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I am working with a topical drug showing flip-flop kinetics. The
calculated terminal half-life is significantly longer than that of
the intravenious formulation, possibly because of the slow rate of
absorption of the active ingredient through the skin. My question is:
by estimating the time to achieve steady state for the topical
formulation should I consider a "true" elimination half-life obtained
from the PK of the intravenous formulation or should I work with the
"mixed" absorption/elimination half-life observed with the topical
product.
Thanks for the clarification.
Maria Burian
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The following message was posted to: PharmPK
Dear Maria,
The time to achieve steady state is determined by the slowest
process. So in
your case you should use the 'apparent' half-life observed with the
topical
product. The 'true half-life' is here irrelevant for the time to reach
steady state.
Best regards,
Hans Proost
Johannes H. Proost
Dept. of Pharmacokinetics and Drug Delivery
University Centre for Pharmacy
Antonius Deusinglaan 1
9713 AV Groningen, The Netherlands
tel. 31-50 363 3292
fax 31-50 363 3247
Email: j.h.proost.-a-.rug.nl
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Dear Hans,
Thank you for your clarification. The problem is that the apparent
half-life of the drug after the multiple dose is significantly longer
than after the single dose (e.g. 80 hrs vs. 30 hrs). Probably due to
accumulation??? What half-life is in this case relevant for the
estimation of time to achieve steady state?
Thanks beforehand.
Maria
[This is getting more interesting ;-) Could it be that after one dose
you are seeing mostly the alpha phase of a two compartment model (for
example) because of assay limitations? As you give more doses the
second compartment starts to fill up and you can now see more of the
beta phase and your observed half-life is longer.
See
generated by the applet at http://www.boomer.org/c/p4/ja/Fig1966/
Fig1966.html by changing the duration of the fast infusion. Not quite
the right simulation but shows the effect of dose regimen duration on
apparent terminal half-life, also illustrates a technique for getting
a better estimate of beta when assay sensitivity is a problem.
To answer the question, the longer half-life - db]
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Dear Maria,
Is the sampling interval similar between the single-dose experiment
and the multiple-dose experiment?
Is it possible that, due to accumulation, you are able to define the
concentration-time profiles for a longer period of time than in the
single-dose experiments?
radu
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Dear Maria,
Is the sampling interval similar between the single-dose experiment
and the multiple-dose experiment?
Is it possible that, due to accumulation, you are able to define the
concentration-time profiles for a longer period of time than in the
single-dose experiments?
radu
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The following message was posted to: PharmPK
Dear Maria,
You wrote:
> The problem is that the apparent
> half-life of the drug after the multiple dose is significantly longer
> than after the single dose (e.g. 80 hrs vs. 30 hrs). Probably due to
> accumulation??? What half-life is in this case relevant for the
> estimation of time to achieve steady state?
Again, time to achieve steady state is governed by the slowest
process. But
the first question is to understand why the half-life after multiple
dosing
is longer than after single dose. Denoting this as 'accumulation'
oversimplies the matter; in case of 'normal accumulation' half-life
remains
constant. There are a few possibilities:
1) Distribution kinetics; see the comment attached to your message by
David
Bourne.
2) Assay limitations; again, see the comment attached to your message by
David Bourne.
3) Nonlinear kinetics due to, e.g., enzyme kinetics. After multiple
dosing
the concentrations are likely to be higher, and thus an apparent longer
half-life will be observed.
Best regards,
Hans Proost
Johannes H. Proost
Dept. of Pharmacokinetics and Drug Delivery
University Centre for Pharmacy
Antonius Deusinglaan 1
9713 AV Groningen, The Netherlands
tel. 31-50 363 3292
fax 31-50 363 3247
Email: j.h.proost.-at-.rug.nl
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Dear Hans,
I agree with the first two explanations of the differences in t1/2
between single and multiple doses suggested by David Bourne. However,
I did not get quite well the issue with the distribution kinetics. In
terms of the topical drugs, the second compartment which starts to
fill in after multiple dose is probably central compartment, isnt't
it? The Cmax in blood is twice as high as after the single dose. In
this case, however, the rate of elimination should increase???
(Please tell me if I am starting to talk nonsense). This should
compensate the increase in t1/2 to some extent. Or?
The second issue that I would like to clarify is liner vs. nonlinear
kinetics. There is no enzyme saturation, since we measure the parent
compound in blood. May it be something different: e.g. permeation
limitations of stratum corneum??? How can I check if we have linear
kinetics or not?
Maria
[If you are looking for systemic delivery with the topical drug then
the blood is (part of) the central compartment and body tissues are
(part of) the second compartment. The transfer from 'skin' to blood
would be the absorption step. The Cmax would start to increase with
more doses because of accumulation (see http://www.boomer.org/c/p4/
c14/c1404.html). The apparent t1/2 change might be irrelevant because
of factors mentioned previously.
Measuring parent compound in blood doesn't rule out enyzme
saturation? Have you looked at single dose kinetics at different
doses? Plot single dose AUC (or Cmax) versus dose to confirm linear
kinetics (in the range studied) - db]
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The following message was posted to: PharmPK
Dear Maria,
David Bourne gave excellent answers to your questions attached to your
message.
> The Cmax in blood is twice as high as after the single dose. In
> this case, however, the rate of elimination should increase???
> (Please tell me if I am starting to talk nonsense). This should
> compensate the increase in t1/2 to some extent. Or?
Assuming linear kinetics, the rate of elimination is proportional to
blood
or plasma concentration; the proportionality constant is blood or
plasma
clearance. In this case elimination half-life is independent of
concentration, dose, time, and so on. In a system consisting of a
series of
processes or compartments, the time to reach steady state, or the
decrease
of the concentrations after stopping administration depends on the
slowest
process in the chain. So, the apparent half-life of the plasma
concentration
decline after stopping administration is determined by the slowest
process,
in your case probably the absorption process, due to e.g. permeation
limitations of stratum corneum as you mentioned. The same holds for
the time
to reach steady state. After 1 'apparent half-life' 50% of the steady-
state
level is reached, after 2 half-lives 75%, and so on. It does not really
matter where the rate-limiting step is located.
Best regards,
Hans Proost
Johannes H. Proost
Dept. of Pharmacokinetics and Drug Delivery
University Centre for Pharmacy
Antonius Deusinglaan 1
9713 AV Groningen, The Netherlands
tel. 31-50 363 3292
fax 31-50 363 3247
Email: j.h.proost.-a-.rug.nl
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)