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Dear All,
What is the difference between the following terminologies:
1. Systemic Availability
2. % Fraction Absorbed
3. Absolute Bioavailability
It appears that the systemic availability and absolute bioavailability are inter-changeable terms.
For an orally delivered, lipophillic drug having hepatic 1st pass effect, should all these values be equal ?
I would like to relate the above-mentioned query to an example of Atorvastatin tablets. Its absolute bioavailability is 12% while systemic availability is 30%. What does this mean and why is this so?
Thanks & Regards,
Neha Bhandari
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The following message was posted to: PharmPK
Hi Neha,
In my understanding, systemic availability refers to the fraction of the administered drug that has passed all the hurdles during its path from formulation (e.g. tablet or capsule) to the blood stream (past liver). This is generally less than % absorbed since the fraction of the drug that is absorbed may still undergo metabolism during its passage through the gut wall and the liver.
Absolute bioavailability is the value comparing the systemic availability after a certain formulation (e.g. a tablet) vs. that after an iv dose. It is understood that the systemic availability after the iv dose is 100% as all the drug is deposited into the blood without being degraded and lost due to incomplete absorption or gut wall/liver metabolism (also known as first pass effect).
Toufigh
Toufigh Gordi, PhD
Clinical Pharmacology, PK/PD analysis consultant
www.tgordi.com
E-mail: tg.aaa.tgordi.com
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Dear Neha,
systamic availability is just bioavailability of the drug. In other words it is the amount of the drug absorbed from the articular dosage form and route of administration. It can be expressed as the fraction of the drug absobed compared with the administered dose.
in case of absolute bioavailability, the bioavailability is compared with the I/V route.
Dr Zafar
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The following message was posted to: PharmPK
Dear Neha,
These terms have been used and misused frequently, and some of their
definitions have evolved over the past few decades.
Fraction or percent absorbed has a specific definition today that differs
from some of the older literature. In older articles the term absorbed was
often used to refer to systemic or absolute bioavailability. This can be
seen in Wanger-Nelson and Loo-Riegelmann IVIVC articles among others.
For an oral dose, the modern FDA-accepted definition of fraction absorbed
(Fa) refers to the fraction of the dose that leaves the intestinal lumen and
enters the enterocytes. From that point, several things can happen to the
drug molecules that get into the enterocytes. They may just pass through to
the portal vein, in which case the FDp (fraction dose to portal vein) would
be equal to the fraction absorbed (ignoring small amounts that might be
retained in the enterocytes).
But often some of the molecules that enter the enterocytes are metabolized
by gut enzymes (CYP 3A4 being the most common, but there are other CYPs,
UGTs, etc.). For some drugs, e.g., saquinavir, the fraction absorbed can be
high (on the order of 85%), but the fraction reaching the portal vein may be
much lower because of gut wall metabolism (for 600 mg saquinavir, on the
order of 15%). So in this case, Fa ~85% but FDp ~ 15%.
After the drug in the portal vein reaches the liver, it may pass through
without being metabolized (e.g., drugs that are not metabolized but are
cleared renally as parent drug) or it may be metabolized in the liver. If
there is no liver metabolism, then the amount eventually reaching the
systemic circulation (F, or absolute bioavailability) would be equal to FDp
(ignoring amounts that partition into hepatocytes but are not metabolized,
and are later distributed back into the plasma). For 600 mg saquinavir,
although FDP is on the order of 15%, additional 3A4 metabolism in liver
reduces the amount reaching the systemic circulation to about 0.5%. So for
saquinavir the approximate numbers would be Fa~85%, FDp~15%, F~0.5%.
Regarding systemic availability and absolute bioavailability, I believe
these terms are customarily used interchangeably when they refer to the
total amount of drug that eventually reaches the systemic circulation from a
dose. I'm not aware of a recognized standard, but there may be a useful
distinction for these terms.
I would suggest _if_ a distinction is desired, that systemic availability be
used as a time-dependent parameter, so that the systemic availability after
so many minutes or hours would have a value that would refer to the amount
of the dose that has reached the systemic circulation up to that time. This
would be distinct from absolute bioavailability, which I suggest should be
used to mean the amount that finally reaches the systemic circulation when
no more drug is available to cause a further increase. If you wait long
enough, the two terms reach the same value.
Best regards,
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (NASDAQ: SLP)
42505 10th Street West
Lancaster, CA 93534-7059
U.S.A.
http://www.simulations-plus.com
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Walt: Thank you for outlining your definitions with the example of saquinavir, since this assists comprehension of exactly what you are saying
Now regarding "absolute bioavailability" term my understanding from (Clinical Pharmacology literature) is quite consistent with the message from Toufigh Gordi repeated below.
"Absolute bioavailability is the value comparing the systemic availability after a certain formulation (e.g. a tablet) vs. that after an iv dose. It is understood that the systemic availability after the iv dose is 100% as all the drug is deposited into the blood without being degraded and lost due to incomplete absorption or gut wall/liver metabolism (also known as first pass effect)."
Therefore if we accept this definition can we say can we say that for the Wagner Nelson and Loo-Riegelmann equations that, following oral administration, more accurately what they provide is (Fraction drug systemically bioavailable) with respect to time and this fraction itself arises from a fraction of drug administered (to account for absolute bioavailability).
Angus McLean Ph.D.
Biopharm Global Inc.
8125 Langport Terrace
Gaithersburg,
MD 20877
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The following message was posted to: PharmPK
Angus,
Thank you for your comment. I also agree with Toughi's definition - IV
provides the reference as it is assumed to be 100% bioavailable (are there
exceptions - for example, can precipitation from an IV dose result in less
than 100% if solid particles are cleared out before they dissolve?).
IVIVC involves deconvoluting systemic availability vs time. I propose not
calling it "absolute bioavailability" until all of the drug that can reach
the systemic circulation has done so. As long as there is still fresh drug
being delivered to the systemic circulation, I propose calling the
cumulative amount that has reached the systemic circulation up to that point
the "systemic availability" at that point in time (or maybe even
"bioavailability vs time" - I was severely criticized once for using that
terminology but I still think there is nothing wrong with it), which I
propose is not yet equal to absolute bioavailability until there is no drug
left to become systemically available.
Note that any deconvolution method must result in exactly the same systemic
availability vs time, given a fixed set of PK parameters. Frankly, I don't
see a great deal of value to a formulation scientist in the traditional
method of correlating systemic availability vs time with in vitro
dissolution vs time. There is so much going on between the in vitro
experiment and the in vivo plasma concentration-time observations that gets
masked with such an approach. I prefer deconvoluting the in vivo
dissolution/release vs time using a detailed mechanistic model, which must
also result in the same systemic availability vs time. This method allows
the formulation scientist to see the differences between in vitro
dissolution and in vivo dissolution/release - arguably much more useful and
intuitive information. When in vivo dissolution/release is complex, the in
vitro experiment may not be at all similar, in which case a new in vitro
experiment can be designed that better mimics in vivo dissolution/release,
and from which a stronger correlation should result. And when the
dissolution/release profiles are quite different, the formulation scientist
can start to ask why - what is it about the in vivo environment that differs
from the in vitro experiment that causes such a difference.
I'm not sure I understand the wording of your last sentence where you refer
to the "fraction of drug administered". Administered, to me, implies the
amount dosed, which is not a fraction, but is just the dose. Can you
explain?
Best regards,
Walt
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (NASDAQ: SLP)
42505 10th Street West
Lancaster, CA 93534-7059
U.S.A.
http://www.simulations-plus.com
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Walt: For absolute bio availability determinations workers focus on having a homogeneous solutions for IV administration. It is possible to have some precipitation, but an effort is made to avoid this eventuality. On occasions solvents such as propylene glycol can be used in the injection medium to keep drug 100% in solution.
"fraction drug administered"
What I am thinking of is say a case of a drug (no metabolism) that is absorbed to the extent of only 90% of the weight administered drug. Let us suppose that 100 mg is administered so we have 90 mg absorbed. This can be referred to by a % weight (90) or it could also be referred to as a fraction (0.90) of the amount (weight) of the administered drug that is absorbed.
In this case the Wagner Nelson equation gives the fraction drug systemically bioavailble with respect to time and reaches 1. At fraction systemically absorbed =1 then the amount of drug absorbed is 90 mg.
I am seeking a better definition of the Wagner Nelson equation. Any comment David?
8125 Langport Terrace
Gaithersburg,
MD 20877
[See http://www.boomer.org/c/p4/c09/c0903.html
where A(max) is F x Dose - db]
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Certain molecules may bind to white cells, or be taken in as receptosomes into white and red cells, other drugs, both peptides and small molecules may be sequestered by platelets add in more complexity to "absolute" availability.
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The following message was posted to: PharmPK
Angus,
Thank you for your response.
I'm aware that when doing IV dosing, precipitation is to be avoided. My
point was that the reference condition of IV dosing assumes 100%
bioavailability, and that the potential exists (albeit rare) for this not to
be true. If it is not, then results for evaluating PO doses could be
misleading.
I think the terminology ("absorption") and mathematical approaches in the
early literature (e.g., Wagner-Nelson) require some caution. Using a method
that always normalizes the amount that becomes systemically available as 1
requires the scientist to recognize that 1 does not mean 100% bioavailable
but means (F x Dose), as David has suggested. These methods also rely on a
number of simplifying assumptions that are no longer necessary with today's
computer power and simulation technologies.
I prefer a mechanistic approach where the deconvoluted systemic availability
is the actual value (not normalized), and is the result of the chain of
processes involved in getting the drug from the ingested dosage form to the
systemic circulation. So the deconvolution process (which must result in the
same systemic availability vs time) is one of direct deconvolution of the in
vivo release, which in turn produces the correct systemic availability vs
time and plasma concentration-time curve.
The use of "fraction dose administered" doesn't appeal to me personally, but
that's my own perspective. I'd be interested in whether others use this
terminology.
Best regards,
Walt
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (NASDAQ: SLP)
42505 10th Street West
Lancaster, CA 93534-7059
U.S.A.
http://www.simulations-plus.com
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