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The Netherlands,
2012-06-01 16:15

Posting: # 8652
Views: 2,517

 Chiral or Achiral Bioanalytical method? [Bioanalytics]

One of our R&D products is a chiral compound. Only its S-enantiomer is present in the Investigational Medicinal Product (IMP). The S-enantiomer is the pharmacologically active enantiomer, the R-enantiomer is inactive.
  1. In case only one enantiomer (the S-enantiomer) is present in the IMP, and is the only enantiomer pharmacologically active, do we have to develop an achiral or chiral bioanalytical method?
  2. I have checked the literature to find any articles on metabolic conversion of the S- to the R enantiomer. Unfortunately, I could not find any articles which show that the chiral compound is metabolically stable. In fact, I did not find any literature on metabolic conversion for this compound. Does this mean (lack of literature) that we have to develop a chiral BA method?
  3. In the theoretical case I would have found literature which showed that metabolic conversion took not place between S- to R-enantiomer, would this have meant that an achiral method would suffice?
Vienna, Austria,
2012-06-01 16:42

@ Petra
Posting: # 8654
Views: 2,204

 Chiral or Achiral Bioanalytical method?

Hi Petra,

nice to have you here. ;-)

Just to quote the GL:

Achiral methods are generally acceptable.
Chiral methods, if all conditions are met or unknown:

  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.

If only one enantiomer is active and the other is inactive or has low contribution to activity, it is sufficient to demonstrate BE for the active only.

I had a case similar to yours two years ago. Only one enantiomer in the product(s), slightly different PK (t½ 10h vs. 13h, almost complete absorption of both). So #1 was debatable, #2 unknown, #3 no idea. We run a chiral method. Got a deficiency letter from the RMS to recalculate the study for the sum of both enantiomers. Oops: we found practically no interconversion; the inactive isomer 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 need even 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.

Helmut Schütz

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