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The following message was posted to: PharmPK
Does anybody have idea whether metabolite of Ethionamide (Ethionamide
Sulfoxide) should be estimated during bioequivalence study of
Ethionamide.
Ethionamide Sulfoxide is an active metabolite. Ethionamide Sulfoxide
is inter-convertible to Ethionamide in vivo.
Regards
Dr Ashish Mungantiwar
Macleods Pharmaceutical Limited
Head-Bioequivalence
Macleods Pharmaceuticals Limited
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dear sir
If its active metabolite the level is more than the drug need to be
quantified for BE studies . The reference is given in the USFDA BE
guidelines.
A.karthik
DMPK LAB,DISCOVERY RESEARCH
DR REDDYS LABORATORIES LTD
MIYAPUR
HYDERABAD
500049.
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Dear Sir,
there are 2 theories supporting to quantitate the drug in BE studies
1. If Ethionamide sulfoxide exists in the intestine after oral
dosing, then since the sulfoxides are ionic they do not get
reabsorbed and get eliminated in the Urine/ Feces. However if the
interconversion to Ethionamide takes place in the GIT then the drug
is reabsorbed and therefore it seems good to add the metabolite conc
to that of the Ethionamide in BE studies.
2. On the other hand even If the drug is given by IV, and the
metabolite circulates in the plasma, then I feel it mandatory to add
the same to the quantitated Ethionamide in BE studies because the
metabolite and the drug are interconvertible.
sampling helps us to obtain the instantaneous amounts of the drug and
metabolite circulating in blood stream, but do not discuss the
interconvertibility of the metabolite (which may happen later) I
strongly believe to take into account the metabolite conc as that of
the drug in case of Ethionamide.
Santosh Kumar, B.Pharm
Lecturer, Shri Vishnu College of Pharmacy, Bhimavaram, AP, India
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The following message was posted to: PharmPK
Dear Milind Karthik
Thanks for your response. However, in one article. it was mentioned
that the contribution of active metabolite (Ethionamide sulfoxide) to
clinical effectiveness is not studied and not known. As per
guidelines, quantification of active metabolite is required when it
is significantly contributing to clinical efficacy and safety. So, in
this situation do you still prefer that Ethionamide sulfoxide should
be estimated
Regards
Dr Ashish Mungantiwar
Head Bioequivalence
Macleods Pharmaceutical Limited
Mumbai
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Dear Santosh:
You wrote: there are 2 theories supporting to quantitate the drug in
BE studies 1. If Ethionamide sulfoxide exists in the intestine after
oral dosing, then since the sulfoxides are ionic they do not get
reabsorbed and get eliminated in the Urine/ Feces. However if the
interconversion to Ethionamide takes place in the GIT then the drug
is reabsorbed and therefore it seems good to add the metabolite conc
to that of the Ethionamide in BE studies.
2. On the other hand even If the drug is given by IV, and the
metabolite circulates in the plasma, then I feel it mandatory to add
the same to the quantitated Ethionamide in BE studies because the
metabolite and the drug are interconvertible.
sampling helps us to obtain the instantaneous amounts of the drug and
metabolite circulating in blood stream, but do not discuss the
interconvertibility of the metabolite (which may happen later) I
strongly believe to take into account the metabolite conc as that of
the drug in case of Ethionamide".
To give a right answer you have to evaluate first what the question
is. The way I understand your question is you are advocating BE for
the combined concentrations of drug and metabolite and/or Drug and
metabolite. If the issue you are trying to address is
Bioequivalence, regulatory bodies unequivocally confirmed they are
interested in seeing only parent drug 90% CI and BE data on
pharmacologically active metabolite can be supportive in nature.
What I wanted to clarify is if you wanted to propose BE based on just
metabolite data your chances of success are slim.
Hope this clarification helps.
Prasad
Prasad NV Tata, Ph.D., FCP
Manager-Pharmacokinetics
Mallinckrodt, Inc.
675 McDonnell Blvd.
Saint Louis, MO 63134
Tel: (314) 654-5325
Fax: (314) 654-9325
e-mail: prasad.tata.aaa.tycohealthcare.com
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The following message was posted to: PharmPK
Subject: Ethionamide formulation BE.
Dear all
The bioequivalence needs to be determined for both, parent as well as
sulfoxide metabolite as both are active.
You can draw a parallel from the case of risperidone that also get
metabolized to produce active metabolites. Here the BE is done by
measuring
the plasma concentration of both, parent as well as active hydroxide
metabolite.
Pls note that ethionamide falls into DESI category. You may seek
suggestion
from FDA if, being a drug belonging to DES category, only parent
molecule
analysis will suffice.
Regards
Rajesh
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