Bioequivalence and Bioavailability Forum

Hi Christian,

❝ A Clinical study is going to be with an enantiomer (not racemate).

Are you talking about bioequivalence?

❝ The enantiomers exhibit different pharmacodynamic characteristics but only the active enantiomer is going to be in the formulation.

❝ There is no in-vivo interconversion.

❝ The reference standard is going to be the enantiomer (not racemate).

❝ Is a chiral method required? Can I go with a simple achiral method?

Which regulation? F.i. the FDA’s requirements concerning chiral methods are diametral to the EMA’s (see also here and there). Can’t find anything in the Mexican one.
One of the prerequisites in BE is that same molar doses of the active ingredient are administered. If the enantiomeric ratio* of the reference is 1:1, IMHO, you would have to administer twice the dose of the test and use a chiral method (assessing only the active enantiomer for BE).

Other opinions are welcome.

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• In sterochemistry, by definition a racemate contains the enantiomers in an equimolar mixture. When it comes to APIs this must not necessarily be the case.
  I once faced this situation: The reference was not declared as a racemate (though only the d-enantiomer was known to be active). It was also known that in purification of the API, the d-enantiomer is enriched. It turned out that the reference product contained 95% d and the test (API of another manufacturer) >99%. Since at that time we had no data about in vivo interconversion and were bound to the EMA’s GL, we used a chiral method. The d-enantiomer passed BE easily and the l-enantiomer would have failed (already expected based on the enantiomeric ratio and therefore, only descriptive according to the protocol). The test was approved in most member states of the EU. However, we received a deficiency letter of the swissmedic (Switzerland is a member of the EEA…) asking to re-evalute the study for the sum of d- and l.