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Hi everyone,
In preclinical PK/PD investigations of CNS active agents after acute
dosing (sc or iv), we often observe a small delay (minutes) between
plasma concentration Tmax and pharmacological peak effect that
results in hysteresis in the concentration-effect (c-e) relationship
(likely a distributional delay). However, often the hysteresis is
more pronounced during the 'down-swing' of the c-e curve due to a
sustained effect while the plasma concentrations levels off. When
applying the classic effect compartment link model, the two 'limbs'
of the hysteresis curve is collapsed by the rate constant ke0.
However, applying ke0 assumes the delay during 'upswing' and
'downswing' in the c-e curve is identical (is this true?). Hence, it
could be argued that effect compartment models are not applicable in
situations like the one described above?
The above scenario we typically observe when applying in vivo
receptor/transporter occupancy in the brain as 'PD-marker'. With this
marker, any drug with fast BBB transport and fast receptor/
transporter on-rate combined with a slow off-rate would be hard to
describe by only ke0. In such situations indirect response models
appears more appropriate or..? - any comments are highly appreciated.
Regards,
Christoffer Bundgaard, M.Sc.(Pharm.)
Discovery ADME
H. Lundbeck A/S
Valby-Copenhagen
Denmark
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The following message was posted to: PharmPK
Dear Christoffer,
Do you have in vitro data in support of the hypothesis that the koff is
rate limiting for binding kinetics in these experiments? Assuming an
affirmative answer you may rather want to adapt your kinetic equations
in order to accomodate the koff. In
http://jpet.aspetjournals.org/cgi/content/full/313/3/1136
an example of PK/PD modeling with kon-off rates can be found.
Describing receptor binding kinetics with an indirect response model
seems rather artificial unless your drug influences receptor dynamics,
see ref below for an example.
NB1: a different model may apply for downstream effects!
NB2: it may be difficult to identify a delay of only a few minutes with
in vivo data
R. Ramakrishnan, D. C. DuBois, R. R. Almon, N. A. Pyszczynski,
and W. J. Jusko. Pharmacodynamics and pharmacogenomics of
methylprednisolone during 7-day infusions in rats.
J.Pharmacol.Exp.Ther. 300 (1):245-256, 2002.
Best regards,
Jeroen
J. Elassaiss-Schaap
Scientist PK/PD
Organon NV
PO Box 20, 5340 BH Oss, Netherlands
Phone: + 31 412 66 9320
Fax: + 31 412 66 2506
e-mail: jeroen.elassaiss.-at-.organon.com
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The following message was posted to: PharmPK
Dear Christoffer,
You wrote:
> When
> applying the classic effect compartment link model, the two 'limbs'
> of the hysteresis curve is collapsed by the rate constant ke0.
If the hysteresis curve collapses when applying the classic effect
compartment link model, this demonstrates that the time delay of the
effect
can be explained by the time delay of the concentration at the effect
site.
However, it does not prove that this is the case. Indeed, indirect
response
models may explain the data as well.
> However, applying ke0 assumes the delay during 'upswing' and
> 'downswing' in the c-e curve is identical (is this true?).
In my opinion this is not true. The delay is not only dependent on
ke0, but
also on the rate of change of the plasma and effect compartment
concentrations. And these rates are likely to be different during onset
(upswing) and offset (downswing). If the hysteresis curve collapses, the
effect compartment can explain the time delays over the entire time
period.
> With this
> marker, any drug with fast BBB transport and fast receptor/
> transporter on-rate combined with a slow off-rate would be hard to
> describe by only ke0. In such situations indirect response models
> appears more appropriate or..?
Yes, the selection of the appropriate model should be based on known
properties of the drug and the system involved, or on reasonable
assumptions
about them. Using a model that fits to the data does not prove that the
model is appropriate in a mechanistic sense.
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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