BE based on Metabolite [Regulatives / Guidelines]

posted by Vineeth KE – India, 2017-10-23 09:53 (2164 d 09:09 ago) – Posting: # 17905
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Dear M.tareq,

Considering the "chloral hydrate (parent compound)", with short terminal half-life (detected only 8 to 60 min) and high variability [from Relative BA of CH and its active metabolite] - Metabolite based BE can be a good approach to prove in-vivo similarity.

However, As per EMA guidance 4.1.5,
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/01/WC500070039.pdf

1. General recommendation - BE based on Parent compound

2. Inactive pro-drugs - BE on parent compound is recommended.
Some pro-drugs may have low plasma concentrations and be quickly eliminated resulting in difficulties in demonstrating bioequivalence for parent compound. In this situation it is acceptable to demonstrate bioequivalence for the main active metabolite without measurement of parent compound.
In the context of "chloral hydrate (parent compound)" - the above criteria maynot be applicable as it is NOT a Pro-drug. [I might be wrong..Pl confirm]

3. Use of metabolite data as surrogate for active parent compound - is not encouraged.
Unless Analytical method sensitivity issues, although the option of using a higher single dose in the bioequivalence study has been explored.
Use of a metabolite as a surrogate for active parent compound is expected to be accepted only in exceptional cases. When using metabolite data as a substitute for active parent drug concentrations, the applicant should present any available data supporting the view that the metabolite exposure will reflect parent drug and that the metabolite formation is not saturated at therapeutic doses.

With the sufficient data, which satisfy/full-fill the above requirements (As per EMA guidance 4.1.5), can approach to respective regulatory agency (Request for Scientific Advice).

Also, approaches to improve the plasma concentrations of chloral hydrate (parent compound) such as study population type, inclusion/exclusion criteria (Rapid/Slow metabolizers) etc.. can be explored, if applicable.

Procedures/Guidances on Metabolite based BE incase USFDA agency related..I'm not too aware.

Thank you..:-)

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