BE-proff
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2015-07-28 21:15
(3165 d 15:41 ago)

Posting: # 15165
Views: 6,753
 

 BE study: modified vs immediate release [Design Issues]

Dear All,

May be my question will seem stupid but nevertheless I ask it.
I have to demonstrate BE between modified release product (taken once a day) and immediate-release product (taken twice a day).
IMHO there is a risk that both product can show different kinetics and they won't be equivalent in 1-time administration of each medications.
To avoid this risk I think of steady state study.

But how to prove my idea based on actual guides?

Does anybody have such experience?
Helmut
★★★
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Vienna, Austria,
2015-07-29 15:06
(3164 d 21:51 ago)

@ BE-proff
Posting: # 15169
Views: 6,001
 

 BE study: modified vs immediate release

Hi BE-proff,

❝ I have to demonstrate BE between modified release product (taken once a day) and immediate-release product (taken twice a day).


Think about (EMA’s) definition of bioequivalence:

Two medicinal products containing the same active substance are considered bioequivalent if they are pharmaceutically equivalent or pharmaceutical alternatives and their bioavailabilities (rate and extent) after administration in the same molar dose lie within acceptable predefined limits.

Will not work (by definition).

❝ IMHO there is a risk that both product can show different kinetics and they won't be equivalent in 1-time administration of each medications.


Not a risk at all; different PK is the rationale for developing modified release formulations (better compliance due to fewer administrations, less fluctuations, etc.).

❝ To avoid this risk I think of steady state study.

❝ But how to prove my idea based on actual guides?


Was too lazy to check Russian requirements, but have a look at EMA’s GL, Section “Application for a modified release formulation of a drug that is authorised in a formulation with a different release rate” for details.

❝ Does anybody have such experience?


Yes. :-D
Single dose, generally multiple dose, food effect, dose proportionality, in vitro dose dumping (C2H5OH) + at least one clinical study. In the EU that’s called a “hybrid application”.

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BE-proff
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2015-07-30 10:27
(3164 d 02:30 ago)

@ Helmut
Posting: # 15172
Views: 5,711
 

 BE study: modified vs immediate release

Hi Helmut,

Thanks a lot for your reply.
Unfortunately I don't have specific guides for modified-release products therefore we ave to use EMA/FDA guides :-|

But one more question - how do you understand section 6.1.1.2?
As far as I understand, having a new modified-release medication at first I have to conduct single-dose study to assess mean AUC0-t/AUC0-inf?

If this ratio <0.90 it says about accumulation and I have to conduct multi-dose study? :confused:
If this ratio >0.90 multi-dose study is not required and I can have some rest? :smoke:

An I right? ;-)
mittyri
★★  

Russia,
2015-07-29 23:49
(3164 d 13:07 ago)

(edited by mittyri on 2015-07-30 07:31)
@ BE-proff
Posting: # 15170
Views: 5,788
 

 MR = twilight zone in Russia

Hi BE-proff,

"Welcome to the twilight zone!" :cool:
First of all ACK with Helmut's suggestion above.

Let's take a look to our "Red Book", p.200, chapter 3.1
"Bioequivalence studies are required."
What kind of studies? :confused: How many?
If you look at this chapter in the EMA GL, you will find the links to the specific GL.
There is no GL for MR in Russia and no published requirements! :-D
All what I know is promising of the experts from FGBU. They should publish something, but no one knows when.
There is no way out...
Sorry, I didn't have any experience for absolutely new MR products in Russia and I don't know what kind of set of studies is enough according to the experts' requirements. :-| BTW AFAIK there were some attempts from some companies, I don't know about consequences.

Kind regards,
Mittyri
BE-proff
●    

2015-07-30 10:10
(3164 d 02:47 ago)

@ mittyri
Posting: # 15171
Views: 5,662
 

 MR = twilight zone in Russia

Hi mittyri,

Yes, you are right.

But you give references to western guides in submitted documents they are usually accepted by Russian experts ;-)
mittyri
★★  

Russia,
2015-07-30 13:04
(3163 d 23:53 ago)

(edited by mittyri on 2015-07-30 15:24)
@ BE-proff
Posting: # 15174
Views: 5,643
 

 MR vs. Russian experts

Hi BE-proff,

❝ But you give references to western guides in submitted documents they are usually accepted by Russian experts ;-)


Sorry for misunderstanding, I corrected the previous post to be in accordance with russian GL.
There are no links to the EMA/FDA GL in russian "Red Book" (I mean this chapter)
Yes, the experts accept the EMA/FDA approaches if you provide the appropriate link.
BTW did you see at least one plan of studies in accordance with EMA MR GL (for example) in Russia?
Even for MR vs. MR studies the requirements stated in the EMA GL are not satisfied. Providing the results of only one BE study performed in Russia (i.e. single dose fed or single dose fasting) is sufficient for registration purposes.

Kind regards,
Mittyri
BE-proff
●    

2015-07-30 13:46
(3163 d 23:10 ago)

@ mittyri
Posting: # 15175
Views: 5,552
 

 MR vs. Russian experts

Hi mittyri,

I heard about cases when single-dose study didn't demonstrate BE between modified and immediate forms.
In this case multi-dose regime would have smoothed curves and chances would have been higher :-(

But how to explain it to experts? :confused:
mittyri
★★  

Russia,
2015-07-30 17:23
(3163 d 19:34 ago)

@ BE-proff
Posting: # 15176
Views: 5,591
 

 MR vs. Russian experts

Hi BE-proff,

❝ I heard about cases when single-dose study didn't demonstrate BE between modified and immediate forms.


What do you mean?
EMA MR GL states:
The aim of the modified release formulation is therefore, in most cases, to reach a similar total exposure (AUC) to active substanceas for the immediate release formulation. This does not necessitate that the same nominal doses are given (the modified release formulation may have a different extent of absorptionor metabolism). In general modified-release formulations are not bioequivalent to their immediate release form. Consequently PK data alone may not be sufficient for evaluatingwhether the benefit/risk ratio of the modified release formulation is comparable to the corresponding doses of the immediate release form.

❝ In this case multi-dose regime would have smoothed curves and chances would have been higher :-(


Yes, you can demonstrate the bioequivalence between MR and IR in SS. BTW do you really think that one study in steady state is sufficient to prove the rationale of development of new MR formulation? :confused:

❝ But how to explain it to experts? :confused:


Just follow the EMA MR GL, I think they will be satisfied :-D

Kind regards,
Mittyri
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