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The following message was posted to: PharmPK
Dear List members,
I had a question from a client who would like to increase the dose of
both innovator and test product in a bioequivalence study to three
times the label dose for the innovator product. The formulation is an
oral tablet.
The argument they offered for this increase in dose was that it would
DECREASE variability. I am a bit puzzled by this suggestion, but
maybe there's something obvious I'm missing. I also have some questions:
1) Would regulatory authorities accept this data without data to show
dose-linearity?
2) Increasing the dose would mean administering three tablets instead
of one. Would this not possibly INCREASE variability?
Thanks in advance,
Ronette
**
Ronette Gehring BVSc, MMedVet (Pharm), DACVCP
Assistant Professor
Department of Clinical Sciences (Agricultural Practices)
Kansas State University, College of Veterinary Medicine
PharmCATS Bioanalytical Services
2005 Research Park Circle
NISTAC Building
K-State Research Park
Manhattan, KS, 66502
Tel: 785 532 6355
E-mail: rgehring.aaa.vet.ksu.edu
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The following message was posted to: PharmPK
Hi Ronette,
1) Regulatory authorities require usually that one single dosing form be
administered. Exception are allowed if the plasma/serum levels are
extremely low for the assay of the analytes. In those situations a
multiple of the dosage units/forms are allowed to be administered for
analytical reason or a study at steady-state after multiple-dose regimen
can be considered if accumulation of the drug occurs.
2) The requirement of one single dosage form to be administered is based
on the possibility of failure. Let's assume that the dosage form (a
tablet) fails to release the active ingredient for one of the drug
product but not for the other. The difference in the concentration-time
profiles will be dramatic if only one tablet was administered.
If from two administered tablets one fails, the difference in the
concentration-time profiles will be maximum 50%.
If from three administered tablets one fails the difference in the
concentration-time profiles will be maximum 30%.
This is the "decrease" in the variability that may occur.
The regulatory agencies are against dosing multiple units at once
because it may mask "bad" formulations. The probability that all three
tablets fail is very low!
The other possible mechanism of decrease in variability occurs when
larger doses will saturate first-pass metabolism. Consequently, larger
doses will lead to larger and less variable concentration levels.
Hope this helps,
radu
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The following message was posted to: PharmPK
Hi Ronette.
It sounds as though their logic is that the surface area of three
tablets is
greater than one which will accelerate absorption and then the data that
people will use is one third of that result. However, I agree that
using
three tablets per dose risks more variation than using one as for
example
when one or two are retained longer in the stomach. That source of
variation
can be minimised by the subjects being upright, since that promotes
gastric
emptying and of course fasting.
If the high degree of variability is due to the compound itself I
think
you have to just eliminate all the sources of variation in subject
selection
and procedure and plan for a possible extension into another group if
the
data does not hold up. If time is critical I would then do some of the
assays while the study is still running, on reserve samples for
example, to
get an idea of the variability being encountered so that I could then
decide quickly on whether to dose the second group.
If both formulations are variable it might pay to use a third dose
that is a
simple liquid, (ie optimising the oral route and subject to taste
etc) then
the new tablet might even look better.
I'd be curious to know what you eventually decide.
Kind Regards
Andrew Sutton
--
Andrew Sutton, MBBS, MD(London), FFA
Guildford Clinical Pharmacology Ltd.
The Technology Centre, Occam Road
Guildford, Surrey, UK. GU2 7YG
URL: www.gcpl.co.uk
Registered in England & Wales
Registration No. 2934719
Registered Office: 8 Baker Street, London W1U 3LL
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