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I´m from Chile, i´m a pharmacist student, and i´m working in a
project about biowaiver.
at this time i need information about permeability, of some
drugs, like Venlafaxine HCl, tramadol HCl, sibutramine HCL, zolpidem
hem., Fluoxetine HCl, Enalapril Maleato, Metoclopramide HCl,
Femproporex HCL.
greetins from Chile
thank you
Alexsy Lobos A.
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Human permeability of Enalapril maleate is 1.9X10-4 cm/sec.
Nasir M. Y. Idkaidek, Ph.D.
College of Pharmacy,
JUST, Irbid, JORDAN.
E- mail: dekaidek.-at-.just.edu.jo
Internet : http://www.geocities.com/idkaidek/
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Dear collegues.
I would need advice with the following topic:
In which cases may a drug be classified as highly permeable
(Biopharmaceuticals Classification System) on the basis of
bibliography values for oral absorption?
Thankyou very much
Carlos Montuenga
Madrid Spain
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Carlos,
according to the BCS (Biopharmaceutical Classification System) a drug
should
be consideres as highly permeable if its absorption is higher than 90%
per
os.
Regards,
Frederic DOC
PFIZER Global R&D
Fresnes Laboratories
FRANCE
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A drug can be classified as highly permeable when the fraction of oral
solution absorbed is greator than 90%
Nasir M. Idkaidek, Ph.D.
College of Pharmacy
JUST, Irbid, Jordan.
E-mail: dekaidek.-at-.just.edu.jo
http://www.geocities.com/idkaidek/
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Dear Carlos,
I believe the log P value i.e. the partition coefficient of a drug in
octanol:water system can give some idea about its permeability. Higher
the value of partition coefficient, higher will be the permeability.
May be on this basis, you can classify a particular drug as highly
permeabale until you get the real permeability using human intestine
method or caco 2 cell line.
regards
Sanjay
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Dear Carlos,
Based on the biopharmaceutical classification system , you can
determine the permeability class of the drug by making use of the
extent of oral absorption data in human or sometime in suitable animal
model that can be well correlated with the extent of oral absorption in
human.You can classify the drug as highly permeable if the extent of
oral absorption is more 90% or more based on the mass balance
determination after oral absorption.You can also use the absolute
bioavailabilty ( IV control) data generated/reported of the drug in
question as the predictor of the extent of absorption.
Kind regards,
Pradeep S. Bhadauria
Ranbaxy Research Laboratories,
INDIA.
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I agree with the concept of the 90% and it is said that when a drug has
an
absolute bioavailability of 90% or higher, it could be assumed that it
is a
highly permeable drug.
However, a new question is:
If a drug has an absolute bioavailability of 65% but, at the same time,
has
a 90% urinary excretion (of ~ 14% drug + ~ 76% metabolite) in relation
with
dose, is it possible to consider that its absorption had been of 90%?
(I think that probably the absorption was of 90% but due to the first
pass
elimination, a reduced absolute bioavailability was determined and, if
this
would be the case, then, such drug could be considered a highly
permeable
one. However, in this rationale we would not be considering that part
of the
metabolites could have been due to the intestinal metabolizing system,
but
is this such an important contribution?)
Silvia
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First of all, a highly permeable drug is of 90% fraction of oral dose
absorbed and Not 90% absolute bioavailability.
A second point is we can not assume 90% absorption when we have 90%
elimination because we still have metabolism issue in between.
Permeability and absorption determination can be done via caco2 cells
(in-vitro), perfusion experiments (in-situ & in-vivo) or by computer
simulations (in-silico).
Nasir M. Idkaidek, Ph.D.
College of Pharmacy
JUST, Irbid, Jordan.
E-mail: dekaidek.-at-.just.edu.jo
http://www.geocities.com/idkaidek/
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Frederic,
For biowaiver in case of generic drugs belonging to BCS classification
I, whose permeability/absorption of the drug is already reported, does
one have to generate permeability data for submission to FDA or
reference to various reports/ innovator data in FOI will be adequate?
Sunil V
Lupin Research Park,
Pune, India.
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Dear Silvia,
As i said a mass balance is required in determination of the oral
absorption. ( considering the parent drug and major metabolite). But
the metabolite appearing in blood because of the gut wall metabolism
should not be considered for the establishing the BCS Permeability
classification. In short you have to document followings before u can
apply BCS based waiver:
1) The drug is stable in the GIT ( free from Gut wall/local metabolism).
2) The PK is linear in practical dose range.
3) The excipients used does not affect the Absorption pattern ( like
Tween 80/Cremophor mimick the glycoprotien pump( MDP) efflux, oleic
acid affect the GI motility).
4) Prodrugs need to be excluded from the BCS criteria ( A debate is
going in FDA working committee).
Once you have established the above parmeters u can even apply the
absolute bioavailability with necessary studies to substantiate the
data.
Thus its quite likely that the extent of oral absorption is say 75 %
and while adding metabolite then actually the extent of absorption is
more than 90% thus the drug will be a highly permeable drug.
Please note that if the contribution of the metablite is moderate then
its OK otherwise if the drug gets metabolized very fast that mandate us
to consider the drug a Highly Variable Drug ( HVD)then BCS could not be
applicable probably as one can not seek biowaiver for HVD .Rather a
biostudy is sometime recommended for all strenghths.
I hope this would answer your querries.
Kind regards,
Pradeep S. Bhadauria
Ranbaxy Research Laboratories.
INDIA.
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Silvia,
you point out the issue when using the bioavailability as an absorption
describing parameter.
While doing this, we take into account a metabolism parameter that does
not
have to be considered in absorption.
According to the FDA guidance, permeability should be determined by a
mass-balance study in humans. But other methods can be used if they
demonstrate their reliability using reference compounds with known
extents
of absorption in humans. Caco-2 monolayer studies are one of these
methods.
Then a compound should be consideres as highly permeable if its Caco-2
permeability is higher than 2.10-4 cm/s.
To answer your question of the intestinal metabolism contribution, I
think
that it is a quite exceptional contribution even if cases of intestinal
cyp
P450 are reported.
Regards,
Frederic
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I brought the issue of evaluating Permeability based on Absolute
Bioavailability because the FDA Guidance for Industry: "Waiver of In
Vivo
Bioavailability and Bioequivalence Studies for Immediate-Release Solid
Oral
Dosage Forms Based on a BCS" says on item III.B: "The permeability
class of
a drug substance can be determined in human subjects using mass balance,
absolute BA or intestinal perfusion approaches. ......... In many
cases, a
single method may be sufficient (e.g., when the absolute BA is 90% or
more
or when 90% or more of the administered drug is recovered in urine).
When a
single method fails to conclusively demonstrate a permeability
classification, two different methods may be advisable......."
So, I used to understand that if Absolute BA is of 90% or more, one
could
assume high permeability or is there any case in which this is not true?
Silvia
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Sunil,
in case of generic drugs you "only" have to prove the bioequivalence of
your
drug in its dosage form (compared to the princeps one) throughout human
data. There is no need (and no obligation as well) for you to re-perform
other studies. Reference to reports is enough to document your generic
drug.
Regards,
Frederic
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Silvia,
you are absolutely right. If BA is higher than 90% that means that 90%
of
your drug is absorbed at least. It can not be less. The problem is when
you
have less than 90% BA with a known part of metabolism. This is the
reason
why the FDA guidance says that you have to perform a mass-balance study.
This allows you to follow the absorbed drug whether it is unchanged or
metabolized.
I would also agree with the use of urine recovery studies. This is
another
method as relevant as the mass-balance study.
So I would suggest:
- if human BA is > or = 90% your drug is said highly permeable
- if human BA is < 90% you perform a mass balance study (or urine
recovery) to calculate the total amount of drug absorbed.
- but if you have a fully validated Caco-2 permeation test it should
be easier and cheaper to use it to check permeability.
Does it make sense ?
Regards,
Frederic
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At 06:47 AM 10/29/02, pradeep bhadauria wrote:
As i said a mass balance is required in determination of the oral
absorption. ( considering the parent drug and major metabolite). But
the metabolite appearing in blood because of the gut wall metabolism
should not be considered for the establishing the BCS Permeability
classification.
Why not?
Absorption is defined as crossing the apical membrane of the
enterocytes. This definition was reinforced at the recent AAPS BCS
Workshop in Arlington, Virginia a few weeks ago. So if the BCS guidance
says 90% absorbed, then it should mean 90% crossing the apical membrane.
What happens after that is not a permeability issue, but a metabolism
issue. So the drug can have high permeability, but still have low
bioavailability. "Extent of absorption in humans can be demonstrated by
mass-balance pharmacokinetic studies or by absolute bioavailability
studies." (BCS Guidance) As long as such studies properly account for
each clearance pathway, and mass balance can be shown by including
metabolite recovery, it would seem that a drug with high absorption
across the apical membrane would meet the 90% requirement even if most
of it is then metabolized in gut. The point of the BCS guidance classes
(as I understand it) is - does the drug in a test formulation get into
solution and subsequently get absorbed at the same rate as the
reference formulation?
Saquinavir is an excellent example of a drug with high absorption but
low bioavailability. Although it's absorption is not quite 90% - our
best analysis to date is that, for a 600 mg dose, over 80% crosses the
apical membrane, but bioavailability is less than 1% due to high 3A4
metabolism in gut (which accounts for most of the metabolism for this
drug) followed by high first pass extraction in liver for the remainder
that survives gut first pass extraction and reaches the liver. (The
solubility of saquinavir is too low for Class I, but if it had higher
solubility, it would almost meet the requirements for Class I.)
Because the variability of bioavailability for such drugs is quite
high, I believe that a biowaiver may not be granted on other grounds,
even if they achieve 90% absorption. However, I think this is a bit
unfair, in that variability in metabolism is present even in the
reference formulation, so a test formulation with similar absorption
rate should be expected to have the same variability in metabolism.
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (SIMU)
1220 W. Avenue J
Lancaster, CA 93534-2902
U.S.A.
http://www.simulations-plus.com
E-mail: walt.at.simulations-plus.com
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