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We have been a bioequivalence study with 30 volunteers for six months
and Cm\0xB7x. is not bioequivalente. The potency is poor and the
variability high. We would want a solution, perphaps adding a subgroup
of 10 persons more. It is this possible?. What normative, bibliographic
and experience there is?. How it would be the statistical analysis?.
We would thank for any information on the matter.
Thanks.
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1. You said about Cmax only. It is important to look in to other
parameters also.
2. You can do sample size analysis with the data already available with
you. Then you can think of adding more persons in the study.
I hope this may help.
Dr. Milan Satia
Cadila Pharma, India
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Dear Jos\0xC8:
Have you statistically analysed a BE study after only one dose (at least
Cmax after the first dose of your multiple dose study)?
Usually unique dose BE studies have much less variability and are more
adequate ("clean") for evaluating differences in plasmatic
concentrations
between two formulations.
Regards, Silvia
Silvia Giarcovich wrote:Back to the Top
'"Usually unique dose BE studies have much less variability and are
more adequate ("clean") for
evaluating differences in plasmatic concentrations between two
formulations.'"
It would be useful if you could provide some references. The statement
does not hold for high
hepatic clearance drugs [see: 1. Rowland M 1985 Models to identify
sources of pharmacokinetic variability. In: Rowland M et al. (eds)
Variability in drug therapy: Description, estimation, and control.
Raven Press, New York, pp 11-28; 2. Terziivanov et al. 1999.
Pharmacokinetic variability of nimodipine disposition after single and
multiple oral dosing to hypertensive renal failure patients: parametric
and nonparametric population analysis. Int J Clin Pharmacol Ther 37:
404-412].
Regards,
D. Terziivanov
Dimiter Terziivanov, MD,PhD,DSc, Professor
Head, Department of Clinical Pharmacology and
Pharmacokinetics,
Clinic for Therapeutics and Clinical Pharmacology,
Univ Hosp "St. I.Rilsky",
15 Acad. I. Geshov st, 1431 Sofia, Bulgaria
Tel:(+ 359 2)8510639;(+ 359 2)5812 828.
Fax:(+ 359 2)8519309. e-mal: terziiv.at.yahoo.com
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Probably the concept does not hold for every case; however, already in
2000,
in an AAPS Workshop on Biopharmaceutics, Washington, Sept. 11-13, some
conferences mentioned that frequently the steady state studies are less
sensitive to formulation differences than single dose studies. Besides,
specifically for phenytoin, already in 1994, the FDA Guidance for
Industry:
Phenytoin/phenytoin sodium, capsules, tablets and suspension in vivo BE,
etc, said: "The Committee concluded that the use of single-dose,
replicate
design studies may be more appropriate than multiple dose, steady-state
studies dor BE assessment of phenytoin/phenytoin sodium formulations
for the
following reasons":... etc and give three reasons, like "Single-dose
studies
are more sensitive in detecting the rate differences, if any, between
formulations", etc.
Regards, Silvia
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Hello!!!
When conducting a bioequivalence study of an IR formulation, the single
dose design is preferable as it is the most sensitive way to assess
bioequivalence. In the steady state study, the sensitivity to detect a
potential difference between two formulations is reduced as a large
fraction of the drug detected in plasma samples originates from the
accumulated drug and does not reflect any difference between two
formulations. In the steady state study you usually use the AUC from
one dosing intervall to assess bioequivalence. What happens with the
sensitivity if you for example take the sum of 3 consecutive AUCs
during steady state for the comparison of two products. Is it reduced
furthermore?
Henrik W
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Dear Henrik,
You wrote:
"When conducting a bioequivalence study of an IR formulation, the single
dose design is preferable as it is the most sensitive way to assess
bioequivalence. In the steady state study, the sensitivity to detect a
potential difference between two formulations is reduced as a large
fraction of the drug detected in plasma samples originates from the
accumulated drug and does not reflect any difference between two
formulations."
IMHO, the single dose design is usually preferred because of lower
costs,
and not because of higher sensitivity to detect potential difference.
Please
note that the plasma concentrations in steady state perfectly reflect
any
difference in bioavailability between two formulations. And since AUC
can be
determined over one dosing interval, sampling can be concentrated within
this interval, and the problem of extrapolation is avoided. Therefore
AUC
estimation is likely to be more accurate in steady state. You are right
that
differences in Cmax may be less pronounced in a steady state study, but
does
it really matter? For drugs given chronically the Cmax after a single
dose
is not relevant, and one should consider the plasma profile at steady
state.
"In the steady state study you usually use the AUC from
one dosing intervall to assess bioequivalence. What happens with the
sensitivity if you for example take the sum of 3 consecutive AUCs
during steady state for the comparison of two products. Is it reduced
furthermore?"
Using the sum of 3 consecutive AUCs will reduce the variability of the
estimated AUC, because of the increased number of data points needed to
get
the AUC accurately (dividing the data points over 3 consecutive
intervals
would be a bad idea), and I would expect that variability is reduced, to
some extent, because of reduction of the intrasubject variability. But
in
this case the analysis should not be based on the sum of the 3 AUCs,
but an
appropriate analysis for repeated measurements should be used.
Best regards,
Hans Proost
Johannes H. Proost
Dept. of Pharmacokinetics and Drug Delivery
University Centre for Pharmacy
Antonius Deusinglaan 1
9713 AV Groningen, The Netherlands
tel. 31-50 363 3292
fax 31-50 363 3247
Email: j.h.proost.-a-.farm.rug.nl
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)