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Dear Colleagues,
I have a query on design of a protocol for multiple dose
bioavailability study. US FDA recommends the following studies to
establish bioavailability for modified release products.
1. Single dose fasting study
2. Single dose Food effect study
3. Multiple dose steady state study.
I have looked in to design of these studies in various drug approval
packages available on USFDA FOI site. In all cases single dose studies
are independent/separate of multiple dose(Steady state) study . My
query is,
- If we generate plasma drug profile after administration of first dose
of a multiple dose study for both test and reference products and then
continue as normal for multiple dose steady state study, can we use the
profile so generated as single dose food effect study? In other words
can we combine single dose food effect and steady state multiple dose
studies?
Best Regards,
Sunil V
Lupin Research Park,
Pune.
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sunil:
You don't say which Regulatory Agency you plan to submit your
protocol/data to. Whichever one it is (FDA, etc) speak with them about
the design before you go any further. They are the "horses mouth."
peter
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Hi Sunil,
Yes you can obtain single dose and multiple dose data from one study.
Nhi Nguyen
FDA/CDER/OCPB/DPE 1
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Sunil,
it seems quite unrelevant to perform both studies at the same time.
I am not very happy with this kind of approach. My view is that if you
perform your multiple dose you should wait for total drug disappearance
in
the plasma after the first dosing to have the whole single dose PK
profile.
This means that you chose a dose interval that is too high to ensure
continuity in the drug infusion. You should then not be able to see any
steady state study in these conditions. Does it make sense?
Regards,
Frederic
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Dear Nhi & Sunil Bhai,
I agreed that economically it makes sense if one can obtained the data
from single study but i have following concerns:
1) More often,it may not be possible to stop the single dose study upto
sampling time of 24 hours specially in controlled release products to
get the stastistically significant clinical outcomes.Usually a dosing
upto 3 elimination half life sampling is required that usually happens
to be atleast 36 to 48 hours in controlled release.
secondly ,based on 24 hours AUC( as after 24 hrs we need to administer
the second dose), we cannot truncate the AUC upto Inf.And as many point
as possible should be considered in ME products as rate is much
critical here.
2)The case becomes more critical as the food effect studies are
essentially nonreplicate design while Multiple dose studies should be
replicate studies specially if the drug is HVD.Single dose fasting
studies are replicate design.Multiple dose studies can also be done in
Fasting state( Dilacor XR). Based on this it seems impractical to get
single dose fed state and multiple dose steady state data from one
study.
3)The wash out period in multiple dose studies can be more than single
dose studies.( Cross over period).
4) If the studies are double blind then , you have to see the plasma
stability of samples as ethically all the samples should be analysed
after completing the steadystate sampling.( or else it will not be
blind).
5) The total one pt of the blood sample can be taken in one study in
one month period per volunteer, this may exceed if both treatment
phases comes in one month period.IRB may question on this it happens.
In my opinion, the study design alongwith the above parameter should be
taken into consideration for the studies aimed for the FDA submission.
Bottomline: Peter and federic can you give opinion on this.
Kind regards,
Pradeep S.Bhadauria
Research Scientist
Ranbaxy Research Laboratories
INDIA.
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Dear Frederic, Pradeep,
You have a good point there about plasma drug level before second dose.
I fully agree that this approach is not possible with drugs having long
(or even moderate) half life.
However there are many drugs which have short half life and some whose
duration of pharmacodynamic response is not related to their
circulation half life. Various proton pump inhibitors, many of the
antibiotics come to my mind by the way of examples. In these cases I
believe we can derive single dose data from multiple dose study. Even
for modified release products you may find that drug is completely
cleared from the system before second dose is administered.
Normally we carry out series of pilot BA studies before attempting full
scale pivotal study. So we have pretty good idea about profile of the
drug in the body, based on which one can contemplate combining single
dose and multiple dose studies. I am very interested in your opinion in
the above circumstances.
The next question is how would regulatory authorities view this
approach. We had one answer in Nhi, however as suggested by Peter its
better to hear from "Horses mouth".
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I agree, however, it will be OK for drugs with an apparent half life up
to ~
8 h.
Silvia
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Sunil,
in a multiple dose study, if your drug is completely cleared from body
before second dose then your study is roughly the same as successive
single
dose studies. And you won't be able to reach the steady state, will you
?
Regards,
Fred
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Dear Sunil bhai/Frederic,
As frederic stated correctly that the complete drug depletion is not
possible although it may be the case that u get arroud 5 -15% drug yet
to come out at 24 hours ( that will contribute to steady state
concentration in one dosing interval) as the apparent terminal half
life from MR will be different than the drug per se. Actually after the
MAT/MDT the drug half life should be considered wherein after that the
elimination will be the favoured frocess from the compartment except
for the drug that have tendency to accumulate heavily.In multiple dose
studies only the pharmacokinetic profiling in the dosing interval needs
to be determined and no extensive blood levels in disposition terminal
phase are called for and in linear systems AUC
during dosing interval in Multiple dose steady state study is
proportional to fraction of the dose absorbed .
Ok as per the FDA guidelines atleast 80% of the reported value of AUC
one should attain before stoping itfor single dose study.If considering
as u said that it does happen in your case then I have the following
point in that.
Based on the concerns raised by me in earlier mail, if your protocol
does not have any ethical hurdle in doing such dual study data
submission from one study, apart from the issue of considering 24 hrs
AUC as substantially complete predictor of the total AUC, then it
makes sense to send the protocol to division of biopharmaceutics for
prior approval
with the back up data to demostrate that the 24 hours AUC covers
virtually complete or more than 80% of the expected value and the
profile attains the pleatue or no the detectable concentartion could
hardly be achieved at pre- second dose administration. ( your pilot
studies could be
your supporting data).
Moreover,I see a legal point here in your favour ,your argument can be
focused on the interpretation of the statute as mentioned in CFR Title
21 part 320.25 & 320.25 wherein it says that "No unneccasay human
research should be done" ( Means the enacted law mandate to avoid the
unnecessary human studies, that actually you are proposing if there is
no other technical issue involved).Based on the above concepts , you
have advantage that u are also avoiding the subject variability here
as same volunteers u are using for both single dose and multiple dose
at same time period.
You can substantiate a single dose study data from a multiple dose if
single dose fasting studies are not of replicate design and Multiple
dose studies your are determined to do in fasting state . However,at
the same time you run the risk of having some ethical difficiencies in
protocol design( Firstly,withdrawing more than 475 ml blood from one
single study in one month if wash out period is not longer, secondly
the psychological stress to patient).
This is merely my opinion.
Kind regards,
Pradeep S.Bhadauria
Ranbaxy Research Laboratories
INDIA.
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