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To: PharmPK.aaa.pharm.cpb.uokhsc.edu.aaa.inet
cc:
From: Keith W Ward .-at-. SB_PHARM_RD
Date: 10-Dec-97 15:39:25
Subject: Apparent Bioavailability in Excess of 100%
Categories:
PharmPK Group,
In analyzing some data recently, we ran across a number of test molecules
which appeared to possess systemic oral bioavailability (F) substantially
in excess of 100% (i.e., 150-220%). Our study design was as follows:
administer a 30-min i.v. infusion on study day one, and calculate standard
noncompartmental PK parameters from the resulting concentration-time data.
On study day two, administer the same compound by oral gavage, in solution,
and again get PK parameters from the conc.-time data. To estimate F, we
used the ratio of the dose-normalized AUCs for each dosing regimen. (i.e.,
DNAUCpo/DNAUCiv *100).
After observing this phenomenon, we re-did several studies with one of the
compounds of interest, lowering the p.o. dose such that it was identical to
the i.v. dose. Each time, our apparent F was on the order of 150-180%.
We have considered several possibilities, including route-dependent
enterohepatic recirculation (if absorption is rapid, the liver could see a
much larger dose after po dosing, and more compound could be excreted in
bile, leading to increased recirculation) and (less likely) pulmonary
elimination of the compound following i.v. dosing.
Input from the group would be most appreciated. Does anyone else know of
examples of compounds with apparent F this large? We can find no such
references in the literature, but would appreciate any references you may
have. Also, are our explanations of the phenomenon reasonable? Are there
others we are missing? If so, how would one design an experiment to test
the alternative hypotheses? Any input would be helpful - I look forward to
reading your discussion postings on this topic.
Thanks for your help,
Keith Ward
Keith_W_Ward.-at-.sbphrd.com
(610) 270-5705
Investigator, DMPK
SmithKline Beecham Pharmaceuticals R&D
King of Prussia, PA
Of course, any comments, opinions, ideas, etc. in this message are mine and
not the company's.
[Comment from David Bourne - Any (other) suggestion of non-linear
pharmacokinetics? Saturable metabolism or saturable protein binding have
the potential to distort the determination of F from AUC ratio calculations
- probably in opposite directions. Non compartmental methods including F
from AUC ratio become much less convenient when there is non linear
kinetics. Have you performed dose ranging studies? I would recommend
simultaneous fitting of IV and oral data with if appropriate non-linear
(saturable) components. Enterohepatic recycling etc. will also make the
'simple' non compartmental analysis invalid]
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X-Sender: jelliffe.aaa.hsc.usc.edu
Date: Thu, 11 Dec 1997 14:34:03 -0800
To: PharmPK.-a-.pharm.cpb.uokhsc.edu
From: Roger Jelliffe
Subject: Apparent Bioavailability in Excess of 100%
Dear Keith:
Sorry about the previous message. It inadvertantly got sent before
I had
finished it.
I think David Bourne's comments are very good. The only other thing I
would suggest is another way of modeling the data. For example, you might
make an iterative Bayesian and also an NPEM model, in which both regimens
can be combined into a single consecutive regimen. You can also get F from
such a mixed IV-PO regimen with this software.
In addition to the basic linear model having an absorptive,
central, and
(if needed) a peripheral compartment, we are now starting to make nonlinear
and larger NPEM models using the Cray T3E at the San Diego Supercomputer
Center. There you can make your model by typing the ODE's, etc, and running
it.
Hope this helps a bit,
Roger Jelliffe
************************************************
Roger W. Jelliffe, M.D.
USC Lab of Applied Pharmacokinetics
CSC 134-B, 2250 Alcazar St, Los Angeles CA 90033
Phone (213)342-1300, Fax (213)342-1302
email=jelliffe.aaa.hsc.usc.edu
************************************************
Take a look at our Web page for announcements of
new software and upcoming workshops and events!!
It is http://www.usc.edu/hsc/lab_apk/
************************************************
[db - Roger has added the dimension of population analysis along with
simultaneous iv/po modeling. The model would need to 'also' include a
nonlinear component. Modeling individual subject data may not require a
Cray ;-)]
---
From: "Bruce"
Organization: School of Pharmacy
To: PharmPK.aaa.pharm.cpb.uokhsc.edu
Date: Fri, 12 Dec 1997 15:42:04 +1000
MIME-Version: 1.0
Subject: Re: PharmPK Apparent Bioavailability in Excess of 100% - REPLY
CC: Keith_W_Ward.aaa.sbphrd.com
Priority: normal
I recall that F values greater tna 100% also have been seen with
oral administration of ethanol if the rate of administration is rapid
enough.
Contact Nick Holford (n.holford.at.auckland.ac.nz) for further details.
Cheers,
BC
+ + + + + + + + + + + + + + + + + + + + + + + + + + + + +
Bruce CHARLES, PhD
School of Pharmacy
The University of Queensland
Brisbane, Qld, Australia 4072
Telephone : +61 7 336 53194
Facsimile : +61 7 336 51688
Email : Bruce.Charles.at.pharmacy.uq.edu.au
+ + + + + + + + + + + + + + + + + + + + + + + + + + + + +
---
Comments: Authenticated sender is
From: "Ralph Quadflieg"
To: PharmPK.at.pharm.cpb.uokhsc.edu
Date: Fri, 12 Dec 1997 12:46:19 +0000
MIME-Version: 1.0
Subject: Apparent Bioavailability in Excess of 100%
X-Confirm-Reading-To: "Ralph Quadflieg"
X-pmrqc: 1
Priority: normal
Dear members,
isn't it possible that there is a new metabolite, which is only built
following the peroral route of administration, and that this
metabolite interferes with the analytic ?
Ralph Quadflieg
Pharmazeutische Technologie und Biopharmazie
Universitaet Bonn
An der Immenburg 4
53121 Bonn
Tel.: 0228 735117
Fax.: 0228 735268
quadflieg.aaa.uni-bonn.de
---
From: Nick Holford
Sender: n.holford-postbox.-at-.auckland.ac.nz
Reply-To: Nick Holford
To: PharmPK.-a-.pharm.cpb.uokhsc.edu
Subject: Apparent Bioavailability in Excess of 100%
Date: Fri, 12 Dec 1997 09:49:09 -0616 (nzt)
Priority: NORMAL
X-Authentication: IMSP
MIME-Version: 1.0
I agree with David's suggestion to think of non-linearities in first-pass
extraction after oral administration. If the rate of absorption after the
oral dose is faster than the IV rate of input and the drug has saturable
elimination then the AUC after the oral dose can be greater than after IV.
This has caused much confusion from the naive interpreters of AUC when
comparing IV and oral doses of ethanol.
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, Private Bag 92019, Auckland, New Zealand
email:n.holford.-at-.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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Another way to increase the oral AUC in the experiment described (one iv
dose and oral dosing the next day) is to inhibit metabolism with the
exposure on the first day. Dichloroacetate, for instance, is known to
inhibit its own metabolism following a single dose to humans. I think that
is described in
Curry, S. H., Lorenz, A., Chu, P., Limacher, M. and Stacpoole, P.W.
(1991). Disposition and pharmacodynamics of dichloroacteate (DCA) and
oxalate following oral DCA doses Biopharm. Drug Disp. 12:375-390.
Obviously there are many experiments that would easily check this
hypothesis, like reversing the order of dosing or only using naive animals.
Hugh Barton
PBPK Modeling
ICF Kaiser
(919)547-1709
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I agree with some hypothesis about enterohepatic recirculation, but I
think that maybe you need to consider changes un half-lives and in MTR.
You do not spicify if they change, but modelling combined IV-PO could be
an interesting way to consider.
One more thing: All population came from same sex?
Hope to help a little bit.
Carlos Ramos Mundo MS
cramos.at.cueyatl.uam.mx
phone & fax: (525)6188739
MEXICO.
Greetings.
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There is one other thought about how this may have occured. Years ago when
we were doing our curve fitting we noticed that occassionally we calculated
a negative mean residence time when we used a polyexponential to fit our
blood level curve. Graphically it looked like we had a good fit (Figure 1
in the reference listed below), however, when we plotted our curve beyond
our last data point, we noticed the curve did not assymptotically approach
zero from above the axis, but dipped below and then came back up to zero
(Figure 2). This can happen if the pre-exponential coefficient (A) of the
smallest exponential coefficient (alpha) becomes negative. If the curve
fitting program does not appropriately parameterize the values being fit,
you can have those types of results. See our short communication in
Biopharm & Drug Disposition 9:579-586 (1988).
Ronald A. Herman, Ph.D.
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Keith,
It would help much if you would give more details on your
experimental
settings including sampling scheme and the limit of quantification
of
your assay method. Also important is how did you calculate AUCs.
The
only examples of abnormally high F I know were not related to any
pharmacokinetics, but rather to experimental methods and data
analysis.
Greetings,
Vladimir
vpiotrov.at.janbe.jnj.com
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Dear Keith
You comment:
> In analyzing some data recently, we ran across a number of test molecules
> which appeared to possess systemic oral bioavailability (F) substantially
> in excess of 100% (i.e., 150-220%). Our study design was as follows:
> administer a 30-min i.v. infusion on study day one, and calculate standard
> noncompartmental PK parameters from the resulting concentration-time data.
Have you considered adsorption or absorption of the substance onto/into the
infusion tubing. Adsorption can be important for biological molecules (eg
proteins like insulin), and absorption can be important for lipophilic
compounds. This would result in a lower dose being administered and hence
an apparent lower F from iv than PO.
> After observing this phenomenon, we re-did several studies with one of the
> compounds of interest, lowering the p.o. dose such that it was identical
to
> the i.v. dose. Each time, our apparent F was on the order of 150-180%.
This is the right sort of order of magnitude for sorption interactions.
Hope this helps.
Steve
=======================Steve Duffull
Christchurch
New Zealand
Ph +64 3 3815280
Fax +64 3 3640902
Email sduffull.at.clear.net.nz
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