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we would like to a BE study of Orlistat.It is negligibly absorbed in
to the systemic circulation and converted to its M1 metabolite.The
remaining drug form complex with the fat and get excreted.we have seen
already the pharmacodynamic study of estimation of fecal fat is a
complicated process.orlistat and M1 metabolite which gets in to the
systemic circulation lacks any systemic effect.Literature shows
orlistat in plasma is detectable only in around 50% samples
studied.same time M1 metabolite is measurable in almost all samples.so
my question is can we prove the bioequivalency by studying only the M1
metabolite.will not it pose any problem with the regulatories?
expecting your reply,
thanks and regards
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The following message was posted to: PharmPK
I think that you will have a problem with that approach. The topic of
BE for locally acting drugs is one that the FDA has recognized as
being an issue and is included in their document on Critical Path
Opportunities for Generic Drugs.
In the document it states:
Bioequivalence of Gastrointestinal Acting Products
Another category of locally acting products is one that treats
gastrointestinal (GI) conditions through local action as opposed to
systemic exposure. FDA has recommended a wide variety of
bioequivalence tests for these products, including an in vitro binding
assay, in vitro dissolution studies, pharmacokinetic studies, and
clinical equivalence studies.
Critical path opportunities include:
Biowaivers for Low Solubility Drugs: Based on the BCS, FDA has granted
biowaivers for immediate release high solubility drugs that act
locally in the GI tract. Further work can explore extension of this
waiver to low solubility drugs.
In Vivo Drug Release for GI Acting Products: Direct comparison of in
vivo drug release (perfusion, tissue sampling, or imaging) could be
used to validate dissolution tests as a bioequivalence method for
modified release products.
Establishment of Biomarkers for Local Delivery to the GI Tract: For
locally acting drugs that are absorbed and can be detected in plasma,
the rate of absorption could be related to the local concentrations in
the GI tract. Thus, it may be possible to establish a relationship
between PK measurements and concentration at the site of action.
Research to evaluate this connection for use as a bioequivalence test
could involve constructing fast, medium, and slow release formulations
(both enteric coated and slow release pellets) and radiolabeling the
drug. Imaging and PK studies could establish the correlation between
the drug delivered to the site of action and the measured plasma
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thanks a lot for your kind reply.from this I understand that this kind
studies require lot of pilot exploratory trials and will add to the
this kind of research are only possible with the pharmaceutical
or academic research institutions.
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