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Hi every one,
I have gotten many important and useful information from this
discussion group. I highly appreciate that.
I want to know is there anybody who has try to figure out the PK AND
PD profile of botanic drugs. Botanic drugs often come from some kind
of extracts of herbs, for example, traditional chinese medicine. So I
want to know is there any methodology for access to PK AND PD of
botanic drugs.
Thanks
Feng
Graduate student
Rutgers, the state university of New Jersey
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The following message was posted to: PharmPK
Dear Feng,
I think the biggest problem with traditional Chinese medicines is
knowing
what the active ingredient(s) is (are). If we knew the structures of the
active molecules we'd have a chance of dealing with them.
Best regards,
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (NASDAQ: SLP)
42505 10th Street West
Lancaster, CA 93534-7059
U.S.A.
http://www.simulations-plus.com
E-mail: walt.at.simulations-plus.com
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The following message was posted to: PharmPK
Feng,
There is no reason why determining the PK of a botanical extract would
be different from that for any other xenobiotic, provided you have two
things:
1) a specific analytical method capable of determining the dose of
"active" administered to the animal model or patient, and 2) a
specific bioanalytical method capable of measuring the concentration
of "active" in blood, plasma or other tissues at various time-points
post-dose.
Of course, if one does not even know what the "active" is, or has no
way of determining its concentration, then one cannot perform PK-PD
analysis.
Peter Rix
Kalypsys, Inc.
San Diego, CA
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thanks.
As to traditional chinese medicine,because of the biosythesis pathway
of its secondary metabolites, they often contain a series of active
compounds with similar structures.And usually, these compound will
pursue similar activies.
Now, I also found that many american research institutes and some
pharmaceutical companies have pay more attention to botanic drugs.
However, I have not found good method for invistating the PK AND PD
profile of these botanic drugs, which is especially important for dose
regimen and toxicity preventing.
So if we find some single compound from botanic drugs has good
activity, should we just focus on this compound ?Often, this single
compound has very low concentration in the crude extracts(botanic
drugs), how could I suppose that major activities come from this
single compound with ignoring the other similar compounds's
contributions.
Now, I plan to do some work to investigate the dose and frequency
regimen of some botanic drugs.
Feng
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The following message was posted to: PharmPK
Hi all
Peter wrote:
> Of course, if one does not even know what the "active" is, or
> has no way of determining its concentration, then one cannot
> perform PK-PD analysis.
I thought it is worth a comment that the above premise is not
necessarily the case. A growing area of PKPD anaylsis involves KPD
models where the PK is imputed based on the PD profile. If the goal of
PKPD is to define the time course of drug effects then this approach
would seem perfectly reasonable in this setting and hence PK
observations are unnecessary. The only, perhaps important, assumption
is that the dose of active is proportional to the dose of botanic that
is ingested (i.e. a leaf of botanic provides a standard amount of
active and this is consistent within a batch).
Regards
Steve
--
Professor Stephen Duffull
Chair of Clinical Pharmacy
School of Pharmacy
University of Otago
PO Box 913 Dunedin
New Zealand
E: stephen.duffull.-a-.otago.ac.nz
Design software: www.winpopt.com
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I highly agree with these comments.
For we just want to focus on one kind of botanic drug which has anti-
inflammatory activity. This botanic drug has been used for clinical
treatment for more than 30 years in China.
However, the dose regimen often come from the physicians'
experience. for example, usually 3 times a day, with dose of 1-1.5 mg/
kg (crude extracts). So how could I give a data supported conclusion
that 3 times a day is the best dose frequency other than 2 or 4 times
a day??
If I want to figure out the time PD file of this botanic drug, what
should I pay special attention to ? I also need some suggestion for
the sample time points (interval) design for collecting blood sample.
Thanks to every one for your kind attention.
Feng
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The following message was posted to: PharmPK
Dear Fing,
The dosage schedule dpend on the PD data and bioassay of the botanic
drug.
It is not possible to identify and analyze the active constituents
therefore the bioassay for particular pharmacological activity(s) may
help
you to suggest the dosage-schedual.
Dr Zafar
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The following message was posted to: PharmPK
Steve wrote:
"A growing area of PKPD analysis involves KPD models where the PK is
imputed based on the PD profile. If the goal of
PKPD is to define the time course of drug effects then this approach
would seem perfectly reasonable in this setting and hence PK
observations are unnecessary."
In my opinion, the goal of PKPD is not to define the time course of
drug effects (one doesn't need any PK data to do that), but to
establish a relationship between a given AUC, AUMC, Cmax, t1/2 etc
with a given pharmacological effect. Once this relationship has been
established, any change in a drug product (new salt, formulation,
dosage form, dosage schedule) or change in the patient population
(hepatic impairment, renal dysfunction, various ethnic populations)
can be addressed through simple PK studies without the need for new
pharmacology/efficacy studies of the drug.
The original poster asked about "PK-PD" of botanical extracts used in
Chinese Medicine. The distinction may just be one of semantics, as
one may not actually need to establish PK-PD of these substances to
achieve the stated goals (determining the best dosing interval for
anti-inflammatory efficacy).
Respectfully,
Peter Rix
Kalypsys, Inc.
San Diego, CA
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The following message was posted to: PharmPK
Dear Feng, Steve, and Peter,
As Steve pointed out, KPD is a possible solution for botanical
extracts.
I also discussed about this with my friend one month ago.
IMHO:
1) If we use KPD and find a PK model, maybe we can compare it with
what
we measure in blood. And then we can find which compound has more
similar PK
profile with KPD estimation. Hopefully, it is a new drug.
2) Safety is a big problem to Chinese medicine. If we do not know
what
it really is, any PK assumption can't help too much. It is better
to dig
out which compound(s) works. Otherwise, safety is always a problem no
matter
how beautiful PK model was made.
Best regards,
Guangli
Uppsala
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The following message was posted to: PharmPK
Peter
> In my opinion, the goal of PKPD is not to define the time
> course of drug effects (one doesn't need any PK data to do
> that), but to establish a relationship between a given AUC,
> AUMC, Cmax, t1/2 etc with a given pharmacological effect.
I think this is where we may hold different beliefs. I believe PKPD =
time course of drug effects. Hence PKPD is more than the sum of PK
and PD. My feeling is that the time course of pharmacological effects
of drugs underpins our understanding of the choice of dose, dose
interval and duration of treatment. Having PK data makes the whole
process much easier (since PK inherently includes a relationship on
time whereas PD does not) and more mechanistic. In the absence of PK
you need to have an easy to measure biomarker, which you hope is on
the causal chain, and the ability to intensively sample the
biomarker. So PKPD without PK is not really desirable but sometimes
necessary.
Choice of AUC as a descriptor of exposure completely eliminates the
time component (as it integrates over time) and hence it would not be
possible to define any time related effects of a drug (e.g. dose
interval). Therefore it would also not be possible to determine the
dose of a drug to be used, since dose without dose interval (for
chronically dosed drugs) is meaningless.
> The original poster asked about "PK-PD" of botanical extracts
> used in Chinese Medicine. The distinction may just be one of
> semantics, as one may not actually need to establish PK-PD of
> these substances to achieve the stated goals (determining the
> best dosing interval for anti-inflammatory efficacy).
I believe you can only determine dose interval when you know the time
course of drug effects.
Regards
Steve
--
Professor Stephen Duffull
Chair of Clinical Pharmacy
School of Pharmacy
University of Otago
PO Box 913 Dunedin
New Zealand
E: stephen.duffull.at.otago.ac.nz
Design software: www.winpopt.com
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