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The following message was posted to: PharmPK
Dear All,
Could you please let me know if in a bioequivalence study between
isosorbide dinitrate (ISDN) oral formulations the bioequivalence
assesment
should be based on the bioavailability data of only the active
metabolite
isosorbide-5-mononitrate or the bioavailabilities of the parent compound
(ISDN) and the other active metabolite isosorbide-2-mononitrate should
also be considered?
Thank you
K. Avgoustakis, PhD
Department of Pharmacy,
University of Patras,
Rio 26500, Patras, Greece
Tel.: ++2610-997726
Fax:++2610-996302
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The following message was posted to: PharmPK
Dear Avgoustakis,
I presume that you are talking about the regulatory submissions. In
such
case the main focus would be on the parent compound irrespective
whether
the active is the parent or the metabolite (prodrug), in addition to
the
parent the active metabolites need to be measured and evaluated.
Of-course,
the evaluation criteria for metabolite would be less stringent.
In the present case of isosorbide dinitrate (ISDN), you are
required to
show the bioequivalence on the data from the parent with 90%
confidence
interval approach and additionally for isosorbide-5-mononitrate
and
isosorbide-2-mononitrate you need to provide the comparative
geometric
ratios (to be within 80-125%).
The guiding principle is that if the active metabolite levels are
more
than 10% of the parent and contributes substantially either to
efficacy or
safety indicating parameters, it needs to be presented as
supportive
evidence.
I hope the above information is what you are looking for.
best regards,
Bangaru RK
Dr.Reddy's Laboratories Ltd.
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The following message was posted to: PharmPK
Dear Ramkrishna
Hello
Do you have any supportive guidance or reference for this 10 %
statement on metabolite in your mail
"The guiding principle is that if the active metabolite levels
are more than 10% of the parent and contributes substantially
either to efficacy or safety indicating parameters, it needs
to be presented as supportive evidence."
For your reference i am attaching parafrom guideline.
with best regards
Dr. Prashant Bodhe
The guideline (3615fnl.pdf) on page 18 and 19 (21-22 in soft copy)
says
B. Moieties to Be Measured
1. Parent Drug Versus Metabolites
The moieties to be measured in biological fluids collected in BA
and BE studies are
either the active drug ingredient or its active moiety in the
administered dosage form (parent drug) and, when appropriate, its
active metabolites (21 CFR 320.24(b)(1)(i)).9
This guidance recommends the following approaches for BA and BE
studies.
For BA studies (see section II.B), determination of moieties to be
measured in biological fluids should take into account both
concentration and activity. Concentration refers to the relative
quantity of the parent drug or one or more metabolites in a given
volume of an accessible biological fluid such as blood or
plasma.
Activity refers to the relative contribution of the parent drug
and its metabolite(s) in the biological fluids to the clinical
safety and/or efficacy of the drug. For BA studies, both the
parent drug and its major active metabolites should be measured,
if analytically
feasible.
For BE studies, measurement of only the parent drug released from
the dosage form, rather than the metabolite, is generally
recommended. The rationale for this recommendation is that the
concentration-time profile of the parent drug is more sensitive to
changes in formulation performance than a metabolite, which is
more reflective of metabolite formation, distribution, and
elimination. The following are exceptions to this general
approach.
· Measurement of a metabolite may be preferred when parent drug
levels are too low to allow reliable analytical measurement in
blood, plasma, or serum for an adequate length of time. The
metabolite data obtained from these studies should be subject to a
confidence interval approach for BE demonstration. If there is a
clinical concern related to efficacy or safety for the parent
drug, sponsors and/or applicants should contact the appropriate
review division to determine whether the parent drug should be
measured and analyzed statistically.
· A metabolite may be formed as a result of gut wall or other
presystemic metabolism. If the metabolite contributes meaningfully
to safety and/or efficacy, the metabolite and the parent drug
should be measured. When the relative activity of the metabolite
is low and does not contribute meaningfully to safety and/or
efficacy, it does not need to be measured. The parent drug
measured in these BE studies
should be analyzed using a confidence interval approach. The
metabolite data can be used to provide supportive evidence of
comparable therapeutic outcome.
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)