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Dear all
We are designing a study to investigate clinical PK behaviors of a new
drug after single dose and multiple dose. The half life of this drug in
humans is quite long, around 40 hours.
The drug will be given to volunteers once a day. After the
administration of first dose, we plan to collect blood samples up to 5-6
half lives to obtain the PK profile of single dose.
Also , we plan to give the second dose (the first dose of the multiple
dose regimen) 10 days after the first dose (single dose study), then
being followed by repeated dose once a day until the steady state is
achieved.
My question is "can we use the AUC0-24h from the first dose for the
calculation of accumulation ratio of multiple dose?". Or should we take
blood samples after the second dose to calculate the AUC0-24h of second
dose for the the calculation of accumulation ratio? Because the second
dose is the start of repeated dosing.
We want to reduce the blood sampling by utilizing AUC 0-24 of the single
dose PK profile to replace the AUC0-24 on 1 st day of multiple dosing.
Thanks a lot for your nice comments!
Mike
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Dear Mike,
Regarding how to combine a single-dose and multiple dose regimen in the
same clinical study for a drug with a long (40-hr) half life, we did
something similar (combined single and multiple dose study) at a major
pharma company in Palo Alto, CA, when I was Project Team Leader and
Head of the DMPK group several years ago, but that drug had a shorter
half life. We collected the day-1 profile, a profile upon achievement
of the estimated half life, and a profile upon administration of the
last dose. I have participated in the conduct of similar approaches
more recently for multiple-dose studies: Day 1 (to confirm PK for the
enrolled cohort), after achievement of t1/2, and at the end.
It will be important to record very clearly in advance, either in the
protocol itself or in a PK plan referenced in the protocol, how you plan
to collect the samples and perform the PK analysis, and any contingency
plans for drop-outs/replacements. I assume that the same subjects will
continue throughout the same dose-level group? How many dose groups
will you have?
Other newsgroup members may have additional comments.
-Tom
Thomas L. Tarnowski, Ph.D.
CACO
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Mike,
Whether you can use the very first dose's NCA parameters or the first
dose of the start of the multiple dosing will depend on if there are any
residuals left from the first to the second dose. If your drug has an
elimination half-life of 40 hours, 10 days wash-out period should fine
so you can use your first dose to compare with the steady state results. I
am just curious, though, how you know the half-life if this is the first
time it's been administered in humans.
My question to you is why you are sticking to noncompartmental analysis
and not planning to investigate your drug's PK properties using a modeling
approach. Applying PK models to your data allows you to get a better
understanding of your compound's PK properties and you don't need to
worry about residuals from the first to the second dose amid the wash-out. It
should also allow you to cut your study duration: You don't need to
investigate your drug's PK after a single dose and multiple dosing
separately, hence your wash-out period will not be necessary. With a
model in hand, you will also be able to simulate various dosing regimens of
your future studies and have a good idea what you can expect in terms of drug
levels. The list of the benefits of a modeling approach goes on and on
and I suggest you take a look at analyzing your data with this approach.
Toufigh
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We've done something pretty similar for a sponsor whose drug had a
half-life of ~35 hours (parent) and ~50 hours (primary metabolite,
suspected active). PK profiles were not collected after the second dose
(start of multiple dose portion of the study); another profile was done
at steady state. The sponsor collected daily pre-dose samples in
between.
--
dean
Dean W. Knuth
President & CEO
Jasper Clinical Research & Development, Inc.
526 Jasper Street
Kalamazoo MI 49007
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Hi Mike
To calculate the accumulation ratio it is OK to use the ratio AUC24 at
steady state/AUC24 for the first dose and to forget the AUC24 of the
first dose of the repeated dosing period (second dose as you called) we
normally do this as well. This is actually a more accurate approach as
given your long elimination half-life your first dose will be certainly
better than the second as after 10 days the elimination of the first
dose might not be complete when you administer the second dose.
What I would suggest also to do is to assess deviations from the
superimposition principle i.e. if the ratio AUCinf single dose/AUC24 at
steady state equals 1 or not (i.e. if your PK are time-independent or
not). To do this it will be enough to collect blood samples for
approximately one week (every 12 or 24 h) to accurately define the
terminal elimination phase after the first dose that will be used for
the extrapolation to infinity of the AUC24 after the first dose.
Finally, make sure that you collect one blood sample on each day of the
repeated dosing period immediately before dosing (Cmin) to assess when
steady state conditions will be reached. In this way you will have
several ways to calculate the elimination half-life: 1) after the single
dose, 2) at steady state, 3) by calculating the accumulation ratio (that
depends only on the "effective" elimination half-life in case of
time-independent kinetics and constant dosing and dosing interval, and
4) if no deviation from the superimposition principle will be found
(i.e. CL and V do not change at steady state compared to a single dose
and therefore the elimination half-life on day 1 and at steady state are
the same.
I hope this helps
Stefano
Stefano Persiani, PhD
Translational Sciences and Pharmacokinetics
Rottapharm Madaus
ITALY
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Dear All:
About single and multiple dose PK, am I missing something? Why not
simply combine all data and make a population PK model? Or you could study
the 2 groups separately, and then think about combining them. And, of
course, nonparametric population modeling approaches are more flexible than
parametric ones, as they do not have to make any constraining assumptions
about the shape of the model parameter distributions. A reference is
Bustad A, Terziivanov D, Leary R, Port R, Schumitzky A, and Jelliffe R:
Parametric and Nonparametric Population Methods: Their Comparative
Performance in Analysing a Clinical Data Set and Two Monte Carlo Simulation
Studies. Clin. Pharmacokinet., 45: 365-383, 2006.
Hope this helps, or please let me know if I am missing something,
Roger W. Jelliffe, M.D., F.C.P.
Professor of Medicine,
Co-Director, Laboratory of Applied Pharmacokinetics
www.lapk.org
USC Keck School of Medicine
2250 Alcazar St, Room 134-B
Los Angeles CA 90033
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