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Back to the forum  Query: 2017-12-13 15:50 CET (UTC+1h)
 
Biostats
Junior

India,
2017-11-25 09:22

Posting: # 18004
Views: 417
 

 calculation of cutoff time point in case of multiphasic modified release [NCA / SHAM]

Dear all,

As per EMA guideline on the pharmacokinetic and clinical evaluation of modified release dosage forms in section 6.8.1.1 single dose studies

“For multiphasic modified release products additional parameters to be determined include partialAUC, Cmax and tmax in all phases. The time point for truncating the partialAUC should be based on the PK profile for the e.g. IR and the MR parts respectively and should be justified and pre-specified in the study protocol.”

Is there any scientific method or formula to calculate the time point for truncating the partial AUC (cutoff time point)?


Edit: Category changed; see also this post #1. [Helmut]
Helmut
Hero
Homepage
Vienna, Austria,
2017-11-25 13:46

@ Biostats
Posting: # 18005
Views: 340
 

 cutoff time point based on PK?

Hi Biostats,

» Is there any scientific method or formula to calculate the time point for truncating the partial AUC (cutoff time point)?

Scientific? Yes. That would be based on PD – not PK as the GL recommends (regulations  science). Examples of biphasic MR products:
  • Methylphendiate (3 hours fasting and 4 hours fed).
  • Zolipidem (1.5 hours fasting and fed).
The first part is for rapid onset of effect and the second for its maintenance. In both cases the cut-off points are based on clinical studies and the justification as given by the FDA.

If have seen studies trying to show BE to Concerta with a cut-off of 2 hours. That’s ridiculous. In many subjects we don’t see a trough between the IR and MR parts in the profiles (only a “shoulder”). Expect large intra-subject variability and opt for reference-scaling (requires a replicate design).

[image]Regards,
Helmut Schütz 
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Biostats
Junior

India,
2017-11-26 07:36

@ Helmut
Posting: # 18006
Views: 292
 

 cutoff time point based on PK?

Dear Sir,

Thanks for your prompt response

As per Methylphenidate FDA draft guidance cut-off time point should be Average of Tmax + 2*SD (Average and SD should be calculated from IR portion).

Can we apply this method for EMA submission?

Can we apply reference-scaling for all seven pk parameters or only for pk parameters from first phase i.e. Cmax(1) & AUC(1) as expected large intra-subject variability in first phase?


Edit: Full quote removed. Please delete everything from the text of the original poster which is not necessary in understanding your answer; see also this post #5! [Helmut]
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