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Dear All,
I would like to hear the comment about how we should calculate AUC
for Bioequivalence study.
If the drug concentrations at 72 and 96 hr post dose for Test
formulation are below detection limit but 72 and 96 hr of Reference
formulation are still above detection limit. Should we calculate the
AUC of Refrence up to 96 hr or we need to ignore the data of
reference at 72, 96 hr as we did for Test formulation.
Best Regards,
Wichittra
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Wichittra,
If the measured concentrations for the test product are BLOQ and if the
test and reference formulations are similar then the values you obtain
for the reference product at 72 and 96 hours should be quite small. In
this case, they will not contribute significantly to the overall AUC and
not significantly affect the estimation of bioequivalence.
I believe that all regulatory authorities would require that you include
the measured data in your calculations. This could be fundamental in
the assessment of bioequivalence. Remember, the elimination rate (or
t1/2) of a drug substance from the body should be the same, regardless
of the formulation. If you notice large differences in the elimination
(e.g. different t1/2 causing measurable levels in one product) then it
is likely that the drug product is different. If the formulation is
significantly different, then the bioequivalent results should reflect
that difference.
Robert Lepage, M.Sc., CCRP
Manager, Biopharmaceutics & Assistant Study Director
Pharma Medica Research Inc.
E-mail rlepage.-at-.pharmamedica.com
www.pharmamedica.com
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Hi Wichittra,
The aim with bioeqivalence studies (as it is now) is to test whether the
test and the reference product (tablet, capsule,...) result in similar
maximum concentrations and total exposure of the drug. You need to
calculate the total AUC, i.e. AUC 0-infinity, for both formulations and
compare them. Obviously, you cannot ignore data. If the equivalency test
fails because your test formulation shows consistently higher
concentrations toward the end, resulting in higher AUC0-infinity values,
you simply need to go back to the laboratory and change the formulation.
Toufigh
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dear wichittra,
the purpose of establishing BE is on the basis of the result what you
get in the experiment/study.
you cant able to ignore the result as at the end time point and dont
worry about the result produce, below detection limit you should as a
Zero as per your inhouse procedure.
regarding thee refe. formulation you mentioned as above detection
limit, i cant understand the term as you mentioned it.
before that you can go for pk repeat if your procedure at lab scale
allow or do you have any procedure for statistical outlier that you
should consider.
but as per my understanding end point at last 72 and 96 doesnt make
any difference at your result.
for AUC 0 to infinite i am with the concern of gordi,
hope i can near about your concern,
expert can comment on this issue.
regards,
paresh
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Dear All,
Thank for the comment on my concern on AUC calculation. I agree with
you (Robert and Praresh) that AUC from o-inf won't make any
different and should not any effect the estimation of bioequivalence.
What I concern is the correct way to do for calculation of AUC0-t ,
if t-last that give concentation above BLOQ of reference and test
are different.
For example if the result from one subject from 0 to 96 hr for Test
formulation, the concentration are higher than BLOQ but for
reference formulation concentration that above BLOQ are from 0-48
hr. In this case, is it correct to calculate AUC0-t for reference by
using data only from 0 to 48 hr and for test from 0 to 96 hr.
Some one suggest me that we need to use data from 0 to 48 hr to
calculate AUC from 0 to 48 h for both Reference and Test. In my
opinion, I don't understand why we have to ignore the data from 48-96
hr of the Test formulation.
Thank for sharing your knowledge with me. I really like this PharmPK
community.
Best Regards,
Wichittra
--
Assoc. Prof.Dr. Wichittra Tassaneeyakul
Department of Pharmacology
Faculty of Medicine
Khon Kaen University
Khon Kaen 40002
Thailand
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Dear Dr. Wichittra,
FDA guidelines state that in Area under the plasma/serum/blood
concentration-time curve from time zero to time t (AUC0-t), t is the
last
time point with measurable concentration for INDIVIDUAL formulation.
I guess, this definition becomes self-explanatory in your case.
Thanks and best regards,
Rhishikesh
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Dear Prof .Wichittra,
In your example, for the reference formulation after 48 hrs, it is
below BLOQ, whereas for the test formulation, it goes below only
after 96 hrs. This shows, there is a difference in the value of K el,
T 1/2 and may be in C max.
For bioequivalence studies we have compare the AUC ( 0 to t) for Test
and reference taking the last time t. Thus we have to compare both
test and reference formualtion taking the time as 96 hrs.
Then with the K el, and last quantifiable concentration ( of course
above BLOQ), we have to extrapolate and calculate AUC ( o to inf) for
Test and Ref and them comparison has to be made to ascertain whether
it is bioequivalent.
Hence I feel, we have to include 96 hrs for both test and reference
for the AUC (0 to t).
T.R.Yegnaraman
Azidus Laboratories limited,
Chennai-600 048.
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