- On 26 May 2006 at 14:12:46, Thenmozhi Arumugam (then_bio01.-a-.yahoo.co.in) sent the message

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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. - On 31 May 2006 at 13:53:02, DDubins.at.allied-research.com sent the message

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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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