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Dear members,
Greetings.
We have conducted "An open label randomized, two-treatment, two-
period, two-sequence OD vs. BID, crossover comparative
bioavailability study".
Two treatments: Test formulation is 400mg tablet and the Reference
formulation is a 200 mg tablet.
Dosing: Test formulation 400mg was administered (Dosed) to the
healthy volunteers at 0.00 hours.
Reference formulation 200mg was administered (Dosed)
to the healthy volunteers at 0.00 hours and 12.00 hours.
The half-life of the values ranges from 25-65 hours, decreasing to
12-17 hours on repeated dose.
Sampling scheduled:
Test formulation is
0.0,1.00,2.00,3.00,4.00,5.00,6.00,7.00,8.00,9.00,10.00,11.00,12.00,16.00
,24.00,36.00,48.00,96.00,144.00 and 192.00.
Reference formulation
0.0,1.00,2.00,3.00,4.00,5.00,6.00,7.00,8.00,9.00,10.00,11.00,12.00,13.00
,
14.00,15.00,16.00,17.00,18.00,19.00,20.00,21.00,22.00,23.00,24.00,36.00,
48.00,96.00,144.00 and 192.00.
We analyzed the samples using the validated LC/MS/MS method. The
concentration data, which we got, is looks like this.
Form Time Conc
T 0.00 0.000
T 1.00 65.510
T 2.00 129.840
T 3.00 204.820
T 4.00 258.380
T 5.00 361.680
T 6.00 561.110
T 7.00 587.650
T 8.00 775.190
T 9.00 837.720
T 10.00 773.910
T 11.00 755.490
T 12.00 788.880
T 16.00 682.770
T 24.00 657.650
T 36.00 539.240
T 48.00 494.960
T 96.00 256.040
T 144.00 135.420
T 192.00 64.450
R 0.00 0.000
R 1.00 606.180
R 2.00 934.960
R 3.00 1178.550
R 4.00 1349.900
R 5.00 1506.610
R 6.00 1542.880
R 7.00 1597.560
R 8.00 1565.890
R 9.00 1459.490
R 10.00 1462.030
R 11.00 1515.500
R 12.00 1580.640
R 13.00 2297.960
R 14.00 2745.560
R 15.00 2976.830
R 16.00 3048.140
R 17.00 3000.410
R 18.00 3155.620
R 19.00 3042.260
R 20.00 2860.920
R 21.00 2903.420
R 22.00 2585.570
R 23.00 3132.010
R 24.00 2828.590
R 36.00 2574.430
R 48.00 2281.640
R 96.00 966.420
R 144.00 494.860
R 192.00 261.090
R 0.00 0.000
R 1.00 435.710
R 2.00 755.250
R 3.00 1114.050
R 4.00 1449.140
R 5.00 1724.020
R 6.00 1704.180
R 7.00 1695.080
R 8.00 1741.210
R 9.00 1427.270
R 10.00 1761.850
R 11.00 1923.650
R 12.00 1851.510
R 13.00 1897.800
R 14.00 2707.840
R 15.00 3256.150
R 16.00 3558.490
R 17.00 3402.960
R 18.00 3369.480
R 19.00 3422.050
R 20.00 3434.020
R 21.00 3376.770
R 22.00 3469.380
R 23.00 3296.210
R 24.00 3336.730
R 36.00 2933.250
R 48.00 3142.030
R 96.00 1479.620
R 144.00 744.460
R 192.00 368.400
Here are my questions:
1. How to calculate Cmax for reference formulation. (Is it
1724.020 or 3155.6200) and AUC values.
2. If I want to calculate the comparative bioavailability of
the formulation. Which formula should I have to use.
3.
If I use the formula AUC(T)/DOSE(T ) should I have to consider the
strength for reference
AUC(R)/DOSE(R)
Formulation is 200 or 400.
I will be very much grateful if some one could clarify me.
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The following message was posted to: PharmPK
Hi Thenmozhi,
Although I have seen designs like this in the literature, I haven't
planned
one so I will just give you my two cents.
You are comparing a 1x400 mg tablet single dose with 1x200 mg tablet
taken
twice daily. I would not think that dose normalization is appropriate
here
since the goal of the study will be to see if a similar
bioavailability is
acheived when switching formulations. I also don't believe that that
Cmax
is an appropriate measure to compare here. The dosing interval doesn't
allow for an adequate characterization of the first dose Cmax for the
reference. In both reference curves, the first Cmax doesn't have a good
chance to plateau. Physiologically, the more relevant parameter to
compare
here is AUC provided that a higher Cmax of the drug does not result
in any
safety issues. If Cmax must be compared, Cmax of the Test should be
compared with the second peak of the reference. This would give you a
Test/Reference ratio of 0.43 (Test/Ref 1) and 0.27 (Test/Ref 2),
which look
very low.
AUC is more straightforward. You would compare the total AUC for one
Test
tablet with the combined AUC of 1 tablet of the reference taken twice a
day, because you are trying to find out how the once daily formulation
compares with the twice a day IR formulation. Are they switchable? This
measure would give you a Test/Ref 1 AUC ratio of 0.12 for Test/Ref 1 and
0.11 for Test/Ref 2. To answer your second and third questions, this is
what I would think should be used for the relative BA calculation
(AUCtest/AUCref with no dose normalization).
It is evident from your data that the once-a-day formulation does not
reach
nearly the same AUC (or Cmax) as the reference products, and based on
these
limited data alone you may wish to reconsider the formulation of the
Test
product. Did you look at a fed study? Modified release formulations
can be
sensitive to the fed state.
One additional comment, I am weary of is planning different sampling
schedules when comparing formulations. I would plan the exact same
sampling
times for both formulations so that you are comparing concentrations
at the
same time points. This would be more robust scientifically,
especially if
you planned to compare Cmax.
Hope this helps,
-Dave Dubins
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)