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The following message was posted to: PharmPK
Dear Sir,
Really I am facing a big trouble in Amiodarone
biostudy to make sampling time points. Can you help
me 2 make.
Note: Single dose, 2 way crossover BE study,
Half-life: 58 days
Thanks and Regards,
Murugan.P
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The following message was posted to: PharmPK
Dear Murugan,
The key to doing a bioequivalence study with samples out to several
months
is to find volunteers who are in work at or near the institute that
conduct
the trial because they will be coming back predictably. We have done
studies
needing samples at six months and collected every single sample by doing
this. A snag is that if volunteers can do only one study over 5 half
lives
(or 290 days in your example), it wouldn't be fair for them to be
excluded
from other trials so you may find that they have to be paid quite a high
honorarium or allowed to enter other studies as defined by the protocol.
You mention that you want a crossover design but I would question
whether
that is feasible using 5 half lives so you will probably have to
compromise.
Either way you will need large group sizes to demonstrate
bioequivalence due
to the wide inter-subject variation of amiodarone or the need to plan
for
considerable dropouts given the long duration of the study.
Good luck.
Andrew Sutton
Guildford Clinical Pharmacology
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The following message was posted to: PharmPK
Dear Murugan, dear Andrew,
don't forget the 'Truncated Area'-approach, which should improve
subject’s
compliance and prevent incomplete data during the long elimination
phase.
‘Once absorption is over, formulation differences no longer apply’ [1].
This was
also shown following theoretical considerations in extensive
simulations [2].
The method of ‘Truncated Area’ is suggested in international guidelines
for drugs
with long half-lives:
‘Relative bioavailability can be adequately estimated using truncated
AUC as long
as the total collection period is justified. In this case the sample
collection
time should be adequate to ensure comparison of the absorption
process.’ [3]
‘Sample collection time should be adequate to ensure completion of
gastrointestinal transit (approximately 2 to 3 days) of the drug
product and
absorption of the drug substance. Cmax, and a suitably truncated AUC
can be used
to characterize peak and total drug exposure, respectively.’ [4]
Amiodarone half-life is reported ranging from 26 to 107 days (mean 53
days), the
main metabolite desethylamiodarone with a mean half-life of 61 days.
These
terminal half-lives are generally not seen after single doses.
After a pilot study (parallel groups) we performed a cross-over study
(200mg s.d.,
cross-over add-on design in 18+18 female/male subjects, wash-out period
4 weeks),
which I will briefly report in the following:
72 hours after dosing plasma concentrations were below 5% of Cmax
(apparent
half-life 16 hours). We did not see any remaining amiodarone or
desethylamiodarone
in any blank plasma sample of the second study period.
What remained uncomfortable is the high inter- and intra-subject
variability. We
found an intra-subject CV (log-ANOVA) of 30.4% for AUC0-72 and 29.6%
for Cmax.
That means 40 subjects are needed for a maximum expected deviation of
the point
estimate of 5% with 80% power. You should add some additional subjects
to allow
for potential drop-outs.
Good luck.
Helmut
References:
[1] MIDHA, K.K., HUBBARD, J.W. and M.J. RAWSON;
Retrospective evaluation of relative extent of absorption by the use of
partial
areas under plasma conentration versus time curves in bioequivalence
studies on
conventional release products
Europ. J. Pharm. Sci. 4, 381-384 (1996)
[2] ENDRENYI, L. and L. TOTHFALUSI;
Truncated AUC evaluates effectively the bioequivalence of drugs with
long
half-lives
Int. J. Clin. Pharmacol. Ther. 35/4, 142-150 (1997)
[3] ANONYMOUS;
Note for Guidance on the Investigation of Bioavailability and
Bioequivalence
EMEA Human Medicines Evaluation Unit / CPMP CPMP/EWP/QWP/1401/98, 1-18
(26 July
2001)
[4] ANONYMOUS [FDA, Center for Drug Evaluation and Research (CDER)];
Guidance for Industry.
Bioavailability and Bioequivalence Studies for Orally Administered Drug
Products -
General Considerations.
http://www.fda.gov/cder/guidance/index.htm - 4964dft.pdf (July 2002)
Helmut Schuetz helmut.schuetz.-at-.chello.at
Head Biostatistics Tel +43(0)1 4856969 62
Biokinet GmbH Fax +43(0)1 4856969 90
Nattergasse 4
A-1170 Vienna/Austria
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