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Dear All,
We recently performed a mice PK study using a mixture of solutol,
ethanol, and water as the dosing formulation but since it was a
suspension, we tried to come up with a solution formulation and that
was achieved using 10% ethanol in labrasol. The PK results came back
with very different profiles for the same compound. In the former
formulation, high Cmax was observed along with short Tmax and T-half
while using the latter formulation, significanly lower Cmax was
observed along with substantially longer Tmax and T-half. The AUC in
the former study was also about twice that of the latter study. I am
aware of PEGylation to achieve something akin to an extended release
thing but this is just a simple formulation so I wasn't expecting such
drastically different results. I cannot find any precedences out
there which utilized a labrasol based formulation to achieve
significantly longer Tmax and T-half so I am at a loss to explain the
observation. Any ideas?
tw
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Dear TW,
could you explain what was the rationale for those formulation choices?
Could you give us the route of administration?
Did you try and show that PK parameters could be impacted by the
formulation? Or did you expect to get the same range of PK data?
I am not surprised that both studies show significantly different
data. The impact of the formulation is oftenly underestimated in PK
studies. This leads to results for which the relevance can be
challenged by field experts.
I've already written about this on the PharmPK forum in the past and
would be glad to help if you need assistance in defining a relevant
formulation strategy for preclinical studies. I've made a lot of work
on this topic at Pfizer and I am still working as a scientific
consultant in this field for some companies in Europe and US.
Please feel free to get in touch with me at the following email
address : fdoc.-a-.acriter-consulting.com
Best regards,
Frederic DOC
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Dear tw,
There is a possibility that Solutol used in your first formulation
decreased the clearance of your molecule and hence, leading to twice
the exposure seen in your 2nd study. There are reports in literature
where Solutol HS15 has decreased the clearance the drugs such as
colchicines.
Regards
Tausif Ahmed, Ph.D.
DMPK, Sai Advantium Pharma Ltd., Pune, India
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What was the final volume of dose delivered to the subject-what was the
final ethanol concentration.
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Final volume of dose was ca. 100 uL and the ethanol content in the
formulation of both is 10%
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Frederic,
Our standard approach was using the ethanol/solutol/water formulation
but I noticed that, although all compounds remained a suspension,
there were varying degrees of dissolved compounds and so I thought the
playing field could be evened by getting either a formulation where no
compounds were dissolved or a solution formulation. I went the
solution route thinking that the cards would be stacked in my favor by
facilitating absorption since dissolution of solid in vivo is no
longer an issue. Honestly speaking, I completely neglected to give
any thought to impact of the formulation (hindsight is always 20/20
eh?) which hints at my non-expert in this area. I was expecting
differences in the data, but definitely not in the magnitude that we
are observing. After reading into this issue more, I am coming to
have a better grasp of the issue but now the question is which set of
data truly or more correctly demonstrates the native behavior of the
molecule in vivo?
Btw, you may have guessed by now that the route of administration is
oral gavage.
tw
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The formulation surely may have a profound impact on PK profile if the
compound in question do not belong to BCS class I (presuming that you
are
talking about oral route of administration). The formulations you have
selected may behave differently under bio-relevent conditions. This
has to
be correlated with the physicochemical properties of the compound in
particular partition coefficient.
The drug has to diffuse (diffusivity) and has to dissolve (dissolution
velocity) in order to be available for absorption in git. Moreover the
potential mechanism of absorption will also be dictated by the molecular
properties and Log P. If a compound of high lipophilicity is being
given in
a lipidic environment, it may tend to absorb via lymphatics and the PK
profile may look substantially different than if it administed in an
aqueous milieu. There could be several propositions to explain the
differential behaviour of your experiments.
I presume that your experiment is part of very early discovery
pharmaceutics and not many laboratories would like to investigate the
reasons and would indulge more in speculations and readymade answers.
But
it will be too much speculation at this point in time to identify one
clear
answer to your question, but surely this sorts of observations are on
the
cards specially with poorly soluble/dissolving/lipophilic compounds.
Vaibhav Sihorkar
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Dear Tw,
Labrasol (Caprylocaproyl macrogolglycerides) is a known solubility and
bioavailability enhancer. It is also used in self-emulsifying drug
delivery systems where sustained drug delivery (prolonged half-life as
observed in your study along with reduced Cmax) can be expected.
Chandra Durairaj
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