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The following message was posted to: PharmPK
Dear readers,
In calculating the absolute bioavailability of drugs in animal model,
is it more accurate to use half-life corrected AUC values or not?
That is: (AUC oral x half-life iv) / (AUC iv x half-life oral) or
just AUC oral/ AUC iv
Thanks
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The following message was posted to: PharmPK
No. The only correction you do is for different doses (if any) between
oral and IV routes.
If you do see a longer half-life after oral, it's because of flip-flop
(Ka
Hope this helps,
Varun
Varun Garg, Ph.D.
Vertex Pharmaceuticals, Inc.
130 Waverly Street
Cambridge, MA 02139
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The following message was posted to: PharmPK
Dear Panteha and Varun,
Any estimation of absolute bioavailability directly from AUCs of iv and
extravascular doses at separate occasions is based on the assumption that
clearance is identical at the two occasions. Of course this is not true,
but the question is whether your estimate of half-life is so highly
correlated to the clearance value to provide a correction that is better
than no correction at all. There are two reasons correction may not be a
good idea. First, changes in half-life may be due to changes in volume of
distribution rather than clearance and second, unless you have a very
precise estimate of half-life, uncertainty in half-life estimate may
introduce a larger error than the one you're trying to correct. As Varun
points out, if the change in half-life between routes is systematic, you
have a different situation to deal with.
Best regards,
Mats
Mats Karlsson, PhD
Professor of Pharmacometrics
Div. of Pharmacokinetics and Drug Therapy
Dept. of Pharmaceutical Biosciences
Faculty of Pharmacy
Uppsala University
Box 591
SE-751 24 Uppsala
Sweden
phone +46 18 471 4105
fax +46 18 471 4003
mats.karlsson.aaa.farmbio.uu.se
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Dear Panteha and Varun:
There is no need to compare AUC's. You can estimate
bioavailability directly from an intermixed IV and PO (or other
absorptive) regimen, without any washout. Just give some doses IV,
and others PO, for example. The fraction of the oral dose absorbed is
simply another PK parameter to be estimated. It works well, in either
parametric population modeling approaches such as IT2B, or
nonparametric ones such as NPEM or the newer NPAG. There is minimal
opportunity this way for the volume or the clearance (or the Kel) to
change between the 2 routes this way, and it is much simpler, and
possibly cheaper, to do. Dave D'Argenio's Adapt program also can do
the fraction absorbed this way. Probably so can NOMEM.
Very best regards,
Roger Jelliffe
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The following message was posted to: PharmPK
Dear Panteha,
Model-based estimates of bioavailability has advantages, but if clearance
changes over time (which it often does) and you want to take that into
account, forcing disposition in the model to be time-constant is not the
proper solution. With NONMEM (and possibly some other of the programs
Roger mentioned) time-variance in disposition can be estimated either as
a systematic or random change over time. See e.g. Karlsson MO, Sheiner
LB. Estimating bioavailability when clearance varies with time. Clin
Pharmacol Ther. 1994 Jun;55(6):623-37. Note though that your data may
limit the possibility to discriminate between different types of changes
over time.
Best regards,
Mats
--
Mats Karlsson, PhD
Professor of Pharmacometrics
Div. of Pharmacokinetics and Drug Therapy
Dept. of Pharmaceutical Biosciences
Faculty of Pharmacy
Uppsala University
Box 591
SE-751 24 Uppsala
Sweden
phone +46 18 471 4105
fax +46 18 471 4003
mats.karlsson.-at-.farmbio.uu.se
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The following message was posted to: PharmPK
Dear Panteha,
The method described in our study:
Dedik L., Durisova M., Comput. Methods Programs Biomed., 51, 1996,
183-192
allows to determine model-based estimates of the extent of drug
bioavailability and of the rate of drug bioavailability (in the numerical
and/or analytical form) in situations when half-lives of termination phases
are equal or not. Furthermore, this method can also be used if an i.v.
dose of the drug is given in an infusion.
Our recent study (it has been accepted in the same journal, and will be
published this year) presents criteria allowing to test intra- and/or inter-
subject similarity between model-based estimates of the extent and of rate
of drug bioavailability.
With best regards,
Maria Durisova
Maria Durisova, Ph.D., D.Sc.,
Senior Research Worker and
Scientific Secretary
Institute of Experimental Pharmacology
Slovak Academy of Sciences
842 16 Bratislava
Dubravska cesta 9
Slovak Republic
Phone/Fax: 00421 2 5477 5928
http://nic.savba.sk/sav/inst/exfa/durisova.htm
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