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I wish to conduct a 2-way crossover study on multiphasic modified release drug product for EMEA
The drug product is a prolonged release formulation with biphasic release pattern (IR+MR). The
initial maximum concentration achieves at about 1 to 2 hours (due to release of IR Part) and Peak
plasma concentration achieves at about 6 to 8 hours.
As per "Guideline on the pharmacokinetic and clinical evaluation of modified release dosage
forms_Jun-2015", For single dose study of multiphasic modified release drug product following
parameters has to show bioequivalence.
AUC0-t, AUC0-∞, partialAUCs and Cmax in all phases.
I have kept AUC0-t, AUC0-∞, partialAUC0-2, partialAUC2-t.
Please provide your opinion on following points.
(1) Please help to understand the meaning of "Cmax in all phases".
Shall I consider it as Cmax(0-2) & Cmax(2-t)? OR shall I consider Cmax(0-t)?
Shall I report the result for Cmax(0-2) & Cmax(2-t) and prove bioequivalence only on Cmax(0-t)?
(2) As per the guideline, Cmax(x+1) and partialAUC(x+1) also need to be evaluated. In this case
shall I consider it as Cmax(2+1) = Cmax0-3 & partialAUC(2+1) = partialAUC(0-3)? Please help to
understand the rationale of Cmax(x+1) & partialAUC(x+1).
Thanks in advance.
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I reviewed these types of products at the FDA years ago so the following is only my personal
I would report 2 Cmaxs and Tmaxs, one for each release component however, even though you expect the
IR component to occur in the first 2 hours and the MR to occur only after that, you never know when
they will actually occur, e.g. the IR component's Tmax could be at 3 hours in some people. So I
would not limit the time ranges. The problem comes it you don't get an interpeak trough and it's
just a shoulder for the first component on a bigger peak. (You can also report an overall Cmax and
Tmax although I consider that simply additional information that's not that useful)
I would also look at the interpeak minimum concentration and the time to that minimum.
As for bioequivalence think of it as two drug products. You can describe the total exposure by AUC
for rate of absorption and partial AUCS but in addition to the partial AUCs for the expected
absorption phase but also consider a second set of partial AUCs for the total extent of exposure
from each component. As for Cmax's the second Cmax will be superimposed on the concentrations from
the first component so there may be some latitude there in decision making.
As for food effects also look at Tlags or overall and intraindividual differences in the Tmax1,
Tmin, Tmax2. A morning meal can affect a lunchtime MR component and a separate lunch can also effect
the MR component so look at both.
I don't really understand what the Cmax(x+1) etc. stands for.
Although you haven't mentioned it, dissolution criteria is a big issue. This of it as needing two
separate complete dissolution profiles to set standards. One for the IR component and one for the MR
component. For the IR component you expect that you will eventually set a single point dissolution
but the second you will need to make sure there's no dissolution before a set time and then a 3
point dissolution standard for the MR component.
So think of it like this with %'s halved as compared to normal if the IR and MR components are each
50% of the dose. You will of course need to change %s depending on the 5 in each component.
IR component 50% of dose >45% dissolution at 30 minutes based on a complete dissolution profile
MR component 50% of the dose
No more than 50% (of total of IR and MR componnet) up to 4 hours (from beginning
of experiment with IR component)
Low control 67.5% +/- (of total IR and MR = 25% of MR) at Time 1
Middle control 75% +/- (of total IR and MR = 50% of MR) at Time 2
High Control > or = 90% (of total IR and MR = 80% of MR) at Time 3
Basically get as much info as you can and don't limit yourself as to when you think the first peak
and second peak will occur and let the data guide you.
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