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The following message was posted to: PharmPK
I have a question to the group. Here is a calculation given to me by
someone else.
At the 15 mg dose to healthy volunteers the peak plasma level
was 1.5 ug/ml.
Blood volume in humans is 70 ml/kg which in a 70 kg person
translates into 4900 mls of whole blood or 2940 mls of plasma.
Therefore, 2940 mls x 1.5 ug/ml = 4410 ug of drug in the plasma
compartment.
4.41 mg/ 15 mg dose ==> at least 29.4 % of the drug is orally
bioavailable
Does this make sense to you?
Thanks.
Peter L. Bonate, PhD
Director, Pharmacokinetics/Pharmacodynamics
ILEX Oncology
4545 Horizon Hills Blvd.
San Antonio, Tx 78229
phone: 210-949-8662
fax: 210-949-8487
email: pbonate.at.ilexonc.com
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[Quite a few answers, interesting calculation - could be useful for
low Vd drugs ;-) - db]
From: Varun_Garg.aaa.vpharm.com
Date: Tue, 6 Nov 2001 12:53:27 -0500
To: david.at.boomer.org
Subject: Re: PharmPK Bioavailability based on single time point
The following message was posted to: PharmPK
I think it makes sense, although it would be most useful for estimating
the minimum bioavailability of drugs that are not highly bound to tissues
and highly bound to plasma proteins.
I checked the F of Indocyanin Green, which is almost completely restricted
to plasma and administered by IV .
After a dose of 0.5 mg/kg, the mean Cmax obtained in serum was 7.2 ug/mL
and the back-extrapolated mean C0 = 13.4 ug/mL.
Using a plasam volume of 2940 mL (the mean weight of subjects was 70.08
kg), this would yield the amount in plasma = 13.4*2940 = 39.4 mg.
F= 39.4/35, so about right for an IV drug.
Varun
Varun Garg, Ph.D.
Vertex Pharmaceuticals, Inc.
130 Waverly Street
Cambridge, MA 02139
---
From: pradeepbhadauria.-at-.sify.com
Date: Tue, 06 Nov 2001 23:21:49 +0600 (IST)
To: david.aaa.boomer.org
Subject: Re: PharmPK Bioavailability based on single time point
The following message was posted to: PharmPK
Dear Dr. Bonate,
As per the classical definition of bioavailability it is the rate and
extent to which it reaches into systemic circulation from the site of
action. Basis of your calculation is not correct in my opinion
because what you have calculated is plasma drug concentration at that
time point of assessment.i.e at Cmax.considering one compartment
model of prediction . Even if you want to calculate the extent of
absorption ( amount reaches in circulation after oral adminstration
i.e. AUC ) you need of have more than one points( Preferably 4-5
points) to calculate the AUC( t =0-infinity) with accuracy.
Any further discussion in said matter will be appreciated.
With best regards,
Pradeep S. Bhadauria
R&D Executive,
Dr. Reddy's Laboratories Limited.
Hyderabad. ( INDIA ).
---
From: Spiresgate.aaa.aol.com
Date: Tue, 6 Nov 2001 14:52:32 EST
To: david.aaa.boomer.org
Subject: Re: PharmPK Bioavailability based on single time point
Dear Peter
It makes sense to me.
Most people assume when quoting plasma concentrations that the plasma
sample is representative of the total plasma in the body. therefore
there must be 4.41 mg of the drug in the systemic circulation, hence
the quoted bioavailability (or rather the total absorbed). the key
to the question perhaps is that this is a minimum - it can't be less
than this, but it could be (and probably is) more.
Joe Chamberlain
Spiresgate.-a-.aol.com
---
From: Norma Rohde
Date: Wed, 7 Nov 2001 07:48:01 +1100
To: david.at.boomer.org
Subject: RE: PharmPK Bioavailability based on single time point
The following message was posted to: PharmPK
Peter,
Seems to me there are three underlying assumptions of your calculation -
tissue distribution of the drug is negligible
the drug is totally absorbed into the systemic circulation at the
measurement timepoint
excretion or metabolism of the drug is negligible up to the time
point of the measurement
There would not be too many drugs that could comply with all these criteria.
Your estimate of bioavailability would definitely be 'at least' but even as
a rough guide could be quite misleading if one or more of the assumptions
aren't true.
Norma Rohde
---
From: hmehler.aaa.mehler.com
Date: Tue, 6 Nov 2001 11:12:31 -0800
To: david.-at-.boomer.org
Subject: Re: PharmPK Bioavailability based on single time point
The following message was posted to: PharmPK
Dr. Bonate:
We should be careful not to confuse the terms "bioavailability" and
"percent of drug absorbed". Bioavailability generally refers to a ratio of
areas under the curve obtained for the same compound administered by oral
and intravenous routes of administration. Your calculation seems to be an
attempt to quantify the percent of an orally administered drug absorbed into
the circulation.
What is the hypothetical volume of distribution of the drug and what
is tmax? Is the drug concentrated in peripheral tissue(s) at a
concentration greater than that of plasma (or whole blood)? If this is the
case would your calculation be biased?
Sincerely,
Howard Mehler
Howard S Mehler PhD JD & Associates Inc
---
From: hmehler.at.mehler.com
Date: Tue, 6 Nov 2001 17:38:18 -0800
To: david.-at-.boomer.org
Subject: Re: PharmPK Bioavailability based on single time point
The following message was posted to: PharmPK
Dr. Bonate:
To follow up to my previous email, here is a simple equation which
demonstrates the relationship between Cmax, F and V.
F x Dose
Cmax = __________
V
This can be found in Pharmacokinetics and Pharmacodynamic Data Analysis (ed
Gabrielson and Weiner) page 335.
Sincerely,
Howard S Mehler
Howard S Mehler PhD JD & Associates Inc
hmehler.-at-.mehler.com
---
From: "Melethil, Srikumaran K."
Date: Tue, 6 Nov 2001 12:41:50 -0600
To: david.at.boomer.org
Subject: RE: PharmPK Bioavailability based on single time point
The following message was posted to: PharmPK
Dear Peter:
Interesting question.
Conceptually, (assuming rapid, homogeneous mixing as with the one
compartment model) the answer makes sense.
Mathematically (one compartment) , [Cp(max) * (Vd)/D)] = F*
[ka/(ka-ke)] * (exp(-ktmax- exp (-katmax).
It would be interesting to know how the computed values by the two
methods compare. I look forward to comments by others
Sri
Srikumaran K. Melethil, Ph.D., JD (2001)
Professor, Pharmaceutics and Medicine
University of Missouri- Kansas City
203B Katz Hall (School of Pharmacy)
Kansas City, MO 64110
Phone: voice- 816-235-1794; fax - 816-235-5190
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[A few more replies - remember Dr Bonate was suggesting/asking about
this as an approximate method for a 'minimum' value for the amount
absorbed - db]
From: "arief hakim"
Date: Tue, 06 Nov 2001 21:24:44 -0800
To: david.at.boomer.org
Subject: Re: PharmPK Bioavailability based on single time point
The following message was posted to: PharmPK
If we want to know how much drug in the body we can use this :
Db = Cp*Vd
and F = Dose*100/Db
---
From: JYOTI PALIWAL
Date: Wed, 7 Nov 2001 13:12:53 +0530
To: david.-a-.boomer.org
Subject: RE: PharmPK Re: Bioavailability based on single time point
The following message was posted to: PharmPK
It makes lot of sense and application to compounds in early preclinical
discovery/development phase where iv data is not available.
As an extension to this concept, if one has 3 to 4 plasma concentrations of
a compound (with linear one compartment kinetics)at terminal log-linear
phase, then concentration at time (Cp0)can be obtained by extrapolation to
zero or linear regression. Further by applying Dr. Bonate's logic, one can
get a close estimate of oral bioavailability.
I look forward to share the opinion and experience of the group.
Jyoti Paliwal, Ph.D.
Ranbaxy Research Laboratories
Gurgaon-122001 (India)
---
From: "Hans Proost"
Date: Wed, 7 Nov 2001 12:02:14 MET
To: david.at.boomer.org
Subject: Re: PharmPK Re: Bioavailability based on single time point
The following message was posted to: PharmPK
Dr. Howard Mehler wrote:
> We should be careful not to confuse the terms "bioavailability" and
> "percent of drug absorbed". Bioavailability generally refers to a ratio of
> areas under the curve obtained for the same compound administered by oral
> and intravenous routes of administration. Your calculation seems to be an
> attempt to quantify the percent of an orally administered drug absorbed into
> the circulation.
This is a strange reasoning. By definition, bioavailability refers to
the fraction of the dose reaching the general circulation. And
bioavailability may be assessed from the ratio of AUC's after an
extravascular and intravenous dose, implicitly assuming that
clearance is the same on both occasions.
> To follow up to my previous email, here is a simple equation which
> demonstrates the relationship between Cmax, F and V.
>
> F x Dose
> Cmax = __________
> V
>
> This can be found in Pharmacokinetics and Pharmacodynamic Data Analysis (ed
> Gabrielson and Weiner) page 335.
This is a strange equation, since it would follow that no elimination
occurs before Cmax is reached, and that distribution occurs
instantaneously. This is never true, so this equation is never
correct. Of course it can be used as a rough approximation, in
particular if elimination is slow, distribution is fast and absorption is
fast.
Dr. Bonate's equation is 'better', since it claims to calculate a
minimum value for F, and this seems correct.
best regards,
Hans Proost
Johannes H. Proost
Dept. of Pharmacokinetics and Drug Delivery
University Centre for Pharmacy
Antonius Deusinglaan 1
9713 AV Groningen, The Netherlands
tel. 31-50 363 3292
fax 31-50 363 3247
Email: j.h.proost.-a-.farm.rug.nl
---
From: "Paul S. Collier"
Date: Wed, 07 Nov 2001 13:08:11 +0100
To: david.at.boomer.org
Subject: Re: PharmPK Bioavailability based on single time point
The following message was posted to: PharmPK
The method for calculation of bioavailability described by someone in
coversation with Dr Bonate is based on 4 assumptions, one or more of
which would almost certainly be untrue for all drugs. These assumptions
are as follows:
1. assumes absorption is complete at the time of the peak plasma
concentration (not true where absorption of the drug obeys first order
kinetics)
2. assumes no elimination prior to achieving and measuring the peak
plasma concentration (I cannot think of a situation where that could be
the case - if it was true, it would make estimation of apparent volumes
of distribution much easier)
3. assumes the drug does not distribute outside of the blood (not many
examples spring to mind)
4. assumes that plasma concentration and blood concentrations are
identical (unlikely to be the case if the drug binds to plasma proteins)
---
From: "Tata, Prasad N"
Date: Wed, 7 Nov 2001 08:17:47 -0600
To: david.at.boomer.org
Subject: RE: PharmPK Bioavailability based on single time point
The following message was posted to: PharmPK
Dear Peter:
I am assuming that you considered hematocrit as 40, which is a conservative
estimate. Other consideration could be 9% body weight for interstitial
fluids (extracellular water including plasma, assuming that there is no
tissue binding by your drug F= 70000*0.09*1.5/15000=0.63. Therefore fraction
of dose absorbed would be 63%. Hope this reasoning helps.
Prasad Tata
Mallinckrodt, Inc.
St. Louis, MO.
---
From: Edmond Edwards
Date: Wed, 7 Nov 2001 09:23:30 -0500
To: david.at.boomer.org
Subject: RE: PharmPK Bioavailability based on single time point
Just some questions:
If there's only one point, how can you be sure it's Cmax? If there's
more than one point (presumably) why not use this information?
Just asking.
... Edmond
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The following message was posted to: PharmPK
To All Interested Participants:
In response to Dr. Proost's comments, for the record it should be noted
that 21 CFR Section 320.1 (a) provides the following definition of
bioavailability:
"Bioavailability means the rate and extent to which the
active ingredient . . . is absorbed from a drug product....
The fraction or percent of drug absorbed indicates the extent of
absorption however 'F' does not provide information on the rate of
absorption and cannot suffice as a measure of bioavailability.
The intuitive equation Cmax = F x D / V was offered to demonstrate the
direct proportionality between the fraction of dose absorbed and the volume
of distribution. For a given Cmax and D, underestimation of the volume of
distribution will cause an underestimation of F the fraction of drug
absorbed. In fact, if you rearrange the equation in terms of F = Cmax x V /
D you have
Dr. Bonate's exact method of calculation ( where V is constrained to the
volume of the plasma compartment).
Sincerely,
Howard S Mehler
Howard S Mehler PhD JD & Associates Inc
hmehler.aaa.mehler.com
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The following message was posted to: PharmPK Howard Mehler wrote:
>To All Interested Participants:
> In response to Dr. Proost's comments, for the record it should be noted
>that 21 CFR Section 320.1 (a) provides the following definition of
>bioavailability:
>
> "Bioavailability means the rate and extent to which the
>active ingredient . . . is absorbed from a drug product....
>
> The fraction or percent of drug absorbed indicates the extent of
>absorption however 'F' does not provide information on the rate of
>absorption and cannot suffice as a measure of bioavailability.
>
Mehler has deleted a key phrase at the end of the 21 CFR 320.1
definition. The complete definition is:
"Sec. 320.1 Definitions. (a) Bioavailability means the rate and
extent to which the active ingredient or active moiety is absorbed
from a drug product and becomes available at the site of action. For
drug products that are not intended to be absorbed into the
bloodstream, bioavailability may be assessed by measurements intended
to reflect the rate and extent to which the active ingredient or
active moiety becomes available at the site of action."
The phrase "and becomes available at the site of action" is the key.
By definition, F *is* bioavailability. Fa is fraction absorbed.
F does provide information on the minimum extent of absorption,
because F >= Fa.
The difference between bioavailability (F) and fraction absorbed (Fa)
is the loss of drug after it is absorbed but before it reaches the
central circulation. The primary loss mechanisms are gut metabolism
and hepatic metabolism.
The most common usage is to define first pass extraction as the
amount of loss of drug that makes F different from Fa. Thus,
F = Fa (1 - FPE)
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
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The following message was posted to: PharmPK
>F does provide information on the minimum extent of absorption,
>because F >= Fa.
>
Can I blame this on jet lag - just got back from Japan when I wrote
this. Clearly,
Fa >= F
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.aaa.simulations-plus.com
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The following message was posted to: PharmPK
If F is bioavailability then
Cl iv
F = _____________
Cl oral
which may be obtained from the ratio of dose corrected total areas under
the plasma concentration curves following oral and intravenous
administration of the same drug in the same subject, on different occasions.
Note that the foregoing equation differs significantly from the
equation [F= (C x V)/D] which began this discussion.
Sincerely,
Howard S Mehler
Howard S Mehler PhD JD & Associates Inc
hmehler.-a-.mehler.com
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[Two more replies - sorry for the delay - the PharmPK archive is now
up-to-date as of the last weekend (http://www.boomer.org/pkin/) - db]
From: Walt Woltosz
Date: Thu, 15 Nov 2001 12:54:30 -0800
To: david.at.boomer.org
Subject: Re: PharmPK Re: Bioavailability based on single time point
The following message was posted to: PharmPK At 01:04 PM 11/15/01
-0600, you wrote:
>PharmPK - Discussions about Pharmacokinetics
>Pharmacodynamics and related topics
>
>The following message was posted to: PharmPK
>
> If F is bioavailability then
>
> Cl iv
> F = _____________
>
> Cl oral
>
>which may be obtained from the ratio of dose corrected total areas under
>the plasma concentration curves following oral and intravenous
>administration of the same drug in the same subject, on different occasions.
>
This equation is based on the assumption that CL is independent of
concentration. This is close enough to reality for many compounds,
but not generalizable to all compounds. For example, for any drug
that undergoes concentration-dependent metabolism (Michaelis-Menten
kinetics), this will not be true
> Note that the foregoing equation differs significantly from the
>equation [F= (C x V)/D] which began this discussion.
>
Actually, what began this discussion was Peter Bonate's question about whether
[F >= (Cmax x Vplasma)/D], not
[F = (C x V)/D]
He did not use the equations, but this is what it amounts to.
The original post by Peter Bonate asked about an indication of
*minimum* bioavailability. The maximum concentration in plasma
multiplied by the plasma volume certainly gives a good estimate of
the amount of drug in in plasma at that time. So, although there may
be more drug in other tissues, there is at least this amount that
made it into the central circulation - the basis for calculating
bioavailability.
I believe that is all Peter was trying to find out, and I think it is
reasonable that bioavailability must be at least this amount.
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.-at-.simulations-plus.com
---
From: "Hans Proost"
Date: Fri, 16 Nov 2001 13:55:16 MET
To: david.aaa.boomer.org
Subject: Re: PharmPK Re: Bioavailability based on single time point
The following message was posted to: PharmPK
Dear Dr. Mehler,
You wrote:
> If F is bioavailability then
>
> Cl iv
> F = _____________
>
> Cl oral
>
> which may be obtained from the ratio of dose corrected total areas under
> the plasma concentration curves following oral and intravenous
> administration of the same drug in the same subject, on different occasions.
This equation including the explanation is correct, but the equation
by itself is misleading. The assessment of F from the dose-corrected
AUC ratio implicitly assumes that clearance on both occasions is the
same.
I strongly advice never using the term Cl_oral for the term CL/F, as
in your equation (and many literature sources as well).
Best regards,
Hans Proost
Johannes H. Proost
Dept. of Pharmacokinetics and Drug Delivery
University Centre for Pharmacy
Antonius Deusinglaan 1
9713 AV Groningen, The Netherlands
tel. 31-50 363 3292
fax 31-50 363 3247
Email: j.h.proost.-a-.farm.rug.nl
Back to the Top
"Bioavailability means the rate and extent to which the active
ingredient or active moiety is absorbed from a drug product and
becomes available at the site of action." so what we calculate either
using the AUC method or by direct measurement is a "systemic
availability" (lets call it Fs) - which we assume to be a measure of
the true bioavailability (Fb).
Dr. Mehler is correct in that the direct measurement of Fb as the
fraction reaching the systemic circulation does not address the
"rate" part of the definition of Fb. but the AUC method of Fb
calculation does. *for a given clearance* the AUC will be higher when
the rate of systemic appearance of the drug will be higher.
therefore, the calculated F will also be higher. but the AUC method
of Fb measurement has its own limitations e.g. when drug clearance is
nonlinear. also, the AUC method of Fb calculation assumes that rate
and extent of absorption go hand in hand. we at Simulations Plus are
in the process of preparing a short manuscript which shows that it is
possible for the AUC to increase while the fraction of drug reaching
the systemic circulation decreases! in that case, should the
calculated Fb be higher or lower?
therefore, we decided to stick to the definition of Fb as the
"fraction reaching the systemic circulation"(Fb=Fraction absorbed
(1-first pass)). the "rate" part of the definition seems fairly
ambiguous - it does not specify what rate of absorption should be
considered the minimum or the maximum or some sort of a time-averaged
rate, etc. on the other hand, the "fraction reaching the systemic
circulation" is a cold hard number. it is hard to estimate from
experiments, but in our simulations using GastroPlus, it can be
calculated directly.
The Cmax method of F estimation is a simplified version of the AUC
method, subject to assumptions such as no distribution, no
elimination until Cmax, etc. so, it is a good estimate of the minimum
F.
maybe it is a good time for these definitions to be re-evaluated and
standardized with the new flood of information available on each of
these processes. for e.g. with the recognition of gut first pass,
absorption is being redefined as the fraction crossing the apical
intestinal barrier and distinct from the fraction reaching systemic
circulation.
Balaji Agoram, Ph.D.
Senior Scientist/Product Manager
Simulations Plus, Inc. California
http://www.simulations-plus.com
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The following message was posted to: PharmPK
Dear Dr. Agoram,
Your comments with respect to the meaning of bioavailability are
correct (differentiating between 'systemic availability' and
'bioavailability'), although I am not quite sure that everybody uses
the same definition. This could start a new thread in the PharmPK
group!
You wrote also:
> Dr. Mehler is correct in that the direct measurement of Fb as the
> fraction reaching the systemic circulation does not address the
> "rate" part of the definition of Fb. but the AUC method of Fb
> calculation does. *for a given clearance* the AUC will be higher when
> the rate of systemic appearance of the drug will be higher.
This is not true. In case of linear kinetics, AUC is independent of the
rate of entering the systemic circulation, and thus are F (either Fs
or Fb). Of course, if kinetics are nonlinear, or if AUC is truncated
due to lack of sensitivity of the assay, then this could be the case.
But not as the general case.
> also, the AUC method of Fb calculation assumes that rate
> and extent of absorption go hand in hand.
Again, I do not agree. In principle, rate and extent of absorption are
independent. Of course, there may be many situations where this is
not the case (e.g. retarded release may result in decreased F), but
this is not the general case.
> we at Simulations Plus are
> in the process of preparing a short manuscript which shows that it is
> possible for the AUC to increase while the fraction of drug reaching
> the systemic circulation decreases! in that case, should the
> calculated Fb be higher or lower?
This sounds interesting! I am eager to read this paper.
> Fb ... is hard to estimate from experiments,
I still think that the AUC ratio is OK, perhaps with exception of some
rather strange cases.
> but in our simulations using GastroPlus, it can be
> calculated directly.
This can be the start for again a new thread: do you prefer
calculated values for F over values obtained from experimental AUC
values? I don't.
> maybe it is a good time for these definitions to be re-evaluated and
> standardized with the new flood of information available on each of
> these processes. for e.g. with the recognition of gut first pass,
> absorption is being redefined as the fraction crossing the apical
> intestinal barrier and distinct from the fraction reaching systemic
> circulation.
I agree. However, the problem is that we do not have easy access to
the experimental data needed to do this. Certainly not in humans.
Best regards,
Hans Proost
Johannes H. Proost
Dept. of Pharmacokinetics and Drug Delivery
University Centre for Pharmacy
Antonius Deusinglaan 1
9713 AV Groningen, The Netherlands
tel. 31-50 363 3292
fax 31-50 363 3247
Email: j.h.proost.-at-.farm.rug.nl
Back to the Top
The following message was posted to: PharmPK
"Balaji Agoram (by way of David Bourne)" wrote:
>
> PharmPK - Discussions about Pharmacokinetics
> Pharmacodynamics and related topics
>
> "Bioavailability means the rate and extent to which the active
> ingredient or active moiety is absorbed from a drug product and
> becomes available at the site of action." so what we calculate either
> using the AUC method or by direct measurement is a "systemic
> availability" (lets call it Fs) - which we assume to be a measure of
> the true bioavailability (Fb).
>
> Dr. Mehler is correct in that the direct measurement of Fb as the
> fraction reaching the systemic circulation does not address the
> "rate" part of the definition of Fb. but the AUC method of Fb
> calculation does. *for a given clearance* the AUC will be higher when
> the rate of systemic appearance of the drug will be higher.
I do not agree with the last statement. If clearance is constant i.e.
we assume first order kinetics then AUC, the integral of
concentration with respect to time, loses all information about time
and thus there can be no information about rate of absorption. This
is a fundamental problem with any method that computes AUC -- time is
lost.
Nick Holford, Divn Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand
email:n.holford.-a-.auckland.ac.nz tel:+64(9)373-7599x6730 fax:373-7556
http://www.phm.auckland.ac.nz/Staff/NHolford/nholford.htm
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The following message was posted to: PharmPK
"Balaji Agoram (by way of David Bourne)" wrote:
>
> PharmPK - Discussions about Pharmacokinetics
> Pharmacodynamics and related topics
>
> "Bioavailability means the rate and extent to which the active
> ingredient or active moiety is absorbed from a drug product and
> becomes available at the site of action." so what we calculate either
> using the AUC method or by direct measurement is a "systemic
> availability" (lets call it Fs) - which we assume to be a measure of
> the true bioavailability (Fb).
>
> Dr. Mehler is correct in that the direct measurement of Fb as the
> fraction reaching the systemic circulation does not address the
> "rate" part of the definition of Fb. but the AUC method of Fb
> calculation does. *for a given clearance* the AUC will be higher when
> the rate of systemic appearance of the drug will be higher.
If the kinetics are linear, AUC should NOT depend on the rate of systemic
appearance of drug. AUC is truly independent of the underlying measure of
absorption rate, namely, Ka, in one or multi- compartment models. See
Phillips, K., Biopharmaceutics and Drug Disposition 14, 643 (1993) and Zha,
J. et al., Drug Information J. 29, 989 (1995).
For the record, concerning the distinction between "absorption" and
"bioavailability" as mentioned previously in this thread, a recent
commentary by Win Chiou attempts to clarify the issue (He recommends using
"bioavailability" in all instances.) and also invites others to contribute
their opinions on the matter. (See: Chiou, W., J. Pharmacokin. and
Pharmacodyn. 28, 3 (2001))
Also, since an ideal metric for rate in bioavailability/bioequivalence
studies is problematic (especially, Cmax), I note that the latest FDA
Guidance now emphasizes thinking in terms of "exposure" rather than "rate
and extent" in such studies.
Best wishes,
Peter
Peter W. Mullen, Ph.D., FCSFS,
Kemic Bioresearch
PO Box 878
Kentville
Nova Scotia, B4N 4H8
Canada
Tel. 902-678-8195 Fax 902-678-2839 URL www.kemic.com
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The following message was posted to: PharmPK
Dear Sir,
At 12:58 PM 11/27/01 -0600, you wrote:
>PharmPK - Discussions about Pharmacokinetics
>Pharmacodynamics and related topics
>
>The following message was posted to: PharmPK
>
>Dear Dr. Agoram,
>
>You wrote also:
>> Dr. Mehler is correct in that the direct measurement of Fb as the
>> fraction reaching the systemic circulation does not address the
>> "rate" part of the definition of Fb. but the AUC method of Fb
>> calculation does. *for a given clearance* the AUC will be higher when
>> the rate of systemic appearance of the drug will be higher.
>
>This is not true. In case of linear kinetics, AUC is independent of the
>rate of entering the systemic circulation, and thus are F (either Fs
>or Fb). Of course, if kinetics are nonlinear, or if AUC is truncated
>due to lack of sensitivity of the assay, then this could be the case.
>But not as the general case.
let us consider a drug, whose fraction absorbed when administered
orally is limited by dissolution. consider two doses of this drug -
dose 1 is made up of smaller particles than dose 2. since the drug is
dissolution limited, it is possible for a higher fraction of dose 1
to be absorbed than dose 2. if the clearance is the same for both
doses and is linear, the "rate of entering the systemic circulation"
of drug from dose 1 will be higher than from dose 2, and so will be
the AUC. i should probably rephrase my original comment as "*for a
given clearance* the AUC will be *equal to or higher* when the rate
of systemic appearance of the drug from an oral dose is higher".
it is true that the in the case that the same amount of drug made it
into systemic circulation the AUC is independent of the rate of
entering systemic circulation. for IV administration, this is true.
for oral administration this may not always be so.
>> Fb ... is hard to estimate from experiments,
>
>I still think that the AUC ratio is OK, perhaps with exception of some
>rather strange cases.
>
>> but in our simulations using GastroPlus, it can be
>> calculated directly.
>
>This can be the start for again a new thread: do you prefer
>calculated values for F over values obtained from experimental AUC
>values? I don't.
i do not suggest that calculated values be used exclusively over the
experimental AUC values. very few have the luxury of calculated F
values from sophisticated modelling programs or extensive
experiments. but it is imperative that people who use experimental
AUC values are aware of the pitfalls in its use. on the other hand,
it is important for modelers to understand experimental limitations.
as far as preference goes, if all i need is an idea of the
bioavailability, then the AUC method will suffice. but the simulated
F also gives me information on the reasons behind low (or high)
bioavailability, thus giving me valuable insight into the behavior of
the drug.
Balaji Agoram, Ph.D.
Senior Scientist/Product Manager
Simulations Plus, Inc. California
http://www.simulations-plus.com
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The following message was posted to: PharmPK
Dear Dr. Agoram,
Thank you for your reply. You wrote:
> let us consider a drug, whose fraction absorbed when administered
> orally is limited by dissolution. consider two doses of this drug -
> dose 1 is made up of smaller particles than dose 2. since the drug is
> dissolution limited, it is possible for a higher fraction of dose 1
> to be absorbed than dose 2.
OK. But this implies a nonlinear process, i.e. the rate of dissolution
is not proportional to the dose. And if the time for dissolution is not
limited due to movement away from absorption sites, the fraction
reaching the general circulation will be the same. You are right to
say 'it is possible', but F also may be the same (which is the 'normal
case' in my view).
> i should probably rephrase my original comment as "*for a
> given clearance* the AUC will be *equal to or higher* when the rate
> of systemic appearance of the drug from an oral dose is higher".
I still not agree. As stated before, in the 'normal case' AUC is
unaffected. You may say: ...the AUC may be higher ... due to an
increased fraction of the dose reaching the general circulation. (and
that was the point of discussion).
> if all i need is an idea of the
> bioavailability, then the AUC method will suffice.
'An idea of the bioavailability' is an understatement of the importance
of bioavailability for the relationship between dose and plasma
concentration. You simply need to know it, and the AUC method is
the most straightforward method to get it. In addition, AUC is a direct
measure of exposure to the drug, which is also a useful concept,
both for single-dose as well as for multi-dose drug use.
For the remainder, I agree with your view.
Best regards,
Hans Proost
Johannes H. Proost
Dept. of Pharmacokinetics and Drug Delivery
University Centre for Pharmacy
Antonius Deusinglaan 1
9713 AV Groningen, The Netherlands
tel. 31-50 363 3292
fax 31-50 363 3247
Email: j.h.proost.aaa.farm.rug.nl
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As far as drug absorption is concern, it is very important in early
phase of drug discovery, more specific is before lead selection to
have an idea of absorption of NCE.So what I feel that if we are
geting the idea of its absorption from single point BA, we can
roughly predict the BA of that entity.Which will increase the speed
in discovery.In CaCO2 cell lines we are measuring the absorption of
drug and not the BA.So I think this single point BA will be useful
for getting a rough idea regarding absorption.Any way in single point
how we come to know about tmax ?For that we have to perform full
experiment.
With regards.
Jakir Pinjari.
Zydus Research Centre-Ahemadabad.
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