Hi Evwerybody,Back to the Top
According to US FDA guidelines, in BE studies drug should be
administered with 240 ml of drinking water.
So Dear all, why this much quantity of water only?
Please share your expert comments.
Thanks and Regards.
DR.Sajjad A Desai
Sajjad,Back to the Top
This amount (240 mL) is the approximate volume of a glass of water that
people usually take (and are told to take) with their PO dose.
(~1L/4~250 mL)
Ahmad
Ahmad Mirfazaelian PhD
Research Associate,
Dept. of Pharmaceutics
University of Washington,
Box 357610
Seattle, WA 98195
Phone: (206) 685-0902
Fax: (206) 543-3204
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Dear Sajjad,
The quantity 240 ml comes from 8 Oz which is equivalent to 1 standard
cup of water. It is assumed that normally a patient consumes 1 cup of
water to take any orally administered formulation.
Best Regards,
Sunil V
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Dear Dr. Desai
I think it is conclusion of compiling experiments, that if we
administered a study medication with 240 mL of water, it is sufficient
for any oral formulations to be swallowed properly. However, this
quantity of water to be given with dose varies from guideline to
guideline. Like Brazilian guideline recommend 200 mL of water to be
given with.
Regards,
Mitesh
Dept. of .Pharmacokinetics,
GLENMARK RESEARCH CENTRE
Plot No. A-607, T.T.C. Industrial Area. MIDC,
Mahape, Navi Mumbai - 400 709. INDIA
Phone: 91-22-55902491/92 Ext: 316/308
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The European Guideline states a minimum of 150 ml for oral
administration.
In our experience especially female volunteers find it difficult to
swallow 240 ml at once.
Regards
Helmut
Helmut Sch\0xB8tz Biokinet GmbH / Dept Biostatistics
Neubaugasse 36/11 Nattergasse 4
A-1070 Vienna/Austria A-1170 Vienna/Austria
tel/fax +43 1 9713935 tel +43 1 4856969 62
no cell phone ;-) fax +43 1 4856969 90
http://www.goldmark.org/netrants/no-word/attach.html
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Greetings again
Helmut Sch\0xB8tz wrote:
"
In our experience especially female volunteers find it difficult to
swallow 240 ml at once.
"
I don't understand why they have to take it all at once. If they drink
it an
over a period of, say 3 to 4 minutes, it will not make a lot of
difference
and be more comfortable for the subjects as well as more like "real
life".
Andrew Sutton
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Its has been suggested to me by a gastroenterologist that a volume of
250
ml of water would be enough to provoke a digestive response in the GI
tract, ie. mimic the arrival of food in the gut. Can anyone confirm
this?
If so, might this not be an argument for restricting the volume of water
used to assist oral dosing in food effect studies?
Ray French.
Raymond French, PhD.
Manager, Pharmacokinetics
Medical Data Sciences
Inveresk
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Dear Ray
The influence of food may not be only resultant of physiological
(digestive) responses but also physical and chemical responses,
including interactions with enzymes (CYP3A4) and drug transporters
(P-glycoprotein).
There are some studies showing the differences in bioavailability as
result of different diet content, for example to indinavir
(high-calorie protein meal significantly reduces the bioavailability
but a light meal does not).
Paula
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I wrote:
"
In our experience especially female volunteers find it difficult to
swallow 240 ml at once.
"
Andrew Sutton responded
"I don't understand why they have to take it all at once. If they drink
it an over a period of, say 3 to 4 minutes, it will not make a lot of
difference and be more comfortable for thesubjects as well as more like
"real life".
"
I agree.
Actually this "quickie" results from the majority off our sponsors, who
want to keep the individual time points of administration within a
certain time range, i.e., subjects are to be dosed every two minutes
;-)
Best regards
Helmut
Helmut Sch\0xB8tz Biokinet GmbH / Dept Biostatistics
Neubaugasse 36/11 Nattergasse 4
A-1070 Vienna/Austria A-1170 Vienna/Austria
tel/fax +43 1 9713935 tel +43 1 4856969 62
no cell phone ;-) fax +43 1 4856969 90
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Dear Andrew Sutton
It is not mandatory to administer a study medication with 240 mL only.
But whatever volume (eg., 200 mL) you are administering to volunteer
should be same for all the volunteers taking part into particular
study. And you have to justify why you administered 200 mL instead of
240 mL.
Regards,
Mitesh Gandhi
Dept. of .Pharmacokinetics,
GLENMARK RESEARCH CENTRE
Plot No. A-607, T.T.C. Industrial Area. MIDC,
Mahape, Navi Mumbai - 400 709. INDIA
Phone: 91-22-55902491/92 Ext: 316/308
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Ray.French.aaa.inveresk.com> wrote:
"
It has been suggested to me by a gastroenterologist that a volume of
250
ml of water would be enough to provoke a digestive response in the GI
tract, ie. mimic the arrival of food in the gut. Can anyone confirm
this?
"
Dear Ray,
At Guildford Clinical Pharmacology and the University of Surrey we have
measured gastric emptying of water or glucose solutions hundreds of
times,
usually with a volume of 500ml in our epigastric impedance technique.
Typical emptying half times are 5 to 7 minutes, which indicates that
there
cannot be much of a "digestive response". On the other hand we do
frequently
see a small plateau around half emptying and that suggests a mechanism
that
is not just a passive hopper, emptying at a constant or mono-exponential
rate. The plateau might last about 3 minutes and is often followed by an
increase in motility during the subsequent downslope and that suggests a
peptide response, possibly invoking motilin.
Our results have been repeatedly validated against other methods and
show
that while meals are as simple as water or 10% glucose, the
electro-conductive effect of secretions such as HCl is minimal, so that
is
good, if indirect, evidence that there cannot be much of them.
Also the epigastric technique has shown that morphine given to
volunteers
slows the emptying of 500ml deionised water meals by about 4 fold [with
means \0xB1SD of 5.5 \0xB11.9 and 21 \0xB19.0 mins .n= 11. See Murphy DB et al,
1997,
Anesthesiology, 87: 765-770]. I think that suggests that the 5.5 minute
t50%
emptying of 500ml is near optimal and I doubt whether the smaller
amount of
250 ml is slowed down very much even if peptide mechanisms for example
are
invoked.
I have seen a memorable video from an ultrasound technique in Bob
Heading's
labs at Edinburgh in which biscuit crumbs are given in water that has
been
boiled to remove air bubbles. The crumbs show up like bright stars in a
night sky and the surprising thing is that they repeatedly moved in and
out
of the antrum to the duodenum and back again, showing that even with
that
simple test 'meal" the gastric emptying was not a simple one-way
traffic.
Ray also wrote:
"
If so, might this not be an argument for restricting the volume of water
used to assist oral dosing in food effect studies?
"
From the above it seems to me that you could even go as high as 500ml
and
not retard emptying greatly. I would not do that in practice because it
wouldn't be the normal condition for taking tablets.
Cheers
Andrew
Andrew Sutton, MBBS, MD(London), FFA
Medical Director
Guildford Clinical Pharmacology Ltd.
Hascombe Ward, Royal Surrey County Hospital,
Guildford, Surrey GU2 7YXX, UK
Tel: +44 (0)1483 406886
Mobile +44 (0) 7770 820 145 (To 5pm EST)
URL: www.gcpl.co.uk
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Mitesh S Gandhi wrote:
"
It is not mandatory to administer a study medication with 240 mL only.
But whatever volume (eg., 200 mL) you are administering to volunteer
should be same for all the volunteers taking part into particular
study. And you have to justify why you administered 200 mL instead of
240 mL.
"
Hi Mitesh and Helmut
I agree, and in two current studies the clients want us to use 150ml,
so it
does vary greatly between studies. I'm not sure about justifying it. I
think the idea is just to use the kind of volume that people would
normally
expect to drink when taking tablets. I have been a bit worried that
150 ml
would not be enough for some subjects who have trouble swallowing
capsules
because we have had 1 subject who needed a second cup of 150 ml water.
I
considered better to allow him that than risk the tablets getting stuck
in
his oesophagus, especially as I knew that such relatively small volumes
make very little difference (See my reply to Ray French).
What I can't quite follow is Helmut's condition imposed by one of his
clients, to the effect that dosing the subjects had to be every 2
minutes. I
have never come across that before and am intrigued to know why it was
necessary. I presume it was nothing to do with Pk
Cheers
Andrew
Andrew Sutton,Guildford Clinical Pharmacology Ltd.
Hascombe Ward, Royal Surrey County Hospital,
Guildford, Surrey GU2 7YXX, UK
Tel: +44 (0)1483 406886
Mobile +44 (0) 7770 820 145 (To 5pm EST)
URL: www.gcpl.co.uk
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Dear All
Japanese Guideline mentions that
"4) b.i. Single dose studies: Drugs are usually given to subjects with
100-200 ml water (normally 150 ml) after fasting for more than 10 hr.
Fasting."
Guideline for Bioequivalence Studies of Generic Products
http://www.nihs.go.jp/drug/be-guide(e)/Generic/be97E.pdf
Does anyone have information of water volume effect on
pharmacokinetics? (especially 150 mL and 240 mL)
Thank you in advance.
Akiyuki Suzuki
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Back in ancient times (>20 years ago) when I worked in a clinical PK
unit, I was told that the 250 mL (8 oz) volume was determined from a
published paper that showed that this was the optimal volume for the
dissolution of a tablet in humans. What drug it was, what formulation
it was, and whether the paper even exists are all open to question. My
guess is there was a paper back in cloudy past, and since it was the
only one out there, people said, better this data than none at all, but
the origins of this are now lost, but might be recoverable through a
search of the old literature. It does seem now that the 250 mL is
taken more on faith than anything else. This is almost an urban legend
at this point.
Dale Sharp
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One issue that I think has not been raised in this thread regarding
fluid volume is the solubility of the drug.
If solubility is low, such that the dose cannot completely dissolve in
the administered volume, then the dosage form will not be completely in
solution. Theoretically, the concentration in the stomach will be the
solubility, assuming sufficient time for dissolution. Depending on the
pKa(s) of the drug, further dissolution may be faster or slower as the
dosage form moves into the small intestine.
With a higher fluid volume, more drug can go into solution faster,
which may affect the time course of absorption, and subsequently plasma
concentration-time. Patient compliance with dose volumes could be
critical to minimizing variability in clinical trials for low
solubility drugs.
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (SIMU)
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
Dear allBack to the Top
Thanks for sharing your knowledge.With continuation of this topic I
will like to ask one question.The drinking water quantity differs from
country to country.Eg.According to Canadian Guidelines it is up to
250ml while CPMP & Malaysian gidelines mention at least 150 ml of
fluid.In MCC it is 200 ml. Why is it so?
Thanks
DR.S.A.Desai
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Andrew Sutton wrote:
"
.... dosing the subjects had to be every 2 minutes
I have never come across that before and am intrigued to know why it was
necessary. I presume it was nothing to do with Pk
"
Perfect guess!
It resulted form one of these arguments which ended up with a statement
like "We do want it that way. Period."
BTW, the argument followed a line of "irrational overstandardisations"
which call for very narrow BMI indices, exclusion of females,
preferable inclusion of twins or triplets, washout periods in crossover
studies adjusted not the halflife of the drug but to the synodic month
of the moon (29d12h44m2.9s).
Regards
Helmut
--
Helmut Sch\0xB8tz Biokinet GmbH / Dept Biostatistics
Neubaugasse 36/11 Nattergasse 4
A-1070 Vienna/Austria A-1170 Vienna/Austria
tel/fax +43 1 9713935 tel +43 1 4856969 62
no cell phone ;-) fax +43 1 4856969 90
http://www.goldmark.org/netrants/no-word/attach.html
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Yes, gastric distention with enough liquid volume can mimic fed state
or so.
Please see :
Rebecca L. Oberle, Tzyy-Show Chen, Charles Lloyd, Jeffrey Barnett,
Chung Owyang,
James Meyer and Gordon Amidon. The Influence of the Interdigestive
Migrating Myoelectric
Complex on the Gastric Emptying of Liquids. Gastroenterology. 1990;
99(5):1275-1282.
Nasir Idkaidek,Ph.D.
Head of Clinical Studis
Triumpharma LLC.
JORDAN
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Nasir Idkaidek wrote" gastric distention with enough liquid volume can
mimic fed state"
I agree that It can abolish the migrating motor complex but a simple
liquid
will still empty much faster than a normal (semi) solid meal, invoke
many
less digestive enzymes and acid secretions and deliver far less of the
digesta to the portal blood system.
Mahesh was asking about 2 formulations of erythromycin. This macrolide
stimulates gastric contractions and hence gastric emptying. Faster
emptying
not only shortens t max but increases Cmax so I can see that if they
have
different potential to do this it might account for the difference in
bioavailability.
Regards to all.
Andrew Sutton
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