Averroes
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Spain,
2011-02-22 15:05
(4783 d 21:43 ago)

Posting: # 6659
Views: 4,099
 

 Pre-dose concentrations in period 2 [Study As­sess­ment]

Dear colleagues,

First of all I would like to give thanks for this forum, it seems very helpful.
This is my first time writting, and I'm very naive in BA/BE studies.

I would like some advice on how to justify pre-dose concentration in the 2nd period, as we found them in around 50 % of subjects. It's very clear that the wash-out period was insufficient, but I would like to report that in an elegant way.

As far as I know it should not be critical as all of them are below 5% of Cmax. Both test and reference were affected equally.

Any suggestion?

Thanks,

Averroes


Edit: Category changed; see also this post #1. [Helmut]
Helmut
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Vienna, Austria,
2011-02-22 15:45
(4783 d 21:03 ago)

@ Averroes
Posting: # 6660
Views: 3,497
 

 Pre-dose concentrations in period 2

Dear Averroes!

❝ I would like some advice on how to justify pre-dose concentration in the 2nd period, as we found them in around 50 % of subjects. It's very clear that the wash-out period was insufficient, but I would like to report that in an elegant way.


Well, nothing to justify here. Shit happens; just report it and learn from it for the next studies. A common mistake is to plan the washout on the mean half-life reported in literature. Remember that higher than expected pre-dose values may occur if there is high inter-subject variability (especially if the drug is subjected to polymorphism). Plan always for the worst case (see this presentation, slides 40-42).

❝ As far as I know it should not be critical as all of them are below 5% of Cmax. Both test and reference were affected equally.


Right. Maybe you will see a slight period effect, which will be accounted for in the ANOVA anyway. Just give it a try: Take the data of any BE study and multiply all values in the second period by let's say 100. The outcome (PE, confidence interval) will be exactly the same – although you will notice a highly significant period effect.

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Averroes
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Spain,
2011-02-22 19:14
(4783 d 17:34 ago)

@ Helmut
Posting: # 6661
Views: 3,393
 

 Pre-dose concentrations in period 2

Dear HS,

Thanks for your comments and for your quick reply!!!
For sure I will take into account for the future.

Do you think we will receive comments from regulatory authorities due to that? or as long as all concentrations are below 5% of Cmax it's OK.

I have to say that I used Mean+SD reported in previous bioequivalence studies and SmPC to calculate washout, so as per your comments I shouldn't have %50 percent of subjects with pre-dose levels. On the other hand, I used a lower LLOQ, then I think pre-dose levels are due to flat part of the profile (pure elimination phase).

I think I will use data on SmPC and literature to justify this fact, hoping that it has no impact on the assessment of the application.

Thanks!!!
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