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Need to know vs. nice to know [Regulatives / Guidelines]

posted by Helmut Homepage - Vienna, Austria, 2018-05-18 12:35  - Posting: # 18780
Views: 944

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.

Cheers,
Helmut Schütz
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