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Dear Sir,
we have done some studies on bioequivalency of Omeprazole
capsul 20 mg in human subjects as 2 way crossover study. The 90%
Confidence Intervals for Cmax are 110-141%, and AUC(0--->t) and AUC
0--->inf are 87-115% and 87-118% respectively. The power value
is >0.8 and there are some references saying Cmax is not correlated
with antisecretary activity where as AUC is to some extent Correlated
with it.
Looking at the above results should we make decision as the two
formulations are bio-inequivalents? . Please let give your opinion
and FDA's perspective in this regard.
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clearly bioinequivalent: you ned clinical data to get approval.........study
in humans of gastric pH and Prilosec. (505 b2 submission)
I have submitted two NDA in the last 5 years on bioavailability type
submissions.
I am available for consulting work since I now have my own business. The
agency is 20 minutes from my house here in Maryalnd.
Dr. Angus McLean
tel number 301-869-1009.
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I would take the following points into consideration:
i - omeprazole has a large therapeutic index, thus the higher Cmax
you observed is unlikely to cause any adverse event. Indeed, for some
highly variable drugs, the interval proposed for Cmax is 70-143%.
ii - with chronic use, the Cmax will fluctuate less and this
difference you have observed between the two formulations should
become smaller.
iii - AUC intervals are within the 80-125%.
My conclusion is that I would accept this formulation as bioequivalent.
Gilberto De Nucci
Cartesius Analytical Unit
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Results suggest faster absorption but similar extent. Clearly Cmax does not
fall within the 80-125% acceptance criteria applied to AUC but this may be
an example where widening the criteria for Cmax to the suggested 70-143% is
appropriate. On the face of it worth putting a case together and discussing
with the regulatory authority.
Mike Neale
Michael G Neale
Consultant in Pharmacokinetics
Soar PK
Tel/Fax 44 1509 412204
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The following message was posted to: PharmPK
We have done six bioequivalence studies (crossover single dose, multiple
dose and food interaction), always with the same reference, and since this
point of view we should say that these results are quite good for
omeprazole. Another thing is the decisi=F3n of bioequivalence, since this is=
a
regulatory convenience, although probably both formulation are
interchangeable. We should discuss with the authorities the relevance of
Cmax in omeprazole effects (see Lind and cols, 1983 and Londong and
cols,1983) and the value of IC limits of 80-125 for drugs with high
interindividual variability (see Steinijans and Hauschke 1993).
Another way to disccuss the results is to test the bioequivalence
hypothesis about early exposure calculating truncated AUC till median
reference population Tmax, according to the last bioequivalence FDA
guideline of October 2000.
-Lind T, Cederberg C, Ekenved G et al: Effect of omeprazole - a gastric
proton pump inhibitor - on pentagastrin stimulated acid secretion in man.
Gut 1983; 24:270-276.
-Londong W, Londong V, Cederberg C, Steiffen H. Dose response study of
omeprazole on meal stimulated gastric acid secretion and gastrin release.
Gastroenterology. 1983; 85: 1373-1378.
-Steinijans VW, and Hauschke D, International Harmonization of Regulatory
Bioequivalence Requiriments. Clin.Res. Reg. Affairs. 1993;10:203-220.
J Frias-Iniesta
Dept. Pharmacology.
UAM Madrid
Jesus.frias.at.uam.es
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Reformulate!! You will be wasting your time trying to convince anyone
that the products are bioequivalent when the test product is clearly
not acceptable. Even if you go to a replicate study, I doubt (just a
hunch without complete stat analysis) the reference will show enough
within subject variability to justify a widening of the CI. Finally, I
would worry that a replicate study with this formulation would show a S
X F interaction. Do the Gore thing and come back with a better
platform.
Art Straughn
Professor and Director
Drug Research Laboratory (DRL)
University of Tennessee
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Art Straughn makes some good points.
There are additional factors that you may wish to think about.
=46irst the approved form of omeprazole is acid labile and is formulated
as delayed release beads.
Second the study was done with an omeprazole dose of 20 mg. However
omeprazole exhibits nonlinear kinetics at doses above 40 mg (well within
the labeled dosage range). In addition, nonlinearity is see at lower
doses in certain populations, probably due to polymorphic metabolism.
Regarding correlation of effect with AUC. So what. It was simply a
simple correlation. In judging the clinical significance of any
difference in BA I would wonder about the drug receptor binding
kinetics. Based upon the mechanism I would suspect time to and duration
above a certain minimum concentration may be more meaningful.
I would recommend that the original poster take a look at the new FDA
guidance:
Bioavailability and Bioequivalence Studies for Orally Administered Drug
Products =97 General Considerations (Issued 10/2000, Posted 10/27/2000)
Which can be obtained through the following web site.
http://www.fda.gov/cder/regulatory/default.htm
Regarding the widening the acceptance criteria. The FDA guidance
mentioned above is now recommending replicate designs for high
variability drugs without any widening of the acceptance criteria beyond
80 - 125.
=46inally, discuss it with appropriate review division.
Ronald E. Kavanagh. B.S. Pharm., Pharm.D., Ph.D.
=46ood & Drug Administration
Office of Clinical Pharmacology and Biopharmaceutics
5600 Fishers Lane HFD-870
Rockville, MD 20857
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)