Dr_Dan
★★  

Germany,
2014-12-08 18:31
(3398 d 12:41 ago)

Posting: # 14014
Views: 9,063
 

 drug-drug inter­action in steady state? [Design Issues]

Dear all
I would like to perform a drug-drug interaction investigation performed as a open, randomized, three-period, cross-over trial in healthy volunteers in order to assess the relative bioavailability of drug1 and drug2 given either alone or in combination:

Treatment A: drug1+drug2 given as a FDC
Treatment B: drug1 given as a mono product
Treatment C: drug2 given as a mono product

In case linear PK applies for drug1 and drug2 a single-dose study is sufficient, otherwise I need to investigate steady state PK, right?

Background Information:
drug1 is extensively metabolised by the liver to inactive metabolites, 50% of drug2 is metabolised by the liver to inactive metabolites which are then excreted by the kidneys. The remaining 50 % is excreted by the kidneys in an unmetabolised form. Since the same route of elimination is partly used there could be a kind of competition. Could this be detected after single dose administration or do you need staedy state PK?

Looking forward to your feed back.
Kind regards
Dr_Dan

Kind regards and have a nice day
Dr_Dan
Helmut
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Vienna, Austria,
2014-12-08 18:43
(3398 d 12:29 ago)

@ Dr_Dan
Posting: # 14016
Views: 8,250
 

 DDI only in steady state

Hi Dan,

❝ In case linear PK applies for drug1 and drug2 a single-dose study is sufficient, otherwise I need to investigate steady state PK, right?


Nope. DDI should always be performed with the highest generally recommended dose in steady state (GL Section 5.4.3).

❝ […] Since the same route of elimination is partly used there could be a kind of competition. Could this be detected after single dose administration or do you need staedy state PK?


Exactly. See 5.4.4 of the guideline. It might well be that you see little effect after a single dose because the enzyme system needs some time to get activated.

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Dr_Dan
★★  

Germany,
2014-12-08 19:15
(3398 d 11:57 ago)

@ Helmut
Posting: # 14018
Views: 7,952
 

 DDI only in steady state

Hi Helmut
Thanks for your quick reply. It´s ages ago that I conducted a DDI study.

❝ Nope. DDI should always be performed with the highest generally recommended dose in steady state


I learned from this that each treatment needs to be investigated in steady state. The longest elimination half life (either drug1 or drug2) determines the duration of each period, right?
Treatment A: consecutive single doses of FDC administerd over 7 days
Treatment B: consecutive single doses of drug1 given as a mono product administerd over 7 days
Treatment C: consecutive single doses of drug2 given as a mono product administerd over 7 days

Allocation of subjects to sequences according to William´s design, right?

Kind regards
Dr_Dan

Kind regards and have a nice day
Dr_Dan
Helmut
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Vienna, Austria,
2014-12-08 19:30
(3398 d 11:42 ago)

@ Dr_Dan
Posting: # 14021
Views: 7,955
 

 DDI only in steady state

Hi Dan,

❝ The longest elimination half life (either drug1 or drug2) determines the duration of each period, right?


Not necessarily. We once performed a DDI with two drugs of very different half-lives (3 and 16 hours) and had a shorter phase for drug A only. I would not recommend that. Logistics was nasty and volun­teers were confused. Keep it simple and follow your suggestion.

❝ Allocation of subjects to sequences according to William´s design, right?


If you read in between the lines (BE-GL p.22 about ODTs), yes. Some forum members don’t see the necessity of keeping variance balanced if carry-over is not part of in the model. Given that, a 3×3 Latin Square should do as well. Up to you.

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felipeberlinski
☆    

Brazil,
2014-12-18 18:37
(3388 d 12:35 ago)

@ Helmut
Posting: # 14113
Views: 7,749
 

 DDI only in steady state

Dear Helmut

Could you please share again the GL posted. DDI is one of subjects that I'm working on.

I've tried to access it although it shows this message:

"The electronic version of this document is currently unavailable"

Thanks in advance :ok:
Helmut
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Vienna, Austria,
2014-12-18 18:59
(3388 d 12:13 ago)

@ felipeberlinski
Posting: # 14114
Views: 7,755
 

 DDI only in steady state

Hi Felipe,

❝ I've tried to access it although it shows this message:


❝ "The electronic version of this document is currently unavailable"


Sorry, I screwed up the link above. Correct:
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/07/WC500129606.pdf#page=29.
If you don’t succeed, contact me by e-mail and I will send you a copy. Note that there is another one issued by the FDA.

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Dr_Dan
★★  

Germany,
2015-01-07 16:42
(3368 d 14:30 ago)

@ Helmut
Posting: # 14238
Views: 7,545
 

 DDI only in steady state

Hi Helmut
I am facing the problem of a DDI with two drugs of very different half-lives (even much bigger difference than your example) and I am wondering if it would be possible to use a sequential design instead of the randomised cross-over. According to my understanding this should be in agreement with the Guideline. The sequence of treatments would be just CBA with C=drug1, short half life, B=drug2, long half life and A=FDC, all treatments in steady state. The advantage would be a reduced study duration and some cost savings. What would be the disadvantages and/or pitfalls?
Any idea?
Looking forward to your or anybody else´s reply.
Kind regards
Dr_Dan

Kind regards and have a nice day
Dr_Dan
Dr_Dan
★★  

Germany,
2015-01-09 13:04
(3366 d 18:08 ago)

@ Dr_Dan
Posting: # 14265
Views: 7,492
 

 DDI active wash-out

Dear all
in addition to my question above: Would I need a complete active wash-out?
For example:
Treatment C, 5 days dosing drug 1
Treatment B, 14 days dosing drug 2
Treatment A, 5 days dosing combination of drug1+2 or
Treatment A, 14 days dosing combination of drug1+2
I beliefe not, since DDI is studied, however, there will be a formulation effect between mono and combi product.
I am looking Forward to your reply and suggestions.
Kind regards
Dr_Dan

Kind regards and have a nice day
Dr_Dan
nobody
nothing

2015-01-09 16:03
(3366 d 15:09 ago)

@ Dr_Dan
Posting: # 14267
Views: 7,465
 

 DDI active wash-out

The wash-out in a DDI study should depend on the effect you expect (from prior knowledge, such as in vitro data etc.). For a PK interaction, wash-out based on PK might be sufficient, if you expect induction or irreversible inhibition (metabol. enzymes, transporters), then things might be a little different.

Example:

rifampicin

Kindest regards, nobody
Dr_Dan
★★  

Germany,
2015-01-09 16:59
(3366 d 14:13 ago)

@ Dr_Dan
Posting: # 14268
Views: 7,375
 

 DDI active wash-out

Dear nobody
You are completely right, but my question is a little bit different. I start my my study with Treatment C, 5 days dosing drug 1 = steady state drug 1. Next step Treatment B, 14 days dosing drug 2 = steady state drug 2. Then I will administer the combination product. But for how long? For drug 1 I need 5 days and for drug 2 I am already at steady state. If I consider the formulation effect I would need to dose 14 days, but is this necessary?
Kind regards
Dr_Dan

Kind regards and have a nice day
Dr_Dan
nobody
nothing

2015-01-09 17:38
(3366 d 13:34 ago)

@ Dr_Dan
Posting: # 14269
Views: 7,402
 

 DDI active wash-out

...but is this necessary?

As you have to be in steady-state: Yes. You can add the short-half life drug only for the last 5 days of the combination period, but overall...

Kindest regards, nobody
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