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Dear All:
It may be a naive question. When a parent drug exhibits erratic
pharmacokinetics (unpredictable absorption profile) and high
variability. Can we arrive at bioequivalence conclusion based onthe
metabolitepharmacokinetics? US FDA guidance on BA/BE studies for
orally administered drug productsissued inMarch 2003 states that
"measurement of a metabolite may be preferred when the parent drug
levels are too low to low to allow reliable analytical
measurement.......... We recommend that the metabolite data obtained
from these studies be subject to confidence interval approach for BE
demonstration.
Our group involved in development of a drug where parent drug is
presenting an erratic PK profile (variation in the concentrations and
absorption pattern), where as its major circulating metabolite yielding
(Pharmacologically inactive)complete and well characterized plasma
concentration-time profile and 5-10-fold higher concentration profile.
Now my dilemma is that can I qualify my product by submitting the BE
criteria being satisfied for themetabolite in lieu or in support of
the parent drugbioequivalence.
Any input from the agency or industry peers is highly appreciated.
Prasad Tata, Ph.D.
St. Louis, MO
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The following message was posted to: PharmPK
Dr Tata,
In BE studies the parent drug evaluation may be preferred because it is
more related with pharmaceutical form than metabolites. In BE studies
are evaluated absorption and metabolism, so the BA of 2 formulations.
If there are informations in literature that describes a analytical
methods for measurement the parent drug, the parent drug may be
evaluated by BE requirements (IC 90%: 0.8 - 1.25%).
Daniel
Health Agency - Brazil
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The following message was posted to: PharmPK
Only when the metabolite is the pharmacologically active compound and
the parent is not can you use it for BE.
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The following message was posted to: PharmPK
Dear Prasad
Interesting regulatory siruation.
Before concluding erratic Pk of parent, I believe you have taken
into consideration all the factors which may be contributing.
Based on preliminary results you will have to design protocol
which has options like following
1. State BE acceptance criteria based on metabolite
2.Aditionally try to put an optional criteria (wider than 80-125)
for parent drug. Reason out based on the erratic data available.
Also state that even if parent compound is out of the stated
bounds, BE can still be concluded based on metabolites.
2. probabaly it may be numbers (of Vol) game for parents PK. The
requirement may yeild an unrealistic figure to be included in BE
trial. Include this justification in the protocol for using
metabolite criteria for BE evaluation.
3. Any in vitro data available on metabolism?
I believe that should be a practical way.
with best regards
Dr.Prashant
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The following message was posted to: PharmPK
It does make some sense from a scientific standpoint; however this
shall prove to be a tough nut to get a regulatory nod. I feel, you
somehow need to put a BE acceptance limit to the "erratic" parent drug
rather than leave it open ended, now the question is how much wider
than the accepted 80-125%.The moment we talk of relaxing this limit,
you have to be sure that the drug in question has a favorable
benefit/risk ratio i.e. a high therapeutic index. This approach can no
way be applied to NTI's like amino glycosides and anticonvulsants where
concentration dependent side effects are prevalent and monitoring drug
plasma levels become essential.
Regards
Natrajan
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