Back to the Top
Hi!
I was searching the net for a reason that could justify the existence
ofr a value out of the aceptable limits for the 90% CI, for the AUC0-
inf of the metabolite in a bioequivalence study of simvastatin and I
found this discussion of yours.
Can anyone please informe me if it is possible to use AUC last
instead of AUC inf to claim bioequivalence for drugs with a very
prolonged elimination half-life?
Back to the Top
The following message was posted to: PharmPK
Hi!
For long half life drugs (e.g. T1/2 of more than 24 hrs), you can very
well use AUClast alongwith Cmax to justify bioequivalence between your
product and the reference, without even calculating AUCinf. However,
this needs to be done prospectively by mentioning the same in the
bioequivalence study protocol.
Regulatory authorities may not accept (not considering AUCinf for 90% CI
calculations), if you try to do the same retrospectively, after having
the data.
Regards,
Hitesh Maheshwari
Asst Director - R&D
Astron Research Ltd, India
Back to the Top
The following message was posted to: PharmPK
Dear Bragafarm,
since you are located in Portugal, I will answer from a European
perspective.
According to the current Note for Guidance:
http://www.emea.europa.eu/pdfs/human/ewp/140198en.pdf
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. If a reliable estimate
of terminal half-life is necessary, it should be obtained by
collecting at least three to four samples during the terminal log
linear phase.
3.3 Characteristics to be investigated
In bioequivalence studies the AUCt is the most reliable reflection of
the extent of absorption.
In other words - contrarily to FDA's guidelines, where you have to
demonstrate BE both for AUClast and AUCinf - in Europe the primary
parameter for extent of BA is AUClast (provided it covers 80% of
AUCinf).
If such an approach is not feasible (long half life), you may go for
a truncated area approach (e.g., AUC0-72). According to the very
short half lives of both simvastatin and the main active metabolite
simvastatin-beta-hydroxy acid this is not applicable.
IMHO FDA's requirement of demonstrating BE both for AUCinf and
AUClast is questionable from a statistical point of view.
Both parameters are highly correlated and are tested at alpha 0.05,
which in common statistical practice would call for an adjustment of
the alpha level (patient's risk).
To quote the subtitle of the movie 'Highlander': There Can Be Only One.
EMEA issued a document 'Points to Consider on Multiplicity Issues in
Clinical Trials' in 2002
http://www.emea.europa.eu/pdfs/human/ewp/090899en.pdf
For simvastin you will also (and mainly?) have to show BE for the
main active metabolite simvastatin-beta-hydroxy acid.
See Paragraph 3.3 of the NfG, and the Paragraph 6 of the Q&A document
http://www.emea.eu.int/pdfs/human/ewp/4032606en.pdf
Best regards,
Helmut
--
Helmut Schuetz
BEBAC
Consultancy Services for Bioequivalence and Bioavailability Studies
Neubaugasse 36/11
1070 Vienna/Austria
tel/fax +43 1 2311746
Web http://BEBAC.at
BE/BA Forum http://forum.bebac.at
Want to post a follow-up message on this topic?
If this link does not work with your browser send a follow-up message to PharmPK@boomer.org with "Extrapolation in Bioequivalence studies" as the subject | Support PharmPK by using the |
Copyright 1995-2011 David W. A. Bourne (david@boomer.org)