Elena777
☆    

Belarus,
2019-12-05 20:34

Posting: # 20933
Views: 519
 

 Active metabolites: to measure or not to measure [Regulatives / Guidelines]

Dear All,

As per EMA, general recommendation is to evaluate BE on the basis of data for a parent compound. But does this mean that EMA experts never ask to measure active metabolites as well?

FDA sometimes recommends determination of an active metabolite without using its data for bioequivalence assessment (supportive data).

So, we have 3 options for a BE study in case of presence of a parent compound and its active metabolite in plasma:

1) to measure the parent compound only and to use its data for BE assessment;
2) to measure the parent compound and its metabolite and to use their data for BE assessment (separate assessment: 90% CI for the parent and 90% CI for the metabolite);
3) to measure the parent compound and its metabolite; to use the data obtained for the parent compound in BE assessment and to use the data for the metabolite as supportive information only without calculating 90% CI for the metabolite.

What to take into account while thinking of what to prefer? And is this always the correct and sufficient decision to use option 1 taking into account that EMA recommendations overweigh FDA recommendations in our environment?

We have had a poor experience recently: a Belarusian expert asked why the active metabolite had not been measured together with the parent (he/she would like us to use option 3). We provided some justification and now are waiting for the response from the expert.
ElMaestro
★★★

Belgium?,
2019-12-05 23:22

@ Elena777
Posting: # 20934
Views: 254
 

 Active metabolites: to measure or not to measure

Hello Elena777,

my recent experience in EU is that they tend to ask for the parent, and only the parent, if this can be measured (and if systemically acting blah blah).
I did not see a dossier recently where they asked additionally into the metabolite.
So, as regards parent versus metabolite they seem in my experience to follow guidelines to the word, but with one exception: You can have a great meeting with 16 questions, all being answered in no time, and you are ready to leave the agency with final handshakes and big smiles, when someone whispers: "Hey, what about back-conversion?" Then all bets are off, especially if you are not 120% sure you have firm control over it. You can be asked to measure everything and do all what that it implies in terms of acquisition of weird reference standards and setting up assays. :crying:


There is also some regulatory wobble regarding enantiomers. Sometimes they ask for a chiral assay, and sometimes they don't and their choice seems not to always follow the formal criteria criteria stated in the guideline. I haven't cracked the code yet, but Hötzi has a good story about it from the horse's mouth. :-D

Hötzi, over to you...

Le tits now.

Best regards,
ElMaestro
Helmut
★★★
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Homepage
Vienna, Austria,
2019-12-06 00:26

@ ElMaestro
Posting: # 20935
Views: 253
 

 Parent only. Chiral assay?

Hi ElMaestro & Elena777,

@Elena777: 1) according to the GL. Full stop.

» my recent experience in EU is that they tend to ask for the parent, and only the parent, if this can be measured (and if systemically acting blah blah).

@ElMaestro: Agree. Guideline =  cookbook  holy book nowadays.

» There is also some regulatory wobble regarding enantiomers. Sometimes they ask for a chiral assay,……

Really? Happened to me only once in 2010 though the other way ’round.

» … and sometimes they don't and their choice seems not to always follow the formal criteria criteria stated in the guideline. I haven't cracked the code yet, but Hötzi has a good story about it from the horse's mouth. :-D
» Hötzi, over to you...

Aye, capt’n!
Nothing to add to this one. In the meantime we have almost 70 APIs covered in product-specific guidances. In none a chiral assay is recommended.

[image]


Cheers,
Helmut Schütz
[image]

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