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RegisterBioequivalence decision affected by ISR? [Bioanalytics]
Dear Ohlbe
Sorry, but I do not like/agree with your reply because you use clopidogrel as an unfair example to justify ISR and in the second part you argue with borderline results (which are out of question) in combination with back-conversion. In case of clopidogrel the amount of the metabolite within the systemic circulation is about 5000-fold! higher than of the parent compound. This is rather unique, right? In this case I agree that ISR is demanded by the Q&A document. However, a conversion of the main metabolite to clopidogrel is chemically an esterification step. Esterifications are bound to different conditions, e.g. presence of an organic acid and an alcohol as well as higher temperature. If within the sample preparation and the chromatography neither the extractions procedure and the final extract nor the mobile phase does contain the relevant molecules e.g. methanol as alcohol for esterification then you could exclude metabolite back-conversion.
What are your objections against the following hypothesis: In case the amount of metabolite(s) is not so high as in above given example and you can exclude back-conversion by the method used* and your 90% CIs are well within the acceptance range than an increase in the analytical variability can only decrease chances to demonstrate bioequivalence.
I am looking forward to your and Other reply(ies)
Kind regards
Dan
* In this case your argument that the lower CVintra of the metabolite will affect/decrease the CVintra of the parent drug does not apply
Sorry, but I do not like/agree with your reply because you use clopidogrel as an unfair example to justify ISR and in the second part you argue with borderline results (which are out of question) in combination with back-conversion. In case of clopidogrel the amount of the metabolite within the systemic circulation is about 5000-fold! higher than of the parent compound. This is rather unique, right? In this case I agree that ISR is demanded by the Q&A document. However, a conversion of the main metabolite to clopidogrel is chemically an esterification step. Esterifications are bound to different conditions, e.g. presence of an organic acid and an alcohol as well as higher temperature. If within the sample preparation and the chromatography neither the extractions procedure and the final extract nor the mobile phase does contain the relevant molecules e.g. methanol as alcohol for esterification then you could exclude metabolite back-conversion.
What are your objections against the following hypothesis: In case the amount of metabolite(s) is not so high as in above given example and you can exclude back-conversion by the method used* and your 90% CIs are well within the acceptance range than an increase in the analytical variability can only decrease chances to demonstrate bioequivalence.
I am looking forward to your and Other reply(ies)
Kind regards
Dan
* In this case your argument that the lower CVintra of the metabolite will affect/decrease the CVintra of the parent drug does not apply
—
Kind regards and have a nice day
Dr_Dan
Kind regards and have a nice day
Dr_Dan
Complete thread:
- Bioequivalence decision affected by ISR? Dr_Dan 2012-12-21 09:52
![[Mix]](https://static.bebac.at/img/mix.png "open in Mix view")
- Bioequivalence decision affected by ISR? Ohlbe 2012-12-21 10:30
- Bioequivalence decision affected by ISR?Dr_Dan 2012-12-21 15:31
- Bioequivalence decision affected by ISR? Ohlbe 2012-12-21 19:12
- Lousy studies? Helmut 2012-12-21 20:19
- Bioequivalence decision affected by ISR? Ohlbe 2012-12-21 19:12
- Bioequivalence decision affected by ISR?Dr_Dan 2012-12-21 15:31
- Tricky question Helmut 2012-12-21 15:23
- Add'l requirements ElMaestro 2012-12-23 05:10
- Bioequivalence decision affected by ISR? Ohlbe 2012-12-21 10:30
Ing. Helmut Schütz