observed
differences between periods within the same subject can be attributed
to the formulations administered.
radu
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The following message was posted to: PharmPK
Thank you for your comments Radu, but I am really trying to stretch the
concept of BE studies outside their normal box to see if there is
something
else we could do with them. The Forum is a great place to do that as
we have
so many minds thinking about the idea...and it is only a "fun" idea
at this
stage anyway.
For example, supposing we speeded up gut transit during a BE study by
using
a prokinetic drug, would that enable us to design better formulations
for
drugs that treat intestinal hurry, as in diarrhoea?
Alternatively, might we use a constipatory drug like codeine to slow
down
intestinal transit because constipation is common yet there are few
studies
on its effect on absorption (References anyone?). Since we have
learned to
control so many other factors we could now do that kind of study more
precisely focused on the factor of interest.
Cheers
Andrew
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The following message was posted to: PharmPK
Dear Radu,
While reading your mail, I asked myself: How far should we go in
selecting a study collective as homogeneous as possible? My
understanding of bioequivalence is to assure that the rate and extent
of absorption (to the site of action) are equivalent for the RELEVANT
PATIENT POPULATION.
1) Can we be sure that dietary habits (e.g. Asian vs. European vs.
American vs. African food) affect the absorption of a test and
reference formulation in "the same" way (no dietary habit by
formulation interaction in the ANOVA)?
2) Can we be sure that females and males "handle" the test and
reference formulation in "the same" way (no sex by formulation
interaction in the ANOVA)?
This will be important when studying exclusively male healthy
volunteers from a single country in a bioequivalence trial. I would
very much appreciate any comments, e.g. on: Are bioequivalence
studies in country A representative for countries B, C, D etc.
Best regards
Juergen
--
Juergen Bulitta, MSc
Pharmacometrician, IBMP - Institute for Biomedical and Pharmaceutical
Research
Paul-Ehrlich-Str. 19, D-90562 Nurnberg-Heroldsberg, Germany
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Dear Juergen,
I will try to answer your questions as best as I can:
1) Yes, I believe that we can be pretty sure that dietary
habits will not trigger difference in the release of drugs from the
immediate release formulations.
The disintegration of a solid oral formulation occurs in minutes and
therefore the excipients used in the formulation will have no impact
on the absorption of the drug.
Once the drug is in solution or suspension in the GI tract the
absorption that follows will be similar between formulations.
The difference in the GI tract environment due to difference in diet
may affect the absorption of the drug (different pH, different
expression of certain enzymes, motility, ...).
However, the impact will be on the drug and the formulation will have
no effect.
In the case of extended-release formulations, the nature and quantity
of excipients are directly responsible for the drug-release, and
interactions of the formulation with the GI tract environment will be
present. For this reason, both fasting and fed bioequivalence studies
are required.
Currently, I am aware that only Nippon regulatory agency require BE
studies to be performed on Japanese subjects.
Other regulatory agencies currently accept studies performed in other
countries.
EU has a policy that recommend that drug-products approved in on
country be approved in all member-countries.
We performed studies in North-America that are intended for European
countries and Australia.
My two cents:
- I do not believe that dietary differences will
cause differences in the bioavailability of immediate-release
formulations
- The fed conditions created by the high-fat, high-
calorie meal currently used in North-America is far from being the
common situation encountered in every day life. However, it was
selected because it is an extreme case. The current thought is that
formulations that are bioequivalent under these conditions will be
bioequivalent under less extreme fed conditions.
2) Currently BE studies are using both female and male
subjects. However, there are no requirement to analyze possible
differences between sexes.
My two cents:
- Based on my experience there is no evidence that
are gender differences in the absorption of drugs
- There are very few example were the metabolization
and/or excretion of drugs are different between females and males
- In most cases these differences are not large
enough to trigger differences in the clinical outcome. I do not
remember seeing dosing recommendations based on gender.
- In most cases were such differences were observed,
the weight normalization of the data eliminates any differences in
the PK parameters. In most experimental situation the subjects are
given equal doses and differences in weight and blood volume between
male and females are overlooked.
I hope this will be some comments to your questions if not THE ANSWER.
Best regards,
radu
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The following message was posted to: PharmPK
Dear Forum
Does anyone have any data on the effect of constipation on drug
absorption,
especially from sustained release forms that are designed to release
compound in the colon?
Thanks
Andrew Sutton, MBBS, MD(London), FFA
Guildford Clinical Pharmacology Ltd.
The Technology Centre, Occam Road
Guildford, Surrey, UK. GU2 7YG
Tel: +44 (0)1483 455375. Direct: 688303
URL: www.gcpl.co.uk
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)