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Hi, folks
I have a wonder staying in my brain for a long time as: Is it possible
to apply PK-PD model into botanic drugs (as a mixture of thousands of
compounds)?
For example, my lab is currently working on an plant extract and pay a
lot of effort to develop it as a true drug. (Comparison of
Tripterygium wilfordii Hook F Versus Sulfasalazine in the Treatment of
Rheumatoid Arthritis,A CLINICAL TRIAL). We want to design the dose
regimen of this extract basing on some scientific data.
The mixture of thousands of compounds is too complicated for us to
track the kinetics of these compounds. However, if the plant is well
growed, and the extract is well handed with SOP guide, maybe we could
assume the componets of the mixture is relatively consistent. So we
could regard the extract as a magic black box which will post the
pharmacology activity.
Does any people have some idea about this? Thanks very much. I am
eager to hear from you.
Feng
Ph.D candidate
Peking Univerisity & Rutgers, the state university of New Jersey
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Feng:
Most herbal products would not qualify for standardization unless you
analyze the components and develop your own standards (verifiy may be
a very difficult step for the FDA. Raw plant extracts vary markedly
based on the time of year, area grown, weather and even time of day
collected.
Your first steps would be to ascertain what the active ingredient or
ingredients is/are and then develop SOPs based on assays of those
ingredients.
Sincerely,
Carol Collins MD
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Hi Feng,
In my opinion, this would be very difficult without any concentration
data. In my experience, even when the production conditions of natural
products are tightly controlled, there is a large variability in the
composition of the components. So I don't think the assumption of a
consistent mixture would be valid.
Thanks,
Beverly Knight
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Dear Feng,
Is it possible to determine these constituents in blood samples?
certainly it is very difficult rather than immpossible to determine
the various constituents in after blood sampling therefore simple PK
studies may be not possible.
Using Pharmacodynamic properties one can predict the relationship dose
and PD properties with respect to time. but again it do need that the
constituents of the plant extracts remains constant and experties are
required to study the PD properties with respect to time.
Dr Zafar
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Dear Feng,
If we can identify the marker compounds (from literature) which may or
may not be biologically active, the pharmacokinetics can be profiled.
Only thing is that for every time we dose the extract we will have to
quantify the batch for the presence of that particular marker. If the
marker is biologically active then it will be really a great
breakthrough.
Best wishes,
Devang P. Shah.
Senior Research Fellow (PhD Tech Fellow),
Dept of Pharmaceutical Sciences and Technology,
Pharmacology Lab II,
Institute of Chemical Technology,
N. P. Marg,
Matunga, Mumbai 400 019.
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Might be able to do somethng with PD but PK would be very difficult,
each component would be expected to have very different behavior.
Might want to pick a few, characterize and follow them.
You would need to get better control and consistency over the product.
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Thanks every people's comments.
I know it is pretty hard to get PK data of multiple constituents. For
some single compound, there also might be several metabolites of this
compound and these metabolites may aslo have some activity. The active
constituents includes the parent drug as also as these metabolites. So
how do people practically do PK-PD research of this compound? What
kind of assumption or consideration should be indicated?
There is a new approach to use K-PD model (absense of PK data) to
predict the dose-response relationship.
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Feng
There is an approach (K-PD modeling) that describes PD in absence of
PK, see, for example
Modelling Response Time Profiles in
the Absence of Drug Concentrations:
Definition and Performance Evaluation
of the K-PD Model.
P. Jacqmin et al.
J. Pharmacokin Pharmacodyn 2007
The presentation below contain a detailed explanation (geared toward
pediatrics where we also want to avid PK as much as possible):
http://www.emea.europa.eu/pdfs/conferenceflyers/paediatric/08girard.pdf
Of course, you need to assume that your drug is consistent from batch
to batch (or introduce variability of the drug properties into the
model)
--
Leonid Gibiansky, Ph.D.
President, QuantPharm LLC
web: www.quantpharm.com
e-mail: LGibiansky at quantpharm.com
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Feng Zeng:
You will need to come up with a standardized product before you
establish any PD relationship. It is also important if you plan to
market your product.
And before you decide how stringent your standards need to be, you
need to decide whether you plan to develop this product as a drug or a
new dietary supplement (or herbal medicine based on the country where
you plan to introduce this drug. Obviously the standardization
requirements for dietary supplements is less stringent but the type of
marketing claims (advertising) is also more limited.
It is certainly tempting to just conduct clinical trials to establish
pharmacodynamics without having spent the money to establish rigorious
standards but I have seen this approach fail miserably for companies.
THEN they went back and found that the product from different sources
varied markedly in content.
Sincerely,
Carol Collins
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The following message was posted to: PharmPK
A suggestion, have you gone to the FDA website, DRUGS AT FDA and
looked at the VEREGEN NDA package? online you can read all of the FDA
reviews for the only botanical drug substance that the FDA has
approved, from it you could see what approach the FDA took to these
very problems and could then design a better strategy.
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