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Hi everybody!!
I have one question that has been bugging me for some time.
Why fed conditions increase variability with highly variabile drugs
and decreases variability in low variabile drugs?
Maybe I am not seeing something but I would always expect that fed
conditions are more variabile as different physiological processes
are involved.
I would be very grateful if somebody could explain me this.
Thx in advance,
lidija
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HI lidiga,
Are you talking about variability across classes. Please quote specific
drugs for understanding it better.
Tripti
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Hy Tripti,
I am not talking about specific drug classes. It's one general rule as I
see it, maybe I am mistaking. My question is about intrasubject
variability.
I did see few crossover studies and intrasubject variability for Cmax
and AUC was decreasing in fed conditions if it was low in fasting and
was increasing or staying the same if variability was high in fasting
conditions.
The thing I don't understand is why we can't observe the same trend for
fed conditions why it contributes differently to intrasubject
variability.
Regards,
Lidija
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Hello Lidija
I would be interested to know which examples have given you this
impression
to see if they fit the following scenarios:
Relatively narrow variation could be due to absorption over a restricted
area of the upper GI tract. With food the tablet or capsule will
still pass
though the duodenum largely as a bolus because....MRI scans show that
the
solid food stays as a central mass for gastric processing while fluid
food
and mucus layers flow around the its margins and adjacent to the gastric
mucosa..... the capsule dissolves rapidly, so soluble drug will be
mostly in
the sub-mucosal layer whence it will be delivered to the duodenum over a
fairly short time. When it gets to the jejunum it will be absorbed
faster if
anything than in the fasted state because the ileum is doing its job of
absorbing food, and faster absorption will reduce variation.
In case 2 assume the wider variation is due to the drug being
absorbed lower
down the gut where there is more time for the drug to be spread out
so there
is inherently more variation in entry into plasma. The delay will
reduce
plasma concentrations due to distribution and the first pass effect will
then remove a greater and more varied proportion of the dose. In
addition,
the same absolute changes are a higher proportion of the means,
increasing
apparent variation that way.
This kind of thing might happen when a drug absorbed as in scenario A
is put
into a sustained or slow release formulation.
I hope this answers your question.
Andrew
--
Andrew Sutton, MBBS, MD(London), FFA
Guildford Clinical Pharmacology Ltd.
The Technology Centre, Occam Road
Guildford, Surrey, UK. GU2 7YG
URL: www.gcpl.co.uk
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Dear Andrew,
If I get it right, you think that immediate release formulations with
highly soluble drugs with absorption over resticted area are less
variabile under fed conditions because this drugs are more rapidly
absorbed.?
Can we assume that absorption of food is happening only in ileum?
This other scenario doesn't really go with the data I recently analyzed.
We had MR formulation with absorption over 12 hours, so it had to be
absorbed throw small and large bowel. In fasting conditions intrasubject
variability was less than 20% so this was a drug with low variability in
fed stat we observed decrease in variability.
I must say that this was a BE study and this variability represents all
the unexplained variations but when you do BE studies under both
conditions and the only thing you change is this meal before
administration of a drug than this difference in variability under two
conditions can be contributed to differences provoked by food and fed
state.
Do you by any chance know a good reference for differences in pH of GI
tract under fed and fasted conditions?
With regards,
Lidija
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Dear Lidija,
I did not follow your whole coversation about variability in fasting and
fed conditions but I seem to recall that you were using rats. If so you
can check: Kararli, Comparision of the gastrointestinal anatomy,
physiology and biochemistry of humans and commonly used lab animals,
1995,
Biopharm&Drug Dispos, 16, for pH in GIT in fasted and fed condition
(rat).
For humans check : Avdeef, Absorption and Drug Development, 2003 John
Wiley& Sons, Inc.
Hope this helps.
Best regards
Jeannine Fleth
--
Bayer Schering Pharma AG
Preclinical Pharmacokinetics
Berlin, S109, 4.OG. R 411a
e-mail: jeannine.fleth.-at-.bayerhealthcare.com
http://www.bayerscheringpharma.de
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The following message was posted to: PharmPK
Ok Lidija
You wrote:
L: If I get it right, you think that immediate release formulations
With highly soluble drugs with absorption over restricted area are
Less variable under fed conditions because this drugs are more
Rapidly absorbed.?
A: Basically yes because more rapidly reduces variability. I agree
that this is not the usual situation but I can just about imagine
that happening if the drug gets quickly into the fluid-mucus
layer around the bolus of food as opposed to being mixed into
the centre of the food. I would imagine that high potency
and solubility of the drug would favour this, but I would be I
interested to read what formulation experts think. This layer
lies adjacent to the stomach wall and flows around the food mass
as the stomach contracts and relaxes and it delivers soluble
material and small particles to the exit of the stomach at the
antrum. That process of squeezing and treating the food with
hydrochloric acid could well break down a normal tablet more
quickly than in an empty and relatively quiescent stomach. It also
possible that capsules in particular can float on the top of gastric
contents, which are there even in the fasting state and the more
so if volunteers are stressed because stress is also well known to
delay gastric emptying. The kind of stress that could do
it is venepuncture in a needle-phobic volunteer or a difficult draw
of a blood sample that causes discomfort.
The stress might be greater if the volunteers had not slept too
well or are bordering on hypoglycaemia due to a prolonged fast.
L: Can we assume that absorption of food is happening only in ileum?
A: Why would you want to do that? I was only saying that if the drug
is absorbed over a short length of gut, that will contribute towards
less variability.
L: This other scenario doesn't really go with the data I recently
analyzed.
We had MR formulation with absorption over 12 hours, so it had to be
absorbed through small and large bowel. In fasting conditions
intrasubject
variability was less than 20% so this was a drug with low variability in
fed stat we observed decrease in variability.
A: If we are talking about intrAsubject variability you must have
measured it several times in the same subject.....as that is unusual
in my experience can you confirm that is what you did? It's more
common to think about intERsubject variability across a group
of volunteers.
Again I would say that variability might be lower if the drug were
delivered
to the absorption site in a more consistent manner. If volunteers take a
standard meal at a standard time relative to dose it's not difficult to
imagine that both intra and inter-subject variations were reduced.
For example, in the fasting state large contraction waves move down the
whole gut from stomach to colon about every 90 minutes. They are even
called housekeeper waves because they sweep all before them. If you
dose
just before one of these leaves the stomach the MR tablet will pass
sooner
into the digestive tract than if you happen not to get one for an hour.
That source of variation is removed by food as it abolishes these
housekeeper waves.
L: I must say that this was a BE study and this variability
represents all
the unexplained variations but when you do BE studies under both
conditions and the only thing you change is this meal before
administration of a drug than this difference in variability under two
conditions can be contributed to differences provoked by food and fed
state.
A: As I hope I have illustrated, we mustn't forget the changing state
of the
volunteers which is a main reason for a balanced distribution of
formulations. For example if they had a painful or prolonged venous
cannulation on just the one day the stress would delay gastric
emptying only
on that day. They might be more anxious on the first day than on the
second
when they have become familiar with the procedures etc.
L: Do you by any chance know a good reference for differences in pH
of GI
tract under fed and fasted conditions?
A: Jeanine has just done that, I see. The only difference that I
know of is
that food provokes acid production in the stomach. The rest of the
gut in
humans at least stays virtually neutral in both fed and fasting
conditions,
although housekeeper waves will propel some acid for short distances
into
the ileum as far as the natural buffering effect will allow
I hope some of this makes some sense.
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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