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Hello,
We're working on a series of compounds for which we wish to assess
bioavailability in a mouse model. These are all relatively
hydrophobic compounds and have required the addition of excipients for
a soluble form to be administered IV. We've just completed an
exercise where we compared bioavailability of a compound administered
IV and oral in a rather exotic formulation including 5% DMSO and 2%
Tween 80 + PEG400 in dextrose to the same compound administered in
cremaphor/ethanol diluted in saline. (I didn't realize the simpler
formulation would work til I had already done the experiment with the
first but this has turned out to be a learning experience :-). What
we found was a huge impact of formulation on the IV noncompartmental
PK parameters but not so much on the oral parameters. That is, the
more exotic formulation decreased Cmax, decreased AUC, increased
volume of distribution, and decreased terminal half life. The net
effect was that the bioavailability appeared artificially? large with
the exotic formulation although the AUC after an oral dose was similar
for both formulations. I guess this makes sense if one expects DMSO
and Tween to impact membrane permeability. Does this make sense to
the group?
I'm now stuck, though, wondering how to proceed. I guess in the ideal
world one would use the same, preferably excipient free, formulation
for both IV and oral, but to compare multiple compounds it may not be
possible to get everything to solubilize in one identical
formulation. If all efficacy testing will be done by oral route,
should I even worry about bioavailability and instead just focus on
exposure after an oral dose? In this latter case it may be possible
to use the same formulation since compounds do not need to be
completely in solution.
The group's thoughts and experiences would be greatly appreciated.
Thanks,
Noelle
[Precipitation after iv from the 'exotic' formulation? - db]
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Hi
It is not surprising since Cremophor-type IV formulation is know to
form micelles and therefore reduce distribution and increase t1/2
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What dose volumes did you use for each formulation? Also, if compound
had precipitated, the response would have been death (the ppt would have
resulted in an emboli, followed by death).
Mary M Sherman, Ph.D.
Aptuit Consulting, Inc.
91 Hartwell Avenue
Lexington, MA 02421
Email: Mary.Sherman.-a-.aptuit.com
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Dear Noelle,
I would like to comment on some points you raised out in your message.
First I would say that your formulations seem to be too exotic to
assess bioavailability in "safe" conditions. I would certainly not
give the advice to use such formulations for PK studies.
Secondly the influence of the formulation is usually (always?) much
more important per IV than per PO.
Why that?
When you dose different solutions per IV what is going to happen
depends on the "affinity" of the drug to keep in solution or not. This
leads to massive precipitation ...or not!!!
When you dose per PO the drug can also precipitate (usually as
amorphous particles) but it redissolves rapidly (if in amorphous
particles) in GI fluids thanks to natural surfactants or adequate pH
along the GI. This is the reason why you see a weak or no difference
between two solutions of the same drug dosed PO.
After a precipitation event per IV the drug redissolves (very) slowly.
The Cmax is not that high and the AUC is decreased ...because the slow
drug redissolution rate is generally lower than the elimination rate.
A quite large part of your drug is then not taken into account in the
AUC calculation. Other consequence : the PO/IV bioavailability is
overestimated!
I hope this helps.
Frederic
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Dear Frederic,
"Secondly the influence of the formulation is usually (always?) much
more important per IV than per PO."
Wow - I've never heard that opinion before!
I understand your points about formulation effects on iv doses, but in
our
experience, formulation scientists spend considerable time and money
developing dosage forms and dealing with often complex formulation
effects
for oral doses. Perhaps because of the nature of our work, we see far
more
effects for po doses than for iv in our customers' data.
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
E-mail: walt.aaa.simulations-plus.com
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Dear Walt,
reading my message and your comments again I understand that I was
misunderstood.
My comments were relating to the use of exotic formulations to keep a
drug in solution in preclinical studies. This has nothing to do with
drug dosage form development.
These observations were the first point to the development of a
rational approach of drug formulation for preclinical studies allowing
"exotic" formulations for "proof of concept" studies and stting up
more "relevant" formulations for PK studies, tox and pharmacoly studies.
I hope this is a better explanation of my view.
Best regards,
Frederic
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Dear Noelle,
Was it confirmed that none of the observations you made could be
related to problems during sample analysis?
We once had some serious issues with ion-suppression from formulation
agent (Tween 80); this was observed in real samples only, particularly
strong after IV dosing and collection time dependent. More detailed
information on the specific case is available in the article below.
Although formulations can have marked effects on pharmacokinetics it
may be worth double checking for artefacts before looking for actual
causes to the observations.
Ion-suppression effects in liquid chromatography-tandem mass
spectrometry due to a formulation agent, a case study in drug
discovery bioanalysis; Larger PJ, Breda M, Fraier D, Hughes H, James
CA; J Pharm Biomed Anal. 2005 Sep 1;39(1-2):206-16
All the best ,
Patrice
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