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Dear all,
We are planning to perform bioequivalence study of a CNS drug to file
an application for prolonged release per oral formulation essentially
similar to a marketed prolonged release formulation with EMEA.
The reference drug formulation is single unit, available in three
strengths, pharmacokinetics is linear. With recommended multiple dosing
(once to twice daily) there is considerable drug accumulation, steady
state is reached after three days. The effect of food on
bioavailability is moderate (food affects absorption rate but not
extent of absorption) and there is no dosage recommendation
(fasted/fed) with the reference formulation. The drug belongs to class
1 of the biopharmaceutical classification system (high
permeability/high solubility).
Comparison of the literature PK data for immediate release formulation
and bioavailability data for the reference prolonged release
formulation indicates similar AUC values, therefore it can be claimed,
that F is not affected by the absorption rate.
We have considered the following EMEA guidelines:
Note for guidance on the investigation of bioavailability and
bioequivalence,
Note for guidance on quality of modified release products: A:Oral
dosage forms B: Transdermal dosage forms Section I (Quality)
and Note for guidance on modified release oral and transdermal dosage
forms: Section II (Pharmacokinetic and clinical evaluation)
Given the data above we would like to hear your opinion and experience
about the optimal strategy for the design, conduct and evaluation of
bioequivalence studies. More specifically, do you think that the
following studies are sufficient to prove biequivalence, given the data
above and if we are able to demonstrate similar in vitro dissolution
properties in different media and the quantitative composition of
different strengths is similar, the active is less than 5%:
- single dose fasted crossover study with the medium dose
- single dose three period fed crossover study with the high dose (2
sequences: Tfed Rfed Tfast and Rfed Tfed Tfast)
- steady state crossover study with the low dose (We don't want to
perform steady state study with the highest dose as the third guideline
recommends, to minimize drug exposure)
Thank you for any input!
Regards,
Iztok Grabnar
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)