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I'm looking for anything published on the use of threshold PK/PD
models to account for schedule-dependent pharmacological effects. I
would be especially interested in a review that discusses the
advantages & disadvantages of threshold models.
Many thanks for any help.
Charlie
Charlie Brindley PhD
Larchwood
Shieldhill Road
Quothquan
Lanarks ML126NA
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Charlie,
Here is one reference that may be useful:
M.O. Karlsson, V. Molnar, J. Bergh, A. Freijs, R. Larsson. A general
model for time-dissociated pharmacokinetic-pharmacodynamic relationships
exemplified by paclitaxel myelosuppression. Clinical Pharmacology &
Therapeutics (1998) 63, 11-25.
It proposes a more general model, where a threshold model would be an
extreme case, but it has discussion of threshold models, and some
references.
Regards,
Katya
--
Ekaterina Gibiansky
Senior Director, PKPD, Modeling & Simulation
ICON Development Solutions
Ekaterina.Gibiansky.at.iconplc.com
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Many thanks, Katya,
I was aware of this one and a follow-up:
FRIBERG L E, BRINDLEY C J, KARLSSON M O, DEVLIN A J.
Models of schedule dependent haematological toxicity of DMDC
Eur. J. Clin. Pharmacol. 2000, 56: 567-574
....with similar conclusions.
If anyone has any other references in this vein, it would be most
appreciated.
Charlie
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Charles,
Can you explain why you are interested in using a threshold model?
All receptor based theory is derived from a continuous relationship
between concentration and response. With only one exception that I
know of there is no pharmacologically rational mechanism for
considering a threshold in pharmacodynamics. The exception is for
mechanisms involving action potentials which themselves have a
threshold for depolarization - a very special biological process.
Nick
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
n.holford.at.auckland.ac.nz
http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford
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Hi Nick,
I'm really looking to assess the usefulness (or not) of threshold
models in
early drug development. I'm aware of their limitations (all-or-nothing
response) but with very little PK & PD information available could
this type
of model be used to help test compound selection? The model may be
wrong but
could it be useful at the drug selection phase?
Charlie
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Charlie,
Following from your all-or-none comment, what would be your view on
this subject when a compound has one activity at one dose level and
another activity after a higher dose? The example I'm thinking of is
zolpidem but there must be others. Zolpidem reverses brain dormancy in
damaged brain tissue but then causes the well known sedation as the
dose increases. It seems to fit Nick's point as I asume there must be
a progressive occupancy or activation of receptors. The sedation
presumably masks the clinical improvement.
Andrew Sutton
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Charlie,
It is impossible for me to guess if using the wrong PKPD model will
still be useful for compound selection.
My own preference would be to develop a mechanism based PKPD model
based on whatever you know about the disease and pharmacological
mechanism. You can then use a Bayesian estimation procedure which
allows you to use your best guess mechanistic priors and then update
the parameters describing drug response which you would use for drug
selection.
Best wishes,
Nick
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
n.holford.aaa.auckland.ac.nz
http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford
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How would the threshold model be interpreted in kindling in seizure
models
or bipolar cycling? Is this what Charlie is looking at?
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Hi Andrew and Nick,
I am convinced that a mechanism-based PKPD model would be the best
approach
to explain schedule-dependency, given appropriate information on
disease and
pharmacological mechanism. In your example of zolpidem, a threshold
model
could be used but it would be a little contrived!
My original question was to find out if threshold models had been used
with
any success to explain and predict schedule-dependency. So far, the
response
is that they haven't and shouldn't...?
Regards,
Charlie
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Hi Ed,
I don't have the experience to comment on use of threshold models in
seizure
or bipolar cycling. My original query was a general one regarding the
use of
threshold models to represent schedule dependent pharmacological
response
early in development.
The PK&PD information that prompted the query was a schedule-dependent
reduction in tumour volume in a murine xenograft (for the same dose
level,
twice-daily dosing was more effective than once-daily dosing). A
threshold
could explain the schedule dependency but is unlikely to represent the
true
physiological mechanism.
So, a more specific question: the threshold model may be physiologically
invalid but could time above the prescribed threshold level reasonably
predict tumour response with different dose regimens? Could this
information
be used to select the most effective dose regimen?
Charlie
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Hi Charlie,
There are a number of tumor growth models developed specifically on
murine xenograft data (see some recent references below). In these
models tumor size depends on relationship between rate of tumor growth
and rate of killing of tumor cells by the drug. The rate of killing is
usually proportional to concentration of the drug in the tumor or plasma
(with/without effect compartments). And both rates (growth and kill)
depend on tumor size (i.e. are dependent on time, since tumor size
changes with time). It does not seem likely that the threshold model
(time above specific concentration) would have a predictive power
outside doses/regimens on which it is established.
Some recent references:
L. Zhao, G. Robbie, D. Jackson, J. Gooya, M. Camara, E. Gibiansky.
Population Modeling of Tumor Growth in a Murine Xenograft Model
Following Administration of Biologic Drug Candidate. American Conference
on Pharmacometrics (2008) http://tucson2008.go-acop.org/pdfs/3_zhao.pdf
F. Del Bene, M. Germani, F. Fiorentini, G. De Nicolao, P. Magni, M.
Rocchetti. Evaluating the Influence of Different Sources of Variability
in the PK/PD Tumor Growth Inhibition (TGI) Model. PAGE 17 (2008) Abstr
1431 [www.page-meeting.org/?abstract=1431]
K. Stuyckens, S. Rossenu, P. King, J. Arts, J.J. Perez-Ruixo. Modeling
Drug Effects and Resistance Development on Tumor Growth Dynamics. PAGE
16 (2007) Abstr 1185 [www.page-meeting.org/?abstract=1185]
M. Simeoni, P. Magni, C. Cammia, G. Nicolao, V. Croci, E. Pesenti, M.
Germani, I. Poggesi and M. Rocchetti. Predictive
Pharmacokinetic-Pharmacodynamic Modeling of Tumor Growth Kinetics in
Xenograft Models after Administration of Anticancer Agents. Clinical
Cancer Research 2004; 64, 1094-1101
Regards,
Katya
--
Ekaterina Gibiansky
Senior Director, PKPD, Modeling & Simulation
ICON Development Solutions
Ekaterina.Gibiansky.-at-.iconplc.com
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