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Ramesh Ramalingam
Junior

India,
2018-04-09 05:54

Posting: # 18654
Views: 1,008
 

 Primidone BE study for USFDA submission [Regulatives / Guidelines]

Dear All,

Till now, USFDA has not issued product specific bioequivalence recommendation to conduct the Primidone BE study. Any one could suggest, what to estimate in the Primidone BE study for USFDA submission, Whether required to estimate parent (Primidone) and metabolite Phenobarbital and phenylethylmalonamide (PEMA) or parent only?


Regards,
Ramesh.R


Edit: Relax; see also this post #9. I deleted your other post which is less than two days old… [Helmut]
jag009
Hero

NJ,
2018-04-09 16:16

@ Ramesh Ramalingam
Posting: # 18656
Views: 834
 

 Primidone BE study for USFDA submission

Haven't looked up the drug but are both metabolites active? To be on the safe side (if you don't want to file control correspondence) then i would measure the active metabolites since FDA usually ask to have the data collected.

John
bebac_fan
Junior

US,
2018-04-10 01:11

@ jag009
Posting: # 18659
Views: 796
 

 Primidone BE study for USFDA submission

Couldn't find any approval packages on Drugs@FDA, so I'm going to have to use science rather than precedent, shucks.

PEMA and PHB are both active metabolites, but based on the FDA general guidance, I am not sure that triggers a requirement to test for them.

However, the guidance specifically recommends PK samples for metabolites when there may be gut/enteric metabolism. Primidone undergoes autoinduction so it is likely metabolized by 3A4, which is in the gut. I suppose this is a trigger for metabolite monitoring?

Another point about autoinduction, is there are persistent effects on metabolism. A long washout period, determined by turnover number of CYPs should be applied. I am not sure what you guys do in practice. PHB can hang with the best of them (like rifampin) in terms of induction.
Ramesh Ramalingam
Junior

India,
2018-04-11 06:07

@ bebac_fan
Posting: # 18665
Views: 693
 

 Primidone BE study for USFDA submission

Dear Bfan,

Thank you very much for your ultimate input.


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]
Ramesh Ramalingam
Junior

India,
2018-04-11 06:05

@ jag009
Posting: # 18664
Views: 691
 

 Primidone BE study for USFDA submission

Dear John

Thank you very much for your input.


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]
balakotu
Regular

India,
2018-04-12 15:01
(edited by Ohlbe on 2018-04-13 10:23)

@ Ramesh Ramalingam
Posting: # 18670
Views: 564
 

 Primidone BE study for USFDA submission

Primidone is absorbed rapidly from the gastrointestinal tract, peak plasma levels being attained approximately 3 hours after ingestion. Primidone is well distributed in all organs and tissues: it crosses the blood-brain and placental barriers and is excreted in breast milk. The pharmacokinetics of primidone are complex because of biotransformation into two metabolites, phenobarbitone and phenylethylmalonamide, that have anticonvulsant activity and complex pharmacokinetic properties.

It is good to analyze the Parent and both metabolites (as they are pharmcologically active).
90% CI date for parent and metabolite data is supportive.

Also look into the safety aspect of drug (whether this product is NTI drug?)
Accordingly study design should be done.


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! [Ohlbe]
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