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Dear Frederic,
Our intended use of the drug would be oral.
Compounds are not water soluble.
We have started preclinical kinetic studies and tissue distribution
studies giving suspensions.
What other things should be considered for such studies and the invivo
pharmacodynamic studies to come?
Thanks in advance..
Dr.Nandu
Dr.Nandu Dhabale
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Dear Mr Nandu.
If your Compounds is not water soluble.In that case you can use
surfactant like PEG,TWEEN 80 etc...
to make it soluble in water and can start your PK studies.
I hope this can help you.
From
jyoti idnani
NCER-PK
Lupin Research Park, Pune.
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Hello,
I would not recommend the use of surfactants for PK studies.
Basically the formulation should not interfere in the determination of
PK parameters. Thanks to the Tween 80 (absorption promoter properties)
your drug could be absorbed at a higher rate when using such a
formulation. I would not take such a risk.
In PK studies I would recommend formulations that are the most relevant
to future oral dosage forms. As tablets or capsules cannot always be
dosed in animals I suggest the use of suspensions with homogenous
particle size. Using suspensions of small particles will optimize the
dissolution phase without forcing the absorption. You do not interfere
in PK parameters determination while maximising the dissolution of the
active.
Does make sense ?
Regards,
Frederic Doc
Pfizer Global R&D
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Fred,
I guess you got a point here about Tween 80. U mentioned about using
suspensions. Could you please let me know which suspension U are
refering
to???. I prefer to use Avicel. But again I have an observation that
Avicel
and Tween show no differences in PK behavior for certain compounds. I
feel
the use of Tween is compound specific also. We also made an observation
that Cmax in Beagle dogs for certain compounds is volume dependent. If
you
make dilute solutions and increase the volume of administration, Cmax
tends
to increase. But I am not so sure whether it's the right way to do so -
and
I prefer to use capsules as they mimic the clinical scenario. What do
you
say ??. Also now capsules for Rat administration are also available.
Let's
wait and see when they become available for mouse and I guess we could
than
dispense with suspensions - be it of Tween or CMC !!!!
Yati
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Dear Jyoti,
I totally agree with Doc. One should perform preliminary prefromulation
studies and then determine the use of any surfactants and their
concentrations as they could be giving you a false profile of your
compound.
Naveen Sharma
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If we dose suspensions of compounds at the early stage of discovery
then consider this possibility and please comment. If one uses
suspension and gets poor absorption, this could have been due to not
only poor particle size, dissolution and intrinsic solubility, but also
due to improper polymorph of the compound. The knowledge of the
polymorph is not available at this early stage and we know that this
has great influence on solubility. In order to circumvent this issue,
won`t oral dosing as solution make sense initially and later confirm by
suspension? Dosing by solution will give the best chance for the
compound for absorption and therefore, one will not be at a risk of
discarding a valuable compound. Please comment.
Garcia
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Yati,
we commonly use 0.5% methylcellulose in water as a suspending agent.
You are right, using Tween 80 does not always make a difference. In
fact it
depends on the compounds as you said. But our strategy is to
standardise the
formulations (po and iv) for early PK studies. To do so we use
suspensions
for oral dosing for each compound so that we never have to worry about
the
possible interference of the vehicle.
Regarding volumes of administration we commonly dose at 5 mL/kg in rats
and
dogs. I am not sure about mice as we do not use this model for PK
studies.
Regards,
Frederic Doc
Pfizer Global R&D
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Garcia,
Obviously we do not have a lot of information regarding polymorphism at
this
stage.
And I agree with you that a solution would be the best oral dosage form
to
perform early PK studies ...if the vehicle is relevant. My
recommendation
is: do not use absorption promoters in an oral formulation for early PK
studies because results could PROBABLY be overestimated. But if your
drug is
soluble enough you can dose a solution in water for instance.
Regarding the polymorphism issue it is well known that the more stable
polymorph the less soluble. And it is also known that a drug would
always
move to the most stable polymorph during storage. In this case my
opinion is
that one should always perform a PK study with the most stable
polymorph to
ensure that this would not dramatically modify its PK parameters. And I
would add that a drug that would present big variations in its PK
profile
due to its polymorphism should not be called a valuable compound. This
is
the kind of drug that is certainly likely to lead to interindividual
variability in in vivo experimentations.
Agree with that ?
Regards,
Frederic Doc
Pfizer Global R&D
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Hi everybody:
I'm planning to do a bioequivalence study for diclofenac extended
release
(voltaren retard 100 mg), in order to acomplish with the mexican
regulation
I need to do the study in the steady state because the product is a
extended
release formulation but the half-life of diclofenac is arround 2 hours
so we
need 2x5 half-lives to reach the ss but the usual dosing time is 100 mg
each
24 hours, therefore I do not expect a consirable accumulation and I
don''t
belive that the steady state be reached after dosing one tablet each 24
hours during 5 days and during the 6 day sampling the volunteer. Beside
I do
not know any paper that recomends study the bioequivalence in the steady
state for diclofenac.
The question is What is the best way to do the bioequivalence study
(single
dose or multiple dose)? And the FDA or EMEA has a guidance for this
product.
Thanks in advance for your kind help
Sergio Morales
VP
Biophade SC
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Dear Sergio Morales,
AS per USFDA the steady state Multiple dose bioequivalence is required
for all extended release products.
I expect, before going for Multiple dose studies, you might have
completed your single dose (fasting/fed) studies atleast at pilot scale
if not pivotal.From single dose study data you can get a fair idea of
drug accumulation if any ( 24 hour sampling point).
If there is no accumulation observed then your steady state study would
be like repeated 5 single dosing and not actual steady state.And with
this data you can approach to regulatory authorities for their comments.
Generally speaking, in extended release products we extend the
absorption time of the drug by maintaing the release for prolonged
period of time and apparent biological half life will change
accordingly and if there is no flip flop phenomenon observed in the
last, there could be some accumulation as against warranted by the half
life of the drug per se.
I hope this helps,
Kind regards,
Pradeep Bhadauria
Research Scientist
RANBAXY RESEARCH LABORATORIES,
NEW DELHI,INDIA.
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Dear Sergio Morales
It has always been my interest of topic for conductance of multiple
dose study. As per the USFDA current guideline for BA-BE studies, they
do not require multiple dose study for any formulations in context to
prove it as bioequivalent (either conventional or modified). They
require fasting as well as fed study for any formulation to be filed
for ANDA. Normally, people do multiple dose study with modified
formula to check whether dose dumping is there or not with the formula
and of course to check when it gives study state level in blood. As
far as my knowledge goes, it is not necessary to conduct multiple dose
study for bioequivalence study. In multiple dose study, dosing
interval is very crucial parameter. Normally to achieve study state
level, dosing interval should not be more than 3 x t1/2 of drug. Then
and then you will achieve some significant amount of drug in blood
prior to next dosing. In that way if you proceed, u will get study
state level after the fifth dosing. For further reference, you can
refer to Ritschel's Handbook of Pharmacokinetics.
Mitesh Gandhi
Pharmacokinetics Division
Glenmark Research centre
New Bombay
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Dear colleagues
I personally prefer to solubilize drug before giving them by po or ip
route.
Recently, I utilized the following formulation that was recommended by
colleagues from Glaxo when poorly water soluble or even molecules not
soluble in water should be tested:
N,N-dimethyl acetamide / castor oil / 0.9% NaCl injectable water
solution in
a 2:2:6 ratio. The formulation could be used for PK and even in vivo
pharmacology studies in lab animals. It is pretty well tolerated by
rats (1
- 1.5 mL/rat via iv or ip) but not by mice (lethargy).
Did somebody already utilize such a curious formulation?
Thanks a lot for your input.
Bernard Ludwig, PhD, CChem M.R.S.C.
ADDEX Pharmaceuticals Ltd
bernard.ludwig.at.addexpharma.com
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As it is an extented release your will have to wait the end of
absorption to
see the elimination (flip-flop). Tmax will be a function of both
absorption
and elimination half live and I would base the time to reach the steady
state on the MRT which reflects both of the process (aborption and
elimination).
Dominique Paccaly, Pharm D.
Drug, Metabolism and Pharmacokinetics/US
tel: 908 231 3006
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)