Bioequivalence and Bioavailability Forum

Hi Petra,

nice to have you here.

Just to quote the GL:

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

• 1. Enantiomers exhibit different pharmacokinetics.
     
  2. Enantiomers exhibit pronounced differences 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.

(my emphasis; if unknown → chiral assay!)

I had a case similar to yours two years ago. Practically only one enantiomer in the product(s) – though not stated as such, slightly different PK (t_½ 10 h vs. 13 h, almost complete absorption of both). Hence, #1 was debatable, #2 unknown, #3 no the slightest idea. Therefore, we used a chiral method. Got a deficiency letter from the RMS to recalculate the study for the sum of both enantiomers. Well, we found practically no interconversion; the (likely) inactive enantiomer was essentially an impurity of the reference’s API. The test product passed BE easily, and the AUC of the inactive was <4% of total. You don’t even need a pocket calculator to see that the total would pass as well.

At last year’s BE conference in Kobe I asked Jan Welink about his experiences with chiral analytics. To my surprise he said that he hasn’t seen a single one [sic]. I don’t know whether sponsors and (some) regulators don’t understand the requirements of the GL or simply ignore them.

But maybe I am total wrong.