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The following message was posted to: PharmPK
Dear all,
I am preparing a protocol for a multiple dose bioequivalence (steady-
state)
study and I will appreciate your opinion on the likely regulatory
acceptability
(EU) of the following study design.
Due to very high intra-subject variability we would like to design a
replicate
study so the number of subjects could be lower.
We were thinking of performing this study in 2 periods in the
following way:
- dosing until reaching steady-state conditions (presumably for 6 days,
once daily).
- sampling at pre-dose each day to confirm reaching of steady-state
- dosing on day 7 with frequent sampling for complete (24h) PK profile
- dosing on day 8 with frequent sampling for evaluation of complete
(24h)
PK profile
We would than cross-over the test and reference drug after certain
wash-out
period and repeat entire schedule described above.
To better illustrate the design would look like this:
Period 1 Period 2
Day 7 Day 8 Day 7 Day 8
Sequence 1 test test ref ref
Sequence 2 ref ref test test
We would than calculate mean AUC(tau) and Cmax for the test and
reference drug for
days 7 and 8 together and see whether the 90% confidence intervals
fall within
bioequivalence limits of 80-125%.
This is not a conventional replicate design but since this drug has a
very
short half-life (0.5-2 hours) we predict that majority of plasma
concentrations
would be below LOQ after 24h.
With this design we can save some time that would be needed to
achieve steady-
state conditions in case we would have 4 periods and switch between
test and
reference drug in each period.
What is your opinion?
Tanja C. Dujc
Researcher
[Unformatted messages without tabs or special characters are a lot
easier to work with - thank you - db]
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The following message was posted to: PharmPK
Dear Tanja C. Dujc,
Without regard to the sequences that you propose, if you have a drug
with
a halflife of 0.5-2 hours, once daily administration will not provide
steady state conditions for your drug. In fact steady state is
reached in
approx 13 hours based on a halflife of 2 hours (6.64x2 Gibaldi &
Perrier).
Therefore, if you dose once daily (infered by the fact that you will be
sampling for 24 hours on Days 7 and 8 then really you will only have
completed a single dose study.
If you have multiple daily dosing...you will reach steady state much
quicker then Day 7, will require multiple pre-dose samples on any one
day
and if you sample for 24 hours on Day 7 will no longer be at steady
state
for Day 8.
If you are looking for a pharmilogical effect to help lower your CV
(i.e.
dosing the -ozoles), you are not really performing a proper steady state
study, and the additional dosing may be questioned by the regulatory
agency.
Additionally, The EU does not require steady-state drug studies for
bioequivalence.
Thank you
Robert Lepage, M.Sc., CCRP
Associate Pharmacokineticist & Assistant Study Director
Pharma Medica Research Inc.
Phone: (905) 624-9115 x3300
e-mail: rlepage.-at-.pharmamedica.com
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The following message was posted to: PharmPK
Dear Robert Lepage,
I forgot to mention that this drug exhibits nonlinear increases in
plasma
concentrations after multiple dosing due to saturation of CYP
metabolism.
Literature data indicate that SS is reached approx. after 5
administrations.
Moreover it is designed to be administered once daily thus this
dosing schedule
was chosen also for BE study.
Let me just add that multiple dose studies have been requested by
regulatory
authorities because of nonlinear kinetics and this alternative design
was
thought of to save some time.
Another problem is to prove that SS was reached which is usually done by
analysing Cmin. Namely as I already mentioned in this case most pre-dose
concentrations will probably be below LOQ.
Do you have any suggestions?
Tanja C. Dujc
Researcher
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The following message was posted to: PharmPK
Dear Robert Lepage,
I forgot to mention that this drug exhibits nonlinear increases in
plasma
concentrations after multiple dosing due to saturation of CYP
metabolism.
Literature data indicate that SS is reached approx. after 5
administrations.
Moreover it is designed to be administered once daily thus this
dosing schedule
was chosen also for BE study.
Let me just add that multiple dose studies have been requested by
regulatory
authorities because of nonlinear kinetics and this alternative design
was
thought of to save some time.
Another problem is to prove that SS was reached which is usually done by
analysing Cmin. Namely as I already mentioned in this case most pre-dose
concentrations will probably be below LOQ.
Do you have any suggestions?
Tanja C. Dujc
Researcher
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