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Hi,
I currently work on a compound (Compound A) with LPS induced
inflammatory model.
I try to establish some correlation between pharmacokinetic and
pharmacodynamic.
there is a similar paper:
Pharmacokinetic-Pharmacodynamic Modeling of the Immunomodulating Agent
Susalimod and Experimentally Induced Tumor Necrosis Factor-a Levels in
the Mouse
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS,
Vol. 291, Issue 1, 199-203, October 1999
It has been reported that the half life of Compound A is just around
15-20 minutes.
When I do pretreatment with Compound A at 1.5h before injection of
LPS(1mg/Kg,Rat), it really works very well. 2h later, the blood
concentration of TNF-a is about 1500 pg/ml
For without Compound A, 2h later after injection of LPS(1mg/Kg,Rat),
the blood concentration of TNF-a is around 9000pg/ml
However, when I do oral treatment of Compound A then soon followed by
injection of LPS(1mg/Kg,Rat), and then detect the blood concentration
of TNF-a, the result is about 8000pg/ml
This looks like no effect of Compound A.
How to explain the pharmacodynamic of Compound A with such short half
life but with good activity when pretreatment??
I am a little confused.
Hope someone could tell me something to help me figure out how to
process my project.Thanks very much!
Feng
Graduate candidate
Rutgers, the state University of New Jersey
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Hi feng,
What about the metabolism of the compound A? Probably your compund A
when given orally is undergoing first pass metabolism thus its not
available for the intended action.
thanks,
with regards,
Rashmi Shiju
Reliance Clinical Research Services,
Navi Mumbai-400701
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The following message was posted to: PharmPK
Hi Feng,
Why do you think the half-life of the drug is important? In other
words, why are you surprised that a compound with a very short half-
life shows good effect a few hours after an iv injection?
You need to learn more about the system/biology of interest. It seems
to me that there is a trigger somewhere in the system that your
compound only needs to start it by being around for a short while.
Once the trigger is on, you don't need to have your compound around
anymore, the PD lives its own life, until the effect of the drug wears
off and you need to give a new dose.
What I would suggest you to do is to model the PK of the drug and then
connect the concentrations of your drug to the observed effect using
some kind of a PD model. The most relevant one in your case is
probably an indirect response model.
With regard to no effect after oral dosing, one of the reasons could
be low bioavailability. Do you know what it is after an oral dosing?
Toufigh
Toufigh Gordi, PhD
Clinical Pharmacology, PK/PD analysis consultant
www.tgordi.com
E-mail: tg.at.tgordi.com
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The following message was posted to: PharmPK
Dear Feng,
When the half-life of a drug is short, the kinetics of absorption are
much more important than half-life for the duration of action. If the
compound has low solubility, or slow permeability, Tmax might be 2 hours
or later, so see if you can find out what it is. Alternatively, the MRT
following the oral dose might be a better indicator of duration of
action than the half-life. I am reluctant to simplify the kinetics of
absorption any more because I will attract a strongly worded email from
Prof Waltosz ;o)
I believe that there is also a difference between mouse and rat in this
pharmacological model. In mouse, much of the TNFa comes from blood
cells. In rat, it appears that all the TNFa comes from the liver. Still,
both liver and blood should get exposed soon after absorption.
Finally, the PK of drugs in rat are dramatically affected by the LPS
injection so you can predict the exposure at the time of LPS injection
but you must take blood samples from the study animals to know what
happens afterwards. I think there is severe vascular leakage as a result
of the cytokine storm, but absorption may also be affected.
Best regards.
Ted
Discovery DMPK, UCB Celltech.
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Hi fing
What was the route given for pretreatment. Is it same (Oral) for
pretreatment and after LPS treatment?If no there may be first pass
effct with the later. If yes, at what time point you checked the blood
levels?
Rajasekhar
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The following message was posted to: PharmPK
Hi Feng,
If you want to look for the PK-PD of your drug then it would be good
if you
derive PK parameter of your drug at intended route of administration.
That will tell you about the fate of your drug in the body .
May be absorption or first pass metabolism could be issue when drug is
administered by oral route. The activity of your drug could also be
driven
by concentration of the drug.
On iv administration of your drug with such a short half life and with
LPS
challenge after 1.5 hr of your dosing suggest that the activity could be
dependent on concentration.
You can use higher doses for oral studies and also change the dosing
time
of LPS treatment after drug treatment , since on oral administration the
time required to reach the systemic circulation could be delayed.
Anasuya Patel
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Thanks for all people's reply very much.
I do want to establish the correlation between its pharmacokinetic and
pharmacodynamics.
All my treatment with Compound A is oral administration, and LPS is by
i.p. injection.
If the half life of Compound A is around 15-20minutes, so
3.5later(1.5h pretreatment, then injection of LPS, 2h later, collect
the blood sample), there is almost no Compound A in the body (the dose
is 0.8mg/Kg), but the immune response has been blocked
Some referrence reported there is 3 metabolites(Compound A-OH,OH group
at different sites), they also have short half life
When I do oral treatment of Compound A, followed by LPS, the TNF-a
concentration-time course does not show much differentce compared to
only LPS.
We want to process the project with pretreatment at different time
points, for what we want to know is how long the activity will last,
and hope this will help determine the dose frequency (how many times
each day)
Thanks
Feng
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The following message was posted to: PharmPK
Feng,
Many a times pharmacokinetic half life is differet from
pharmacodynamic half life. The compound A might have short PK half
life but longer Pd half life. Which means compound A downregulates the
target (enzyme/receptor) when it peaks to such an extent that you get
effect for longer duration (longer PD t1/2). There are examples of
such compound in market. Best example are statins. Simvastatim plasma
t1/2 is 1 he but they are administered once daily. Due to followin
reasons
1. It undergoes first pass effect. But site of action is liver so
continuis circulation of parent and metabolites. Although their t1/2
in bile is 4-6 hrs not enough for once daily dosing
2. It's metabolite are active
3. It takes one week for LDL receptor to down regulate but once
downregulated once daily dosing is enough for maintainance of
cholesterol level.
There is completely opposite example of antidepresants for ex.
Fluoxetine.
It has plasma half life of 21hrs and t1/2 in brain even longer. So it
stays in brain fir long long time at conc. Much above it's ic50 for
SERT inhibition.
But when do we see the effect ! After 3-4 weeks. Why? Because it takes
this much time toovercomethe negative feedback mechanism driven by 5-
HT1A receptors.
So as I said PK t1/2 can be different from PD t1/2.
If you want to investigate of t1/2 then dose compound A at different
time points before LPS and plot time vs effect plot and calcullate.
One more simple explanation is - LPS might be reaching the target
before compound A when administered simultaneously. Try both compound
and LPS by I.p route one after other.
I use to give dexamethasone I.p just before LPS And it worked
Regards,
Vishal
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Firstly, I assume that both times you administer compound A orally
such that bioavailability is not an issue (e.g., you did not specify
route for the pretreatment).
Secondly, you have not told us anything about the supposed mechanism
of action for compound A. For example, something that induces
apoptosis of immunity mediating cells might produce this.
Alternately, something that requires gene transduction... One could
postulate any number of PD or PK phenomena. Please help the community
to help you by giving some background.
Jeff
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Thanks again, really appreciate your kind help very much.
As many people request, herein is the pharmacokinetic of Compound A:
parameter oral(mg/kg) i.v.(mg/kg)
ka(1/min) 0.6 1.2 2.4 0.6
ke(1/min) 0.37 0.39 0.251
V/F 0.03 0.04 0.03
T1/2ka(min) 0.32 0.33 0.22 1.27
T1/2ke(min) 2.19 2.06 3
AUC(0-tn)(ug?L*min)
21.7 16.81 20.4 15.1
Tmax(min) 7057.14 10445.67 14538.98 9791.18
Cmax 11 10 10
CL/F(L/min/kg)
254 446.65 537.33
0.06 0.06 0.06 0.06
so compound A could be absorbed very quickly, and metabolized quickly,
and no tissue accumulation has been founded.
This case is so complicated for me.
Compound A act on the tumer necrosis factor(TNF)-a/ tumour necrosis
factor receptor 2 pathway and thereby has an attenuating effect on
activation or nuclear factor-kB.
Thanks
Feng
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The following message was posted to: PharmPK
To all:
There is one fundamental element in the ongoing discussion on the
relation between PK and PD that most people continue to forget: that
BLOOD PK may not have a direct relation with the mechanism of action
of a drug. Blood is generally the medium of transport of the drug from
the site of administration - oral, IV, IP, etc - to the target site -
brain, tumor, etc. What is critical is how much of the drug is taken
up at the target site(s) and how long it stays there - e.g., trapping.
What will be most relevant in determining the characteristics of the
response (PD) is the target pharmacokinetics. Let me suggest we call
that tPK, to differentiate from classical PK.
In those cases where the target PK (tPK) is solely or overwhelmingly
determined by blood PK, then conventional (blood-based) PK
measurements are sufficient. But is those cases, such as in cancer,
where blood PK and tumoral PK may be significantly different, it is
critical to be able to measure tPK directly. And the best way to do so
is by using noninvasive imaging methods (nuclear, MRI, MRS).
There is one other element that also needs to be considered to
understand response: the rate at which the drug interacts with
effector sites inside the target.
Thus, response is a function of 3 separate and often independent
processes: transport TO the target site, uptake BY the target site and
metabolism/binding IN the target site.
--
Professor Walter Wolf, Ph.D. Distinguished Professor of Pharmaceutical
Sciences
Director, Pharmacokinetic Imaging Program
Department of Pharmaceutical Sciences, School of Pharmacy
Chair, Biomedical Imaging Science Initiative
University of Southern California 1985 Zonal Ave., Los Angeles, CA
90089-9121
E-Mail: wwolfw.at.usc.edu
http://www.usc.edu/research/initiatives/bisi/
http://www.macnis.org/
http://www.usc.edu/schools/pharmacy/faculty_directory/detail.php?id=59
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The following message was posted to: PharmPK
Hello
Nesiritide is one example.
Venkatesh Atul Bhattaram
Pharmacometrics
Office of Clinical Pharmacology
US Food and Drug Administration
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Hi,
Do you have any data regarding the metabolism of the Compound A?
May be the metabolite of the compound is very active pharmacologically
compared to parent and that may be reason why pretreatment 2 hours
before is being effcacious rather than simultaneous
administration......!
Regards,
Sharath
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NF-kB, as you know, is a nuclear transcription factor. Anything
acting along this pathway is likely to have a time-profile of PD
effects akin to nuclear receptor targets (e.g., corticosteroids,
etc...). As such, the indirect family of PD models that characterize
the underlying kinetics of the key steps along the pathway leading to
the measured response seem to be a good starting point. Jusko's lab
has numerous publications examining with mechanistic detail the
multiple steps of nuclear receptor activation, translocation,
transduction of RNA and protein synthesis, and turnover of the various
measured intermediates. There are also numerous examples of semi-
mechanistic models that are able to describe such complicated systems
successfully.
As an aside, it may well be that PK is not important at all in this
case. We, as a community primarily made up of trained
pharmacokineticists, tend to start with PK and eventually we may get
around to understanding the PD. This is a good case for starting with
the PD, describing the key steps mathematically to produce a
predictive model, and if there are remaining sources of variability or
unexplained phenomena then perhaps PK or some other covariate can
account for it.
Good luck. From the little you have disclosed it appears that you are
in a hot area and one which needs solid PD understanding.
Jeff
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The following message was posted to: PharmPK
Hi Feng ,
Can you please specify which model you have used for deriving PK
parameter?
What were the time points for blood withdrawal?
The Tmax in your case looks off. Please go through it once.
Anasuya Patel
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Hello, Anasuya
Thank you very much.
These data come from a reference paper. They use Drug and Statistics,
ver1.0, and applied one compartment model to iv. data
Basing on these data published, what I have known about this compound is
very short half life: 15-20minutes
very quickly absorbed:T1/2ka is around 2-3minutes
quickly metabolized, no tissue accumulation
The author collected the blood sample at 2,5,10,30,60,90,120,180min
I collected the blood sample at 5,10,15,30,45,60,120,240,480min,each
time point, about 600ul whole blood is collected, and get around 300ul
plasma, 200ul for determination of compound a, 100ul for determination
of cytokine
Now, i have just done the cytokine analysis. and get that kind of
result.
I am try to find method to extract compound A from plasma, then apply
hplc-ms to analyse.
I am a little confused for I do not have much knowledge about system
biology or pharmacology.
Some people has mentioned that maybe compound A just need some time
to trigger something, then compound A is not necessary to exist in the
body system.
Although Compound A has very good activity, as also as toxicity.Some
data show that for mouse, the LD50 is 0.8mg/kg.
in my experiment, at least, these rats survive 8h.
Acturally, when we do pretreatment, these rats with Compound A looked
much much better than the other ones, and the cytokine determination
also showed cytokine level is much lower than the other ones.
I try to understand the NF-kb pathway and TNF-a action mechanism, hope
i could find something helpful.
By the way, what is the criteria to determine which standard
(external standard or internal standard ) could be used?
Thank you all very much.
Feng
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