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Back to the forum  Query: 2017-12-13 15:51 CET (UTC+1h)
 
M.tareq
Junior

2017-10-22 00:32

Posting: # 17901
Views: 898
 

 BE based on Metabolite [Regulatives / Guidelines]

Dear all,

I have a question about conducting comparative bioavailability study between the active metabolite produced following an oral dose of the parent drug and a new formulation containing only that active metabolite

If the parent drug is converted to metabolite (A) and we want to compare the relative bioavailability of compound (A) to a new formulation containing the active metabolite.



So, The Reference product would be the active metabolite produced following oral dose of parent drug and the test product will be the new formulation containing only the active metabolite.

If the two products shows similar rate and extent of absorption, can we conclude BE using TOST and claim that the new formula can be substituted for the parent drugs since it produces similar pk profile based on metabolite data ?:confused:

The metabolite has longer t1/2.
No registered drug containing only the active metabolite.
The drug product is Chloral hydrate and its trichloroethanol as active metabolite.

Relative BA of CH and its active metabolite

Thanks in advance.
Vineeth KE
Junior

India,
2017-10-23 07:53

@ M.tareq
Posting: # 17905
Views: 706
 

 BE based on Metabolite

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..:-)
jag009
Hero

NJ,
2017-10-24 05:41

@ Vineeth KE
Posting: # 17908
Views: 647
 

 BE based on Metabolite

Hi,

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

Tada!

@&#^! :confused::party::blind:
J
nobody
Senior

2017-10-24 19:02

@ jag009
Posting: # 17915
Views: 616
 

 BE based on Metabolite

....dabigatran... and ...

Kindest regards, nobody
jag009
Hero

NJ,
2017-11-19 06:35

@ nobody
Posting: # 17990
Views: 323
 

 BE based on Metabolite

» ....dabigatran... and ...

?
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