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We are conducting a bioequivalence study with two formulation strengths.
Each formulation is administered over a 21-day or 28-day dosing period.
In order to compare AUC at steady state, we have proposed using Cav as the primary parameter.
FDA have recommended to divide the 21-day and 28-day regimens into sub-groups and compare AUC
separately.
Is anyone aware of anything published that uses Cav to compare exposure?
Any arguments against using Cav is this context?
Thanks,
Charlie
Charlie Brindley
KinetAssist Ltd
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Dear Charlie,
I guess you are looking for comparision of steady state PK parameter.
Since you are using AUC at steady for comparision, I would recommend use Cmaxss for comparision
instead of Cav.
Your assumption ideally at steady state would there is no change in trough and peak concentration
after a certain timepoint. Therefore your Cmax at steady state should vary much and most probably
variability would also be less (I am not sure), in my opinion you must think of using Cmaxss for
comparison instead of Cav.
Kindly let me know what do you think.
Regards,
Atish
[How are you calculating Cav (or Cavss)? AUC / tau? - db]
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Hi Charlie,
> We are conducting a bioequivalence study with two formulation strengths.
> In order to compare AUC at steady state, we have proposed using Cav as the primary parameter.
> Any arguments against using Cav is this context?
>
I guess you will calculate Cav as AUCss/tau? By applying a constant to a PK metric you will get
exactly (!) the same T/R-ratio and its CI. Why do you want to make oranges out of apples?
Helmut
--
Ing. Helmut Schuetz
BEBAC - Consultancy Services for
Bioequivalence and Bioavailability Studies
1070 Vienna, Austria
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Hi Helmut,
I should have emphasised that we need to compare two different formulations using two treatment
regimens (21-day and 28-day dosing intervals).
It has just been confirmed that the FDA will not accept Cav because of the risk of non-stationarity
(time dependency).
We have evidence that the 21-day and 28-day is bioequivalent based on Cav; however, I don't think
the FDA would change their minds for this bioequivalence study.
So, we will need to carry out bioequivalence assessment separately on the different dose regimens
using AUC0-tau.
We are also comparing PK from a subcutaneous formulation (7-day dosing interval) to historical data
from an intravenous formulation (21-day and 28-day schedules).
In this case, we have no option but to use Cav. Would you agree?
Regards,
Charlie
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Hi Charlie,
> I should have emphasised that we need to compare two different formulations using two treatment
> regimens (21-day and 28-day dosing intervals).
>
OK, no problem – if you attained steady state with both regimens.
> It has just been confirmed that the FDA will not accept Cav because of the risk of
> non-stationarity (time dependency).
>
I don't get it. Can you eleborate what you mean by "non-stationarity"?
> We have evidence that the 21-day and 28-day is bioequivalent based on Cav; however, I don't think
> the FDA would change their minds for this bioequivalence study.
>
Try it: If you are able to demonstrate BE for Cav, you will be BE for
AUCtau as well. So why don't you feed the beast with the red meat it wants?
> So, we will need to carry out bioequivalence assessment separately on the different dose regimens
> using AUC0-tau.
>
See above. Shouldn't be a problem.
> We are also comparing PK from a subcutaneous formulation (7-day dosing interval) to historical
> data from an intravenous formulation (21-day and 28-day schedules).
> In this case, we have no option but to use Cav. Would you agree?
>
Out of curiosity: How will you do that? Do you have the subjects’ data
or only means and/or a CI? In the former case you could run a
Welch/Satterthwaite-test (see FDA’s guidance: you must not assume equal
variances). If you have only Cav, you still can calculate AUCtau as
Cav*tau and base the comparison on it.
Helmut
--
Ing. Helmut Schuetz
BEBAC - Consultancy Services for
Bioequivalence and Bioavailability Studies
1070 Vienna, Austria
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Hi Helmut,
We will have achieved steady state with both regimens.
FDA will definitely NOT accept Cav for this study; we have discussed this possibility with them.
They are concerned that the two dose regimens will not be equivalent because of the different dosing
intervals; i.e. there could be an alteration in the kinetics beyond 21 days.
In other words, the FDA consider that there could be a time-dependent difference in the kinetics. I
know that this is unlikely (and we have evidence that the profiles are superimposable), but Cav
simply will not be accepted a primary parameter for bioequivalence assessment.
"Stationarity" is a term that describes the predictable "linear" kinetics over time. I'm not sure if
this term is widely used.
For the historical comparison, we will have AUC0-tau (and therefore Cav) for all subjects; however,
how can we compare AUC0-tau when the values will be greater for the 21 and 28-day treatments
compared to the 7-day treatment? The AUC values have to be adjusted for dosing interval to make a
meaningful comparison. This is not a formal bioequivalence study but we will use a bioequivalence
approach to compare the formulations.
Regards,
Charlie
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Hi Helmut,
Please ignore my previous response; we can, of course, compare AUC0-tau at steady state with
different dosing intervals.
We only need to assume linear (dose and time-independent) kinetics.
I should have remembered my school teacher's maxim "think before you ink"!
With apologies,
Charlie
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