BE of racemic drugs (EMA vs. FDA) [Regulatives / Guidelines]

posted by Helmut Homepage – Vienna, Austria, 2012-01-12 19:21 (3487 d 01:46 ago) – Posting: # 7917
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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…


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.


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.

Dif-tor heh smusma 🖖
Helmut Schütz

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