Mahesh M
★    

India,
2016-05-12 09:07
(2877 d 22:26 ago)

Posting: # 16296
Views: 3,670
 

 Pharmacokinetic interaction study [Regulatives / Guidelines]

Dear All,
My concern regarding Pharmacokinetic interaction study for new combination product, what are the criteria for passing (or how we can say not interact with each other) the Pharmacokinetic interaction study? Is it same as conventional Bioequivalence study criteria (90% CI 80 – 125%).

Please share If any guidance or literature available.

Thanks
Helmut
★★★
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Vienna, Austria,
2016-05-12 15:15
(2877 d 16:18 ago)

@ Mahesh M
Posting: # 16297
Views: 3,139
 

 FDCPs: generally BE (higher BA under certain conditions)

Hi Mahesh,

❝ My concern regarding Pharmacokinetic interaction study for new combination product, what are the criteria for passing (or how we can say not interact with each other) the Pharmacokinetic interaction study? Is it same as conventional Bioequivalence study criteria (90% CI 80 – 125%).


From your wording I assume that you want to develop a new FDCP (and not a generic of another FDCP). Such a development is complex and has to take advantages (f.i. more conventient for the patient, better compliance) and disadvantages (f.i. no dose-titration of individual APIs possible, initial vs. chronic doses) into account. For an overview see the WHO’s TRS No. 929, Annex 5 (2005) and the EMA’s GL (2009) and concept paper. Quoting the WHO:
  • If a study of bioequivalence finds that the two treatments are bioequivalent, it may be assumed that any pharmacokinetic interactions between the actives were the same, even if one treatment comprised an FDC-FPP [fixed-dose combination finished pharmaceutical product] and the other comprised separate products.
  • During analysis of the results of a bioavailability or bioequivalence study for an FDC-FPP, the parameters to be reported and assessed are those that would normally be required of each active if it were present as a single entity and the same statistical confidence intervals and decision criteria should be applied.
However,

Interpretation of the results of bioavailability and bioequivalence tests involves both quality and medical considerations. For example it is not acceptable that bioavailability is reduced or variable, when compared with that of single entity products, because of poor formulation, but an interaction between two actives that leads to an increased bioavailability may be one of the advantages that is taken into account when balancing advantages and disadvantages.


Please see also this post (Section 3).

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nobody
nothing

2016-05-12 15:41
(2877 d 15:51 ago)

@ Helmut
Posting: # 16298
Views: 3,032
 

 FDCPs: generally BE (higher BA under certain conditions)

Hi!

...just to add: There is a MAY-2015 draft of the EMA guideline on this topic, not further addressing the criteria for DDI studies, iirc...

Kindest regards, nobody
Mauricio Sampaio
★    

Brazil,
2016-05-19 07:47
(2870 d 23:45 ago)

@ nobody
Posting: # 16331
Views: 2,671
 

 FDCPs: generally BE (higher BA under certain conditions)

Thinking about a new Fixed Dose combination of two inhalers drugs in a same capsule, should be conducted tests to elucidate any pharmacokinetic or pharmacodynamic interaction between the actives as well as?

Until the moment, I was thinking that all interactions studies are used to predict interactions in drugs administrated by oral which metabolic effects can be observed.

:confused::confused::confused::confused:
Dr_Dan
★★  

Germany,
2016-05-19 12:05
(2870 d 19:27 ago)

@ Mahesh M
Posting: # 16332
Views: 2,668
 

 Pharmacokinetic interaction study

Dear Mahesh M
If you develop a new FDCP (and not a generic of another FDCP) you are obliged to investigate possible DDI. AFAIK/my experience: A DDI study is not a konfirmatory study, you only need to describe the pharmacokinetic interaction by means of each single entity and the same statistical confidence intervals. But you do not need to show bioequivalence by means of the acceptance range of 80-125%. If you meet the bioequivalence criteria everything is fine. If you are not (strictly) bioequivalent, you need to discuss the results with respect to risk and benefit of the new FDCP. However, if your new FDCP is a combination of two inhaler drugs in a same capsule I do not think that a simple DDI study would be sufficient since the systemic availability of the drugs might not reflect their combined local effect. A clinical phase III study can not be avoided.
I hope this helps.
Kind regards
Dr_Dan

Kind regards and have a nice day
Dr_Dan
nobody
nothing

2016-05-20 11:40
(2869 d 19:53 ago)

@ Dr_Dan
Posting: # 16343
Views: 2,882
 

 Pharmacokinetic interaction study

I would support this opinion (at least for EU), as the EMA DDI Guideline as of 2012 does not require formal BE testing. Why should this be more rigid for new FDCs?

Kindest regards, nobody
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