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The following message was posted to: PharmPK
Dear Colleagues,
Is it useful to conduct statistical tests
(e.g.,t-test, ANOVA) on PK parameters obtained on two
different cycles during the course of therapy? We may
conclude there is a statistical significance or not
but I am not sure what would be the use of these data
in terms of clinical/biological significance.
Rostam
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The following message was posted to: PharmPK
Rostam
Rostam Namdari wrote:
>
> Dear Colleagues,
>
> Is it useful to conduct statistical tests
> (e.g.,t-test, ANOVA) on PK parameters obtained on two
> different cycles during the course of therapy?
If you mean that the only difference between the two cycles is the
passage of time then most likely you can probably expect to find no
difference between the mean PK parameters on the two occasions. I
therefore agree that a t-test/ANOVA to test a null hypothesis that is
of dubious interest is unlikely to be useful.
However, there is strong interest in identifying and quantifying the
within subject variability in PK (and other) parameters. This has
practical benefits for improved modelling of PK parameters based on
mixed effect models (Karlsson & Sheiner) and also provides quantiative
criteria for deciding what process to use to individualize dose
(Holford 1999, 2001).
Karlsson MO, Sheiner LB. The importance of modeling interoccasion
variability in population pharmacokinetic analyses. Journal of
Pharmacokinetics & Biopharmaceutics 1993; 21(6):735-50.
Holford NHG. Target Concentration Intervention: Beyond Y2K. British
Journal of Clinical Pharmacology 1999;48:9-13.
Holford NHG. Concentration controlled therapy. In: Breckenridge A,
editor. Esteve Foundation Workshop. Amsterdam: Elsevier Science; 2001.
p. 135-144.
Nick Holford, Divn Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
email:n.holford.aaa.auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
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The following message was posted to: PharmPK
Dear Nick,
Thanks for your response. Is it true that generally
more than 20% increase in AUC from one treatment cycle
to another considered to be clinically significant?
How do we evaluate the clinical/biological
significance of drug accumulation based on PK data?
Any input from the group is appreciated.
Rostam
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The following message was posted to: PharmPK
Rostam,
Rostam Namdari wrote:
>
> Dear Nick,
> Thanks for your response. Is it true that generally
> more than 20% increase in AUC from one treatment cycle
> to another considered to be clinically significant?
There is no true answer to this question. Clinical significance is a
matter of judgment. As I tried to say before the issue is not the MEAN
change e.g. 20% but the VARIABILITY from cycle to cycle that is of
probably of more importance. The MEAN change is likely to be a random
variability so focussing on the differences between any two cycles is
not important.
However, if you happen to have real data with a consistent change from
the first to the second (or subsequent) cycle then you should be
thinking about time dependent changes in PK parameters e.g. like
carbamazepine which induces its own clearance.
> How do we evaluate the clinical/biological
> significance of drug accumulation based on PK data?
What EXACTLY (give me an equation) do YOU mean by drug accumulation?
Nick
Nick Holford, Divn Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
email:n.holford.-a-.auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
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The following message was posted to: PharmPK
Dear Nick and Jogarao,
Thanks for your comments and recommended reference.
Nick, regarding what I meant by drug accumulation, I
was referring to use of AUC (simply comaring the AUC
of the two cycles) or actual acummulation factor R =
AUCss/AUC0-t (t= dosing intervals).
Rostam
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The following message was posted to: PharmPK
Rostam Namdari wrote:
> How do we evaluate the clinical/biological
> significance of drug accumulation based on PK data?
....
> Nick, regarding what I meant by drug accumulation, I
> was referring to use of AUC (simply comaring the AUC
> of the two cycles) or actual acummulation factor R =
> AUCss/AUC0-t (t= dosing intervals).
The accumulation ratio of concs at steady state to concs after the
first dose is most simply evaluated based on its magnitude. If the
ratio is close to 1 it means negligible accumulation; greater than 2
means at least 4 dosing intervals are required to approach steady state
and concs will be at least twice those seen after the first dose.
I can't think of any biological significance of the ratio. Any drug can
have any accumulation ratio -- it just depends on the dosing interval.
Clinical significance must take into account the time course of
beneficial and adverse effects. E.g. judge whether a loading dose would
be appropriate to get more rapid onset of benefit without unacceptable
adverse effects.
Even when a loading dose would seem like a good idea the occurrence of
initial adverse events can make it unwise. It can happen that tolerance
to adverse effects develops after the first few doses and better
overall results are obtained by not giving a loading dose e.g. oral
theophylline.
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
email:n.holford.-at-.auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
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