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Dear Group,
Our company is intending to register a multi-strength generic in the
UK. This product acts on the CNS and is available as 6 mg, 4 mg, 3
mg, 2 mg, 1 mg & 0.5 mg tablets.
It is well known that the bioequivalence study has to be performed on
the highest strength of a product. Bio-waiver for the lower strengths
can be hence possible, provided they follow dose proportionality adn
linear kinetics.
However, we are intending to perform the bioequivalence study of this
product, which is an antipsychotic drug, on the 1 mg strength for
safety issues and to avoid any serious health impacts on healthy
volunteers.
In this case, will bio-waiver be granted to the upper strengths (2,
3, 4 & 6 mg) and lower strength (0.5 mg) provided that dissolution
profiles for all strengths are comparable?
In general, what are the requirements for the measurement of active
metabolite of a parent drug during bioequivalence study in Europe?
As per US FDA requirements, it is sufficient to measure only the
concentration of a parent drug, which has an active metabolite that
is approximately equi-effective with the parent drug, to prove
bioequivalence between the reference and test products. Is this
applied as well in Europe/UK?
Shall appreciate your valuable comments, considering that the
submission is targeted to MHRA.
Thank you all, in advance.
Best regards,
Kumar
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hi kumar,
we also faced a silmilar situation. one of psychotropic drugs with
multiple strengths that we developed for european market, we did BE
with the highest strength and measured active metabolite also,
although US RLD was 1mg due to safety reason and US did not ask for
metabolite data.
however, indian subjects could not tolerate this high dose
(experience with lower dose study) so we skipped pilot with this
strength and carried out direct pivotal in international CRO.
Cordially,
Dr. Renu Jain
Research Associate
Clinical Research & Regulatory Affairs
Torrent Research Centre
Phone: 079 - 2396 9100 Ext.: 607
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The following message was posted to: PharmPK
Dear Kumar
You should not have problems regarding the dose proportionality. EU
guideline specifically states that the choice of the strength used to
conclude for BE should be justified based on analytical,
pharmacokinetic and safety grounds. There is no reference on the
highest dose. In fact, when the drug input is not linear, the
guideline asks for a study with the strength with largest sensivity
to identify differences in the two formulations. In some cases this
could be achieved with the lowest dose.
Regarding the metabolite, you only need to quantify the metabolite if
it contributes significantly to the total activity and the
pharmacokinetic system is non-linear. In this case you need to
demonstrate BE with the parent and the metabolite. Evan so,
prevalence is made on the parent compound BE.
Hope it helps
Paulo
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