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Dear all,
I have a query regarding consumption of meal in a bioequivalence study.
The molecule in the question is a extended release formulation. In
period 1, approximately 25 % of the subjects did not consume 100 % of
the meal served at 4.0 hr lunch. The amount of food consumed for those
subjects varies from 60 - 90 %. Nausea was a common complaint of the
subjects who did not complete full meal.
1. Can we continue the subjects in the study?
2. If we continue them in study (for period 2), for the subjects who
did not consume full meal, should we give equal amount of meal what
they had consumed in period 1?
3. If yes, will it violate ethics? suppose one of the subject is
hungry and he wants to consume full meal though he did not consume
full meal in period 1.
4. Suppose in period 2, we give full meal to all subjects and all of
them consume full meal and study passes. Can we justify regulatory
bodies stating that food doses not have any effect on medicine
absorption.
Waiting for your reply.
Thanks in advance,
Sirat B.
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Dear Sirat
Please find below answers to your queries.
> 1. Can we continue the subjects in the study?
Is it a food-effect/fasting study? Also, you have not mentioned PK
properties of the study drug like Tmax,Half-life. From your email, it
seems that this is a fasting study.In my opinion you can continue the
study.
> 4. Suppose in period 2, we give full meal to all subjects and all
of them consume full meal and
> study passes. Can we justify regulatory bodies stating that food
doses not have any effect on
> medicine absorption.
In Period II, you must give study meal as per your IEC approved
protocol/meal plan. Otherwise, this becomes protocol violation.
All the best.
Sajjad
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Dear Sirat,
This is a very common problem with many CNS drugs (antidepressants,
antipsychotic etc.)
Assuming it is fasting study, by 4 hours most of your drug would have
got absorbed and hence it may not produce any significant difference.
That is the reason for keeping a minimum of 4 hours post dose fasting.
Moreover this is a variation part of your study and happened because
of an adverse event related to the drug, you have to accept it. Hence
there is no need to withdraw the subjects based on this. (Scenario is
totally different if it has happened with high fat breakfast in a food
effect study).
In the subsequent period you have to provide them the full meal, which
is both ethically and scientifically justifiable.
May be after the study, you can ask your PK/stat person to find out
the significance of this variation just for your information.
Hope this clarifies.
Regards
Dr. M. Joseph
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Dear Dr. Sajjad / Joseph/ others,
thanks for your response.
As per your query, I am providing more information regarding the study
as follows.
1. Tmax of medicine is 5-8 hr. Apart from this information I am again
informing that the formulation is an extended release formulation.
2. Thalf is around 10 hour.
3. The study is a fed study i.e. high fat breakfast was provided.
4. Subjects did not consume food because of nausea feeling which is a
reported adverse event of the medicine.
5. Literature states that food does not have any effect on absorption
of molecule.
Waiting for your response.
Thanks,
Sirat B.
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Dear Sirat,
My response remains the same. Because being an extended release
formulation, the drug is going to get absorbed from the intestine as
well and by the time you serve the lunch 4 hours post dose, your drug
will be moving down the intestine along with the breakfast chyme.
Hence it is the breakfast composition that is going to influence your
drug's absorption rather than the lunch.
Regards
Dr. M. Joseph
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Yes the comments seem to be valid as once the drug enters the small
intestine, either of the conditions (fed or fasting) will not affect
transit time. Accordingly complete consumption of breakfast would be
more critical.
Regards
Manoj K. Paruthi, Ph.D.
Sr. Manager, Head, R&D
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Dear Sirat
As food does not have any impact on the absorption of study drug,
Please continue your study. Also note that, as the nausea seems to be
the main AE of the study drug, you should withdraw subject who vomits
any time during the study. The PK data of such subject can be deleted.
All the best.
Sajjad
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