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Dear All,
According to US FDA guidelines, in BE studies drug should be
administered with 240 ml of drinking water. Is there any difference
between using chilled water and water at ambiant temperature.
Please share your expert comments.
Thanks and Regards.
Dr.Padmavathi Vutukuru
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Dear Dr Vutukuru
Ambient temperature is recommended. Chilled water may speed gastric
emptying.
Best wishes
Gilberto
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Gilberto,
Do you have a reference for this. I'd be very interested to see it as I
would have expected slowing.
Andrew Sutton
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
Mobile +44 (0) 7770 820 145 (To 5pm EST)
URL: www.gcpl.co.uk
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It's interesting because I wouldn't expect there to be much of a
difference; however, the TPD guidance (Conduct and Analysis of
Bioavailability and
Bioequivalence Studies - Part A: Oral Dosage Formulations Used for
Systemic Effects) goes a step further than the FDA, stating:
"On the morning of the study, up to 250 mL of water may be permitted up
to two hours before drug administration. The dose should be taken with
water of a standard volume (e.g., 150 mL) and at a standard
temperature."
We are now talking about a heat transfer problem. What would be the
gastric temperature from mixing alone? The volume of the human stomach
in the fasted state is about 1.5 L (from
http://hypertextbook.com/facts/2000/JonathanCheng.shtml). Given that we
are adding 250 mL to 1.5 L, this gives an instantaneous volume of 1.75
L after drinking. Assuming perfect and instantaneous mixing, a crude
estimation of gastric fluid temperature could be a weighted average:
T(stomach + cold water) = (1.50 L * 37 + 0.25 L * 0) / 1.75L = 31.7
degrees
T(stomach + tepid water) = (1.50 L * 37 + 0.25 L * 21) / 1.75L = 34.7
degrees
The difference is 3 degrees. This calculation assumes adiabatic
conditions, which is physiologically untrue since the walls of the
stomach will be providing heat as well. This calculation is only
looking at the stomach, whereas your drug will most likely be absorbed
elsewhere as well.
-Dave
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We use a fluid volume in human stomach in fasted state of 50 mL (before
the dose). The actual stomach volume may be 1.5L, but according to our
information, that volume is not filled with fluid. In fact, we use 1 L
as the fed state volume (before the dose).
The suggested dose volume would seem to provide more consistent
dissolution and gastric emptying in a study with multiple subjects. If
all subjects were allowed to take whatever volume of water they liked,
considerable variation in dissolution and gastric emptying could arise
with low solubility dosage forms. I know I am not one to take 240 mL at
once with tablets that I take - I probably take half that amount or less
typically.
Unless I have a headache. I remember listening to Gordon Amidon once
saying that if you want faster relief when you take something for a
headache, be sure to drink lots of water with the dose. It works.
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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I agree with Walter that the residual volume in a truly fasting stomach
will
not be anywhere near 1.5l and near 50ml is far more likely. One reason
why
I know this comes from using non-conductive test "meals" of pure water
(500ml) to cause a measurable increase in total upper abdominal
electrical
impedance while the stomach is filling. (The subsequent decrease gives
us
gastric emptying). The increase happens because pure water is
non-conductive. We know when a volunteer is not truly fasting because
the
gastric contents are then highly conductive and when present in
significant
amounts they contaminate the test meal of water (electrically speaking)
so
we do not observe the normal increase. From this I know that the vast
majority of subjects do have empty stomachs on fasting. Those that
don't
have ether cheated by eating breakfast and not telling us or they are so
anxious that their physiological background emptying of secretions has
stopped, making the secretions accumulate.
I suspect that COMPLETE gastric emptying of 50ml will be faster than
250ml,
so Walter's quicker onset of analgesia is not likely to be due to faster
delivery of the WHOLE dose. However, the leading edge part of the dose
will
progress along the ileum faster when the "meal" volume is larger, so
delivering the analgesic more quickly to a larger area of absorption
sites.
In addition we have some evidence from volunteer models of experimental
pain that analgesic activity is increased by faster rates of change of
concentration at the effective site. An example is showing analgesia in
a
laser pain threshold model after 2 separate doses of 1g acetaminophen
when
there was no such effect after 2g in a slow release formulation.( see
Nielsen JC et al, 1991, Br J Clin Pharmacol.)
Another possible reason is that some peptides normally released by food
entering the stomach such as CCK are thought to have a "well being"
effect
that might counter the headache or other pain. Most of us have probably
observed this when watching a contented baby feeding.. Walter's 250 ml
might
release more such peptides than half the volume.
Then of course there is the whisky he added to the water....
Andrew Sutton
Guildford Clinical Pharmacology Ltd.
The Technology Centre, Occam Road
Guildford, Surrey, UK. GU2 7YG
Tel: +44 (0)1483 455375. Direct: 688303
Mobile +44 (0) 7770 820 145 (To 5pm EST)
URL: www.gcpl.co.uk
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Dear Gilberto,
Its interesting to know that chilled water may speed gastric
emptying. Can you futher explain and give some reference. Thanks
R. C. Gupta
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along these lines.....
where can i find or does anyone know what the average maximum human
gastric volume is?
or range of volumes based on some criterion?
sincerely
J. Daniel Fleming, DDS, BS Pharm.
1819 Wyandotte
Kansas City, Missouri 64108-1901
816-841-0206, fx 816-841-0208
e-mail toxlevel.aaa.aol.com
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Whisky with acetaminophen?
Never -- that's a big no-no!!
(Maybe with aspirin . . .)
Walt : )
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The following message was posted to: PharmPK
Dear Gilberto
Its good to know about that there is temperature effect of water during
consumption of study drug. But I would know about that if we give
chilled water which causes vasoconstriction of stomach which delays
stomach emptying time. So how can chilled water speed gastric emptying?
Can you give some references about temp effect of water during drug
consumption?
Thanks and regards
Dr. Ilesh
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Hi Dr. Ilesh,
I did a quick search as this subject interests me. One interesting
study by Macedo et al. looked at the effect temperature of coffee (at
58, 37, and 4 degrees C) administered with a nasogastric tube after a
liquid test meal (1). They looked at intragastric temperature, gastric
acid secretion, and gastric emptying. Far from my original thinking, it
took about 17 minutes for the hot coffee to reach body temperature and
about 24 minutes for the cold coffee to reach body temperature.
However, they found "that over a wide temperature range, the
temperature of a liquid meal has little effect on gastric function in
humans."
There is a study about cold pain prolonging gastric emptying (2). The
authors concluded that "Cold pain stress delayed gastric emptying of
liquid but not solid meals." However the "cold pain" was administered
by dipping subjects' hands in ice water. There is another article in
Portuguese (3). The authors conclude, "The data permit us to conclude
that administration of water at low temperature inhibits the process of
gastric fluid emptying, but repeated administration of cold water does
not cause a cumulative inhibitory effect, at least at the time interval
studied here". Another study varied the temperature of orange juice (4,
37, and 50 degrees C) and examined the effects on gastric emptying (4).
They found that intragastric temperature returned to normal within
20-30 minutes, and found that the cold drink had a slower initial rate
of gastric emptying than the control drink (body temperature); however,
there was no change from control with the warm drink. Another study
found that "liquid meals, colder or warmer than body temperature have
an inhibitory effect on gastric emptying and show that a significant
delay in gastric emptying of liquids is obtained only with a warmer
meal." (5) Another nasogastric tube study (with 16 infants) found that
"the results showed a significant larger gastric retention for low
temperature one. Possibly, low temperature solutions decrease the
gastric peristalsis in accordance with hypothesis that low temperature
solutions may inhibit vomiting."
There was an animal study performed on monkeys (7). This study did not
find a difference in gastric motility or gastric emptying with
different temperatures of fluids infused through nasogastric feeding
tubes. I question the results however, since the monkeys were
restrained, I wonder how much stress had something to do with it.
As an aside, there was an interesting study where administration with
and without 150 mL of water didn't seem to have an effect on the
pharmacokinetics of an oral disintegrating lansoprazole tablet (8).
Looking at the data available, there doesn't appear to be a general
trend to support a sweeping blanket statement about the effects of
temperature on gastric emptying. Given that it can take 1/2 hour for
intragastric temperatures to return to normal, I would expect
consequences on dissolution and disintegration times, which would vary
depending on the formulation and solubility of the drug being studied.
Hope this helps,
-Dave
(1) McArthur KE et al. Am J Clin Nutr. 1989 Jan;49(1):51-4.
(2) Nakae Y et al. J Gastroenterol. 2000;35(8):593-7.
(3) Macedo Ada S et al. Arq Gastroenterol. 1986 Jul-Sep;23(3):184-8.
(4) Sun WM et al. Gut. 1988 Mar;29(3):302-5.
(5) Troncon LE, Iazigi N. Braz J Med Biol Res. 1988;21(1):57-60.
(6) Collares EF, Brasil Mdo R. Arq Gastroenterol. 1981
Jul-Sep;18(3):123-6.
(7) Williams KR et al., Nurs Res. 1975 Jan-Feb;24(1):4-9.
(8) Iwasaki K et al. Drug Metab Pharmacokinet. 2004 Oct;19(5):390-5.
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Hi Walt,
No problem as long as it in the modest amounts I had in mind. They
would be
less than many cases where people take acetaminophen, or paracetamol as
we
call it, for a hangover when they still have a skinful of alcohol.
Cheers
Andrew
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
Mobile +44 (0) 7770 820 145 (To 5pm EST)
URL: www.gcpl.co.uk
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)