Bioequivalence and Bioavailability Forum • Clopidogrel

Clopidogrel [Regulatives / Guidelines]

posted by Ohlbe – France, 2013-04-10 12:34 (4434 d 07:49 ago) – Posting: # 10393
Views: 15,217

Dear Outlaw,

❝ [...] I'm not sure I understand what you mean by the EMA getting trapped. Do you mean that there are ways around justifying clopidogrel, or other drugs known for back-conversion, that EMA hadn't considered

Oh no... If the drug is know for back-conversion, I don't really see a way out.

❝ (the paper you quoted where the authors found a way of controlling back-conversion)?

Which means there is a need to study back-conversion anyway...

❝ If that's not the case, mind expanding on this

What I mean to say is that it may not be sufficient to test known metabolites for back-conversion, or to just say that the drug has no known metabolite which could be back-converted. What EMA recommended for clopidogrel was to demonstrate the lack of back-conversion of clopidogrel carboxyacid, the main metabolite, to clopidogrel. The simplest way to do it would be to spike blank plasma with clopidogrel carboxyacid, process it, and check that no clopidogrel is generated. It made sense: one could imagine that clopidogrel carboxyacid could be re-esterified with methanol, and that this could explain the back-conversion issues with clopidogrel which some people were talking about.

Problem: the metabolite which is back-converted is not the carboxyacid, but the acylglucuronide* (not described in the literature when EMA published their recommendation, as far as I know), by a transesterification mechanism. Silvestro et al. clearly demonstrate in their paper that what was recommended by EMA just doesn't work. Only ISR allowed them to first identify the issue, then develop a method with no back-conversion issue.

In addition to a number of posters, see another paper by Silvestro et al.
Silvestro L, Gheorghe M, Iordachescu A, Ciuca V, Tudoroniu A, Rizea Savu S, Tarcomnicu I
Development and validation of an HPLC-MS/MS method to quantify clopidogrel acyl glucuronide, clopidogrel acid metabolite, and clopidogrel in plasma samples avoiding analyte back-conversion.
Anal Bioanal Chem. 2011 Aug;401(3):1023-34
doi: 10.1007/s00216-011-5147-4

—
Regards
Ohlbe

Complete thread:

Incurred sample reanalysis sarada06884 2013-04-09 12:22 [Regulatives / Guidelines]
- Incurred sample reanalysis Ohlbe 2013-04-09 14:09
  - Incurred sample reanalysis The Outlaw Torn 2013-04-10 08:40
    - ClopidogrelOhlbe 2013-04-10 10:34
      - Clopidogrel The Outlaw Torn 2013-04-10 11:31
        
        Lack of ISR / only 5% ISR in study with 656 samples Helmut 2013-04-22 17:01
        
        Lack of ISR / only 5% ISR in study with 656 samples ElMaestro 2013-04-22 18:56
        
        Lack of ISR / only 5% ISR in study with 656 samples Helmut 2013-04-22 19:35
        
        "Meth" - apologies ElMaestro 2013-04-22 20:03
        
        "Meth" - apologies The Outlaw Torn 2013-04-23 08:27
        
        "Meth" - apologies ElMaestro 2013-04-23 14:29
        
        "ISR" - apologies The Outlaw Torn 2013-04-24 07:44
        
        Repeat use ElMaestro 2013-04-24 11:08
        
        Repeat use Ohlbe 2013-04-24 11:41
        
        Repeat use ElMaestro 2013-04-24 13:45
        
        "ISR" – resolved Helmut 2013-09-20 21:50
        
        "ISR" – resolved Dr_Dan 2013-09-22 16:56
        
        Lack of ISR / only 5% ISR in study with 656 samples ElMaestro 2013-04-23 23:31
        
        Some more stuff Helmut 2013-04-24 02:08
        Lack of ISR / only 5% ISR in study with 656 samples nobody 2014-10-23 10:06