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Dear all,
I am a student and I am beginning in PK bioequivalence studies.
Is someone could provide me ressources for BEQ assessment and mainly
for limit in percentage of AUC extrapolation.
In fact I cannot find the acceptable limit for AUCinf in BEQ studies
(20%, 30%...??) in textbook or guideline.
Hanna-Liza Jooste in the first message dated 21 Jul 2003 talks about
20%. Where is this limit written in guidelines or any other textbook?
Thank you by advance for your help.
Theo MEZ
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The following message was posted to: PharmPK
Hi Theo,
I wouldn't recommend looking in textbooks for bioequivalence
recommendations as they tend to change. It's better to get your
answers from the horse's mouth. Here are a few links:
Helmut Schuetz put together what is likely the most useful and
inclusive collection of bioequivalence guidances worldwide, here:
http://bebac.at/Guidelines.htm
Some other links:
FDA:
http://www.fda.gov/cder/guidance/#Biopharmaceutics
TPD:
http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/bio/index_e.html
EMEA:
http://www.emea.europa.eu/htms/human/humanguidelines/efficacy.htm
I composed a summary Excel chart of BE regulations for the FDA, TPD
and EMEA here:
http://individual.utoronto.ca/ddubins/BE_Criteria.xls
This was last updated in February 2008.
Now, after you review the guidances, realize that in general they
specify covering at least 3 half-lives of the drug, which is quoted in
some guidances as covering 80% of the AUCinf, and others slightly more
(FDA specifies 88% in an obscure reference). As long as you indicate
in your SOPs/protocol the way you are handling percent extrapolation
you will be fine, and I have seen very different approaches used by
different companies. Perhaps it would make a good publication to talk
about different techniques and how they affect BE assessment? I've
seen studies on the edge of BE limits fail and then pass depending on
what technique you use.
I'd like to add that I have never seen or heard of any one particular
study shot down by a regulatory body for the way AUCinf was
determined. It's one of the grey areas of this industry.
Also search this newsgroup's database, as the topic has been discussed
here.
Hope this helps,
-Dave
--
David Dubins, Ph.D., B.A.Sc.
Global Bioequivalence Consulting
Assistant Professor, Leslie Dan Faculty of Pharmacy
University of Toronto
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The following message was posted to: PharmPK
Dear Theo,
you wrote:
> In fact I cannot find the acceptable limit for AUCinf in BEQ studies
> (20%, 30%...??) in textbook or guideline.
OK, have a look at the European Guideline (Section 3.1 Design):
'The sampling schedule should be planned to provide an adequate
estimation of Cmax and to cover the plasma concentration time
curve long enough to provide a reliable estimate of the extent
of absorption. This is generally achieved if the AUC derived
from measurements is at least 80% of the AUC extrapolated to
infinity.'
(http://www.emea.europa.eu/pdfs/human/ewp/140198en.pdf)
Limiting the sampling interval to 72 h irrespective of the
extrapolated area is considered for the revision of the
European guideline (2008/2009).
....or WHO (Section 6.6.1 Sampling times):
'Generally, sampling should continue for long enough to
ensure that 80% of the AUC (0-infinity) can be accrued, but
it is not necessary to sample for more than 72 hours.'
(http://healthtech.who.int/pq/info_general/documents/TRS937/WHO_TRS_937__annex7_eng.pdf
)
- and many other countries as well (e.g., Australia,
Malaysia, Brazil, South Africa,...)
See http://bebac.at/Guidelines.htm
Best regards,
Helmut
Ing. Helmut Schuetz
BEBAC - Consultancy Services for
Bioequivalence and Bioavailability Studies
Neubaugasse 36/11
1070 Vienna, Austria
e-mail helmut.schuetz.at.bebac.at
web http://bebac.at/
contact http://bebac.at/Contact.htm
forum http://forum.bebac.at
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