mittyri
★★  

Russia,
2018-05-17 22:47
(925 d 00:06 ago)

Posting: # 18779
Views: 2,690
 

 is Perindoprilat optional? [Regulatives / Guidelines]

Dear All,

could you please enlighten me what is the reason to analyse and describe PK of Perindoprilat when one of APIs is Perindopril (as an example)?
As EMA stated
Also for inactive prodrugs, demonstration of bioequivalence for parent compound is recommended.
The active metabolite does not need to be measured.


What is the reason why the experts could insist to include Perindoprilat to the list of analytes?

Kind regards,
Mittyri
Helmut
★★★
avatar
Homepage
Vienna, Austria,
2018-05-18 12:35
(924 d 10:17 ago)

@ mittyri
Posting: # 18780
Views: 2,383
 

 Need to know vs. nice to know

Hi Mittyri,
Hence, the study likely was performed before even the draft BE GL was published (24 July 2008). The applicable Note for Guidance (2001) was ambiguous:

In most cases evaluation of bioavailability and bioequivalence will be based upon the measured concentrations of the parent compound. In some situations, however, measurements of an active or inactive metabolite may be necessary instead of the parent compound. Such situations include cases where the use of a metabolite may be advantageous to determine the extent of drug input, e.g. if the concentration of the active substance is too low to be accurately measured in the biological matrix (e.g. major difficulty in analytical method, product unstable in the biological matrix or half-life of the parent compound too short) thus giving rise to significant variability.
Bioequivalence determinations based on metabolites should be justified in each case bearing in mind that the aim of a bioequivalence study is intended to compare the in vivo performance of test and reference products. In particular if metabolites significantly contribute to the net activity of an active substance and the pharmacokinetic system is non-linear, it is necessary to measure both parent drug and active metabolite plasma concentrations and evaluate them separately.

Don’t think that the PK of perindopril is nonlinear.

In the study the parent perinodopril was the primary and “data from perindoprilat were used as supportive data” (PAR page 68).

» What is the reason why the experts could insist to include Perindoprilat to the list of analytes?

I don’t think that they insisted. Was the company’s decision (maybe if the study failed the parent to have sumfink to start an argument). Nowadays in the EEA the metabolite is only nice to know and definitely not mandatory.
Interesting that the FDA requires perindoprilat as “supportive evidence of comparable therapeutic outcome” and the following data should be submitted: individual and mean concentrations, individual and mean pharmacokinetic parameters, and geometric means and ratios of means for AUC and Cmax.

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mittyri
★★  

Russia,
2018-05-19 23:46
(922 d 23:06 ago)

@ Helmut
Posting: # 18790
Views: 2,149
 

 where nice to know is mandatory

Hi Helmut,

thank you for detailed answer (as always!)

» » What is the reason why the experts could insist to include Perindoprilat to the list of analytes?
»
» I don’t think that they insisted. Was the company’s decision (maybe if the study failed the parent to have sumfink to start an argument). Nowadays in the EEA the metabolite is only nice to know and definitely not mandatory.

Well, I got some discussion with colleagues a while ago. They are confused by the fact that Russian experts insisted on Perindoprilat as mandatory additional analyte.
After referencing to the actual Russian/EEU guidelines (see above) they mentioned that 'there's an actual (common) practice to analyse and to present Perindoprilat within Perindopril in Russia and other counties'
So I was wondering what kind of countries they were mentioning?
OK, FDA/USA.
Then why the hell the guideline is written using EMA approach??
Have you seen so far that experts could insist on metabolites?

Kind regards,
Mittyri
ElMaestro
★★★

Belgium?,
2018-05-18 14:26
(924 d 08:27 ago)

@ mittyri
Posting: # 18782
Views: 2,325
 

 ...and apart from that Perindopril is not a difficult analyte

Hi,

apart from the answer from Helmut above I think that Perindopril itself is a pleasant drug to work with. It absorbs well, not too fast and not too slow, the peak can be nicely captured and does not requirement enormously sensitive detectors, and any conversion to perindoprilat in plasma can be easily controlled.

I could be wrong, but...

Best regards,
ElMaestro

No, of course you do not need to audit your CRO if it was inspected in 1968 by the agency of Crabongostan.
Ohlbe
★★★

France,
2018-05-18 15:26
(924 d 07:27 ago)

@ ElMaestro
Posting: # 18783
Views: 2,299
 

 ...and apart from that Perindopril is a difficult analyte

Dear El Maestro,

» [...] and any conversion to perindoprilat in plasma can be easily controlled.

But beware of the back-conversion of the acylglucuronides, both of perindopril and of perindoprilat. They are well known for their instability. Some people have run into trouble.

Regards
Ohlbe
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