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Dear All,
I would like to ask for your opinion regarding study design of
bioequivalence study for generic product: capsules with rivastigmine,
of several doses 1,5mg , 3mg, 4,5mg, 6mg.
The problem is that it shows linear pharmacokinetics up to 3 mg BID
but is non-linear at higher doses. Doubling the dose from 3 to 6 mg
BID results in a 3-fold increase in AUC. According to that situation
is it necessary to perform bioequivalence study with healthy
volunteers for each dose separately as cross-over single dose? I've
heard suggestion that for the lowest dose, multiple dose
bioequivalence study should be performed according to the European
guideline CPMP/QWP/EWP/1401/98.
Following the information for originator, the incidence and severity
of adverse events generally increase with higher doses, hence
performing bioequivalence study with higher doses could be too
dangerous for healthy subjects....How to assess if BE study for
rivastigmine should be conduct with patients?
Finally, how do you feel, is it necessary to determine the major
metabolite ZNS 114-666 (also known as NAP 226-90), which In in vitro
studies caused a dose-dependent inhibition of AChE activity. No
inhibition of AChE by ZNS 114-666 was detected ex vivo, which might
be due to poor blood-brain-barrier penetration.
Thank you in advance,
Aleksandra Osolinska
Regulatory Affair Specialist
R&D Department
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