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Hi everyone,
Does anyone have any experience regarding the regulatory viewpoint on
BE study on paroxetine Tablets?
Literature data: As per the literature, Paroxetine is recommended to
be given with food [as per EU product information]. The commonly
recommended dose is 40mg/day and the highest recommended dose is 60mg/
day in the morning. Paroxetine kinetics is non-linear with more than
proportional increase observed at higher doses partially due to
saturable first pass effect. However, the non-linearity is generally
small and confined to some patients with low plasma levels.
Regulatory perspective-The ideal case: As per the Q & A section of
the BA and BE guidance, we may be requiring to do a BE in the fed
state. However, guideline also says that in case of non-linear drugs
the study should be done on the lowest as well as highest doses. an
exception is when greater than proportional increase is seen in the
kinetic parameters, then study on commonly recommended highest dose
shall suffice. Thus the ideal case for paroxetine would be a three-
way cross over study with the commonly recommended highest dose i.e.
40mg/day.
Practical perspective: With food the overall bioavailability is
remaining unaffected, but only the Cmax is some what higher with
early Tmax. Also the non-linearity is very small and seen in few
patients only. In such cases shall not a single dose fasting study on
the highest dose strength suffice? Or can we be still asked to stick
to the ideal case as per the guidance i.e. doing the fast as well as
fed study and that too on the hightest recommended dose?
I would be grateful if some one in the forum could share their
experience/opinion regarding the same.
Regards
Kaushal Prajapati
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The following message was posted to: PharmPK
Pinkoo
I actually did the first-in-man study on paroxetine and I would ask
why you
would need to give the highest possible single dose in healthy
volunteers. I
ask because after the first RDS some volunteers told me that they had a
anxious irritable feeling that was quite unpleasant. I have seen
the same
thing with metoclopramide.
You will not really need to give 40mg so why not settle for the more
moderate 20mg dose?
Andrew
Andrew Sutton, MBBS, MD(London), FFA
Guildford Clinical Pharmacology Ltd.
The Technology Centre, Occam Road
Guildford, Surrey, UK. GU2 7YG
Tel: +44 (0)1483 455375. Direct: 688303
URL: www.gcpl.co.uk
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Dear Dr.Andrew,
I agree that the subject tolerability should be taken into account.
But, since i am going for a generic application in Europe, i shall
require to follow the guidance on BE studies for Europe. The Q & A on
the BE guidance recently published in EU clearly states that for non-
linearity they mean the highest and lowest DOSE and NOT FORMULATION
STRENGTHS.
Now, since there is non-linearity with paroxetine [although small]
the guidance says an ideal case would be to prove BE on "The lowest
dose" and " The highest dose" of the drug in healthy volunteers. It
also says that in case the highest dose is not tolerable in healthy
subjects, then it should be proven in patients [which is more complex
situation].
Further, the guidance says that, if the non-linearity is such that
there is "More than proportional increase at the higher doses" then
BE study only on the HIGHEST DOSE is acceptable if justified.
Now, if the regulators in Europe are going to stick rigidly to the
wording of the guidance, then i feel i would be keeping my
application at risk by not doing the BE on highest commonly used dose
i.e. 40mg/day for paroxetine UNLESS I HAVE SOME SOLID JUSTIFICATION
FOR THE SAME.
Hence, I require to consider risk-benefit ratio for "safety in
volunteers" and "the regulatory requirements for my application"
before deciding on the dose strategy.
I wish you could comment on the same.
Thanks and regards,
K. Prajapati
Scientist-Regulatory Affairs
APL Pharma
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The following message was posted to: PharmPK
Hello Dr Prajapati
Thanks for your reply of the 9th November. Of course a linearity
study would
involve at least 3 doses while I was thinking you intended to do a
single
dose bioequivalence study.
I agree with the logic of spreading the dose range as wide as
possible. I
think a single dose of 20mg will be well tolerated but is probably your
middle dose as the authorised dose range for the non-elderly is 20 to
even
50mg daily and 40mg tablets of Paxil(R) are marketed. I suggest you use
single doses of 10, 20 and 40mg.
The early Phase 1 studies used 30 mg daily for 30 days and there was
then
appreciable accumulation due to saturation of key enzymes and steady
state
was reached at about 10 days. There is therefore quite a difference
between
single and steady state kinetics and it may be necessary to find out
from
your regulatory body whether they need both single and repeat dose data.
Good luck
Andrew Sutton
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