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Dear all,
I would like to know about Bioequivalence in vivo in animals (mouse),
VALID ? CONFIABILITY ?
BERNARDINO SILVA
UNIDADE DE AVALIACAO DE ESTUDOS DE BIODISPONIBILIDADE E
BIOEQUIVALENCIA DE MEDICAMENTOS / UABBE
GERENCIA GERAL DE MEDICAMENTOS - GGMED
AGENCIA NACIONAL DE VIGILANCIA SANITARIA - ANVISA
MINISTERIO DA SAUDE- MS
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Dear Bernardino,
In pharmacokinetics studies in animals (mouse) is not used
pharmaceutical formulations. The drug is dissolved in a vehicle (for
example: water or DMSO). So, it is impossible to evalute the effect of
formulations in the absoption of drugs aplying these models (mouse or
rat).
Therefore, the only way to evalute BE is the in vivo study
(volunteers). But nowadays are starting a discussion (in Brazil) about
biowaiver considering BCS. Biowaiver of class I drugs are done in USA
according to FDA Biowaver Guidance (2000).
Best regards,
Daniel Rossi de Campos
Brazil
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Dear Jose,
In my previous experience with PK research, we tried to establish
bioequivalene of formulations in Rabbits but not in rats / mouse (as
you have to administer as solutions) to see the invivo permeation
capabilities into blood stream. but size of the formulations depend.
may be you will try your liposomal product as a capsule (if admin per
oral). hope this helps.
Regards,
Santosh Tata, BS (Pharm. Sci),
Bioanalytical Laboratory,
Clinsys Clinical Research Ltd,
C-46, Sector-62, NOIDA,
Uttar Pradesh, India.
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The following message was posted to: PharmPK
I don't think so. these are usually conducted on healthy human
volunteers.
zafar
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BE studies in animals are not valid in lieu of human data regardless
of the type of drug that you are investigating (NCE, biologic,
liposome) or route of administration.
With specific regard to liposomes, there is a draft FDA guidance on
liposomes
http://www.fda.gov/cder/guidance/2191dft.pdf
but it specifically states that it does not provide recommendations on
bioequivalence studies or those to document sameness. The whole
guidance should be viewed with caution since it has been draft since
2002. However, one take home message from the guidance is that it is
important to measure the encapsulated drug and unencaposulated drug.
This isn't easy to do and the literature is patchy on such assays.
Conducting a BE study for a generic version of Doxil will be
challenging since the appropriate assays weren't used to describe the
PK of Doxil at the time of its submission (and most probably since
then).
The FDA is aware that there will be generic liposomes coming on the
horizon and have BE for liposomes an activity on their list of
Critical Path Activities for generics
http://www.fda.gov/oc/initiatives/criticalpath/reports/generic.html#liposome
The document states that:
Liposomes encapsulate drugs in spherical phospholipid vesicles that
passively target drugs to specific tissues, especially cancer tumors.
Critical path opportunities in this area include:
* Bioequivalence Methods for Liposome-based Formulations: Because
liposome products target specific tissues, the plasma concentration
may not be related to the concentration of drugs at these specific
tissues, and work is needed on novel bioequivalence methods to
determine if two liposomes with the same composition but produced by
different manufacturers have the same therapeutic profile (e.g., by
assessing how they deliver drug to relevant tissues).
How the determination of drug concentrations in tissues can be
determined is an interesting question. Perhaps imaging will be of use
in this situation. Care should also be taken regarding the statement
"relevant tissues." This should be read as being the target organ for
efficacy and the target organs for toxicity. For Doxil, these will be
tumors and skin/heart respectively.
It should be also noted that the statement made in the CP document
appears to make the assumption that the liposomes are stable in the
blood and only release drug in the tissues. If only that were true.
It will be interesting to follow the development of generic liposomal
products. They will be harder to develop than generic NCEs but easier
to develop than generic biologics.
Regards
Mark Milton
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Where the liposome drug product is meant for animals (Veterinary
pharmacy) it is okay to conduct Bio-equivalent studies in mouse.
However where the product is for human consumption Ideally it should
done in healthy human volunteers.
This on the assumption that the liposome product does not fall under
the category of investigation's new drugs where the physiochemical
properties are not well known.
s.o.o
[If the liposome dosage form is liquid, 'mouse portions' could be used
for initial bioavailability evaluation - db]
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Bernardino,
Is there any reason to go for a bioequivalence study in mouse instead
of humans? It is usually not recommended but I think that one has to
see if there is any specific reason for this choice.
If the lipossome drug is administered iv it is possible to conduct the
pharmacokinetic study in animals once you can inject the formulation.
There is a lot of literature about that, as an exemple, try to look
for doxorrubicine liposome pharmacokinetic studies, you will find a
lot of studies in animals, including some that evaluate formulations.
Paula Macedo Cerqueira, PhD
Wissen Consultores Associados Ltda.
Sao Paulo - Brazil
www.wissenconsultores.com.br
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I would still be very nervous about conducting any kind of PK studies
in an "irrelevant" species. It has been long shown that liposomes
interact with serum proteins, including lipoproteins (this process is
known as opsonization). It has been previously shown that when
hydrophobic drugs are incoroprated into the lipid bilayer, they can
rapidly be abstracted by serum lipoproteins. It is also possible that
the lipoproteins can also disrupt the lipid bilayer and release drugs
that are simply entrapped withing the liposomal lumen.
Given the fact that the lipoprotein composition varies across species,
there is the possibility that a PK study in the mouse may give
misleading data and not predict what may occur in the relevant species.
If the question that you are trying to address is the stability of the
liposomal formulation, an ex vivo stability assessment in the plasma
of the relevant species may be the quickest and cheapest way to go and
generate the most relevant data.
The observation that drugs can be abstracted from liposomes raises an
interesting question: "Will there be a food effect on the PK of
liposomal drugs?"
Regards
Mark
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