scorp2011
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India,
2012-01-12 12:21

Posting: # 7914
Views: 4,948
 

 Bioequivalence of racemic drugs using non-steriospecific bio [Regulatives / Guidelines]

Dear ALL,
My question is related to the bioequivalence requirements of chiral drugs.
How to substantiate the use of achiral bio-analysis for racemic drugs with enantiomers having differing pharmacokinetics. Please also comments on the recommendations on the use of chiral/achiral methods as presented in the current Bioequivalence guideline (CPMP/QWP/EWP/1401/98 Rev.1).

Thanks in anticipation.

Regards
scorp
Helmut
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Vienna, Austria,
2012-01-12 18:21

@ scorp2011
Posting: # 7917
Views: 4,226
 

 BE of racemic drugs (EMA vs. FDA)

Dear Scorp!

» How to substantiate the use of achiral bio-analysis for racemic drugs with enantiomers having differing pharmacokinetics. Please also comments on the recommendations on the use of chiral/achiral methods as presented in the current Bioequivalence guideline (CPMP/QWP/EWP/1401/98 Rev.1).

FDA's and EMA's requirements are contradictory…

FDA

For BE studies, this guidance recommends measurement of the racemate using an achiral assay. Measurement of individual enantiomers in BE studies is recommended only when all of the following conditions are met:

  1. the enantiomers exhibit different pharmacodynamic characteristics,
  2. the enantiomers exhibit different pharmacokinetic characteristics,
  3. primary efficacy and safety activity resides with the minor enantiomer, and
  4. nonlinear absorption is present (as expressed by a change in the enantiomer concentration ratio with change in the input rate of the drug) for at least one of the enantiomers.

In such cases, we recommend that BE factors be applied to the enantiomers separately.


EMA

The use of achiral bioanalytical methods is generally acceptable. However, the individual enantiomers should be measured when all the following conditions are met:

  1. the enantiomers exhibit different pharmacokinetics
  2. the enantiomers exhibit pronounced difference in pharmacodynamics
  3. the exposure (AUC) ratio of enantiomers is modified by a difference in the rate of absorption.

The individual enantiomers should also be measured if the above conditions are fulfilled or are unknown. If one enantiomer is pharmacologically active and the other is inactive or has a low contribution to activity, it is sufficient to demonstrate bioequivalence for the active enantiomer.


For the FDA you have to show BE only if all conditions are met. BE has to be demonstrated for both enantiomers in such cases.
For EMA essentially the same conditions are given. Note the subtle different wording “generally acceptable” vs. “recommended” in the lead. Beware of the nasty trap in the phrase “if the above conditions […] are unknown”. If you want to comply with the GL and still want to go with an achiral assay you have to justify that the conditions are not applicable (guilty until proven innocent)! That’s tough. At least you have to show BE for the active enantiomer only (FDA: both).
When the GL was published I expected many applications to go with chiral assays (at least I did). On the contrary my friends at European agencies told me that they have ‘rarely, if ever’ seen such applications. I’m confused as well.

Cheers,
Helmut Schütz
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scorp2011
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India,
2012-01-13 05:11
(edited by Jaime_R on 2012-01-13 08:43)

@ Helmut
Posting: # 7922
Views: 3,987
 

 BE of racemic drugs (EMA vs. FDA)

Dear HS,
Thanks for the detailed information.
I have a question. A BE study of racemic drug was conducted for EU submission and the bioequivalence was concluded based on the measurement of racemic drug. In the study enantiomers were not measured. The BE study was approved by the several EU regulatory authority. Now one of the EU regulatory body has asked to justify why enantiomers were not measured and why BE was concluded on racemic compound???

Please help in getting out of this situation.

Regards
scorp


Edit: Full quote removed. Please delete anything from the text of the original poster which is not necessary in understanding your answer; see also this post! [Jaime]
Helmut
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Vienna, Austria,
2012-01-13 15:02

@ scorp2011
Posting: # 7928
Views: 4,064
 

 BE of racemic drugs (EMA’s practice)

Dear Scorp!

» A BE study of racemic drug was conducted for EU submission and the bioequivalence was concluded based on the measurement of racemic drug. In the study enantiomers were not measured. The BE study was approved by the several EU regulatory authority. Now one of the EU regulatory body has asked to justify why enantiomers were not measured and why BE was concluded on racemic compound???

When was the study planned (=protocol submitted) and submitted to regulatory authorities? The current GL came into effect on 1 August 2010. Some regulators might assess the study according to the previous NfG (2010), which had more relaxed requirements:

[…] bioequivalence studies supporting applications for essentially similar medicinal products containing chiral active substances should be based upon enantiomeric bio-analytical methods unless (1) both products contain the same stable single enantiomer; (2) both products contain the racemate and both enantiomers show linear pharmacokinetics.

Some European regulatory authorities (f.i. Austria’s) assess all studies submitted after 1 August 2010 according to the current GL – regardless the date they have been performed.

» Please help in getting out of this situation.

Sorry, I can’t do that. If you cannot exclude the conditions required for an achiral assay stated in the GL, the term “unknown” will hit you.

BTW, assessors are a strange bunch. Last year we submitted a study on a single enantiomer IR product with a chiral assay in order to (exploratory) assess potential in vivo interconversion. Both PK and PD of the enantiomers are known to be different. The enantiomeric purity of the generic’s API (99.9%) was much better than the reference’s (95.5%). BE easy: 96.84–101.54% (AUCt), 98.86–112.09% (Cmax). Were asked by a (large!) European authority to perform a sensitivity analysis on the sum of both enantiomers…
:confused:

Cheers,
Helmut Schütz
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scorp2011
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India,
2012-01-16 12:08

@ Helmut
Posting: # 7944
Views: 3,926
 

 BE of racemic drugs (EMA’s practice)

Dear HS,

Thanks for the details. Will update the details regarding outcome of the regulatory response.

Regards
Sonu
valivetiananth
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India,
2019-12-30 12:45

@ scorp2011
Posting: # 21037
Views: 282
 

 BE of racemic drugs (EMA’s practice)

Dear Associate

Please update us the status of your query. same query was received from agency.

Regards
Valiveti


Edit: Full quote removed. Please delete everything from the text of the original poster which is not necessary in understanding your answer; see also this post #5[Helmut]
Helmut
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Vienna, Austria,
2019-12-30 13:35

@ valivetiananth
Posting: # 21038
Views: 277
 

 BE of racemic drugs (EMA’s practice)

Hi Valiveti,

» Please update us the status of your query. same query was received from agency.

Are you aware that you are replying to an almost eight years old post? Looking at the profile of scorp2011 you would have discovered that he/she logged in for the last time 4½ years ago. An answer is unlikely.

Which agency? See this post (linked others within and followings). In none of the EMA’s product-specific guidances an enantiomeric separation is recommended. Are you a victim of the “backdoor”? More details, please.

Cheers,
Helmut Schütz
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