Back to the Top
Hi there
In the drug Lipitor drug dosage rather than systemic drug levels
correlate better with LDL cholesterol reduction.
I have been trying to find other examples of drug measurement in the
plasma compartment not having a strong correlation with pharmacodynamic
effect.
Can anyone suggest a good way to look this up? Does anyone know of
other examples that I might research?
Thanks for your help!
Rachel Mandell
Back to the Top
The following message was posted to: PharmPK
Inhaled corticosteroids serum drug concentrations and effect on lung
function. There are correlations between serum drug concentrations of
drugs such as fluticasone, budesonide, beclomethasone, etc., and
systemic effects such as cortisol suppression; but serum drug
concentrations do not correlate well with therapeutic response
(spirometry (FEV1, FVC), quality of life, symptoms, etc)
Glenn Whelan, Pharm.D.
Adjunct Clinical Pharmacologist/Clinical Coordinator
National Jewish Medical and Research Center
1400 Jackson Street
Office J329
Denver, CO 80206
phone: 303-398-1448
fax: 303-270-2189
pager: 303-281-1375
Email: whelang.-a-.njc.org
Back to the Top
The following message was posted to: PharmPK
Dear Dr. Whelan,
Just out of curiosity, I would like to know the plasma/serum
concentrations
obtained following fluticasone and budesonide inhalations related to
their
typical dose administration. I would also appreciate if you could
provide
related publications.
Thanks so much,
Chandra Chaurasia
Back to the Top
The following message was posted to: PharmPK
Rachel,
You can start with M. Gibaldi and D. Perrier's text "Pharmacokinetics"
(Marcell Dekker).
Sri
Srikumaran Melethil, PhD, JD
Professor Emeritus, Schools of Pharmacy and Medicine, University of
Missouri-Kansas City (Pharmacokinetics/Drug Delivery)
Attorney at Law (Drug Law/Pharmaceutical Patents)
Chair, Regulatory Sciences Section, Amer. Assn. Pharmaceutical
Scientists
8428 Constance Street, Lenexa, Kansas 66215
Phone: 913-492-8185, Fax: 913-888-1829
email:melethils.aaa.umkc.edu
website: www.lawandscience.com
Back to the Top
The following message was posted to: PharmPK
Dr. Chaurasia,
Budesonide: following a 1000 mcg dose from the Turbuhaler
Healthy patients Cmax: 1.63 (1.33-1.98) ng/mL
AUC0-t: 4.52 (3.66-5.68) ng*hr/mL
Asthmatic patients Cmax: 1.85 (1.33-2.54) ng/mL
AUC0-t: 5.55 (4.90-6.24) ng*hr/mL
These values were converted from nmol
(ThorssonL, Br J Clin Pharm 2001;52:529-538)
Fluticasone: CFC + Spacer 1000 mcg dose:
Healthy patients Cmax: 0.383 (0.302-0.546) ng/mL
AUC0-t: 2.87 (2.26-3.95) ng*hr/mL
Asthmatic patients Cmax: 0.117 (0.091-0.159) ng/mL
AUC0-t: 1.08 (0.085-0.450) ng*hr/mL
(Brutsche Lancet 2000;356:556-561)
With the Diskus, a dry powder formulation 1000 mcg dose:
Healthy patients Cmax: 0.25 (0.20-0.30) ng/mL
AUC0-t: 1.75 (1.45-2.15) ng*hr/mL
Asthmatic patients Cmax: 0.20 (0.15-0.25) ng/mL
AUC0-t: 1.50 (1.10-2.05) ng*/mL
These values were converted from nmol
(ThorssonL, Br J Clin Pharm 2001;52:529-538)
On average, fluticasone will give an order of magnitude less in serum
concentrations when compared to the other inhaled corticosteroids,
mostly due to high first pass metabolism. The diskus/dry powder
formulations should give an even lower concentration profile because of
their larger particle size distribution compared to the CFC (and HFA)
formulation.
-Glenn
Back to the Top
The following message was posted to: PharmPK
Rachel,
Plasma levels of antiretroviral drugs such as nucleoside reverse
transcriptase inhibitors (AZT and co) are not related to efficacy and/or
toxicity.
Regards
Henri BENECH
CEA/Saclay
Service de Pharmacologie et d'Immunologie
91191 Gif-Sur-Yvette Cedex, France
tel : 01 69 08 72 98 ou 99
Fax : 01 69 08 59 07
henri.benech.aaa.cea.fr
Back to the Top
The following message was posted to: PharmPK
Plasma concentrations are often still several steps away from the site
of
action, and would often be poorly related to concentration at the site
of
action. In toxicological kinetic modelling there is a lot of thought
given
to the choice of the best "dose metric" for the toxic effect (see ME
Anderson 1995, "What do we mean by ...dose?", Inhalation Toxicology 7
p909-915), and these ideas apply equally to drug therapy.
In the most general terms, if there is a specific binding site in the
target
tissue, or if plasma-tissue equilibrium is not achieved due to
retention in
a "deep" target tissue compartment then you might have a poor
relationship
between plasma concentrations and biological response. Also if the drug
doesnt work directly, but works by initiating a chain of events
resulting in
a biological response, then would might also expect plasma
concentrations to
relate poorly to response. Peak plasma conc or AUC could still have
some
relationship to response in these cases, especially for a single dose,
but
less so for for multiple doses. The timing of the response relative to
the
timing of the plasma concentrations would also be separated. You could
imagine situations where administered dose correlates to response better
than plasma concentration, simply because the administered dose happens
to
be correlated better to concentrations at the target site.
Kim
Back to the Top
The following message was posted to: PharmPK
Rachel:
For the great majority of anticancer drugs, perhaps even all, systemic
drug levels do not correlate with their drug levels in tumors - e.g.,
the target site, which is one of the factors determining the
therapeutic effectiveness of anticancer drugs. On the contrary, there
is a significant association between drug levels in tumors and
pharmacodynamic response, as documented in those anticancer drugs where
tumoral drug levels could be measured directly. The most effective and
most patient friendly method for such measurements is through the use
of noninvasive imaging methods, including NMR spectroscopy (MRS) and
Positron Emission Tomography (PET).
--
Professor Walter Wolf, Ph.D. President, Correlative Imaging Council,
Society of Nuclear Medicine
Distinguished Professor of Pharmaceutical Sciences
Director, Pharmacokinetic Imaging Program
Department of Pharmaceutical Sciences, School of Pharmacy
University of Southern California 1985 Zonal Ave., Los Angeles, CA
90089-9121
E-Mail: wwolfw.aaa.usc.edu
Telephone: 323-442-1405
Fax: 323-442-9804
Back to the Top
The following message was posted to: PharmPK
This is a commonly cited example that has several explanations
1) The target (HMG CoA reductase) is in the liver and is hit by the
drug
and its metabolites during first-pass
2) Most importantly, there are multiple active metabolites (that appear
to
be inversely correlated in their exposure to some degree). If you look
at
HMG-CoA reductase inhibition from samples, its variability is much lower
than that of the parent moiety.
3) AUC is not the most relevant measure of drug exposure, because target
inhibition isn't necessarily linear and nor is its relationship to
LDL-cholesterol reduction.
4) LDL-cholesterol is a (nonlinearly) integrated endpoint over weeks of
drug exposure, yet it is typically correlated with a single days AUC.
Obviously, day-to-day variability creates noise in this relationship,
compared to putting dose on the x-axis.
The examples you are looking for will fall into three categories - high
IOV,
genuine presystemic site of action (that is nonlinearly related to
plasma)
or most commonly, a limited PKPD approach (not accounting for points 2.
and
3. for example) leading to a false conclusion of no relationship.
Now, if I remember PharmPK well, I look forward to a stream of
counterexamples and criticism.
Best regards, James
Back to the Top
The following message was posted to: PharmPK
I have seen several replies with regard to examples of unrelated PK and
PD. I think we need to elaborate more on the question in order to get a
better understanding of the issue.
My question is: what is meant by a relation between PK and PD? Are we
talking about a linear relation between plasma concentrations of the
drug and an effect? Does it mean a simple nonlinear plasma level/effect
relation? Are we taking into account possible time delays, which might
make us believe that there is no apparent correlation?
One of the reasons I advocate the use of PK/PD modeling in studying the
actions of a new compound is that modeling enable us to establish a
relation between drug concentrations and its effect that goes far beyond
a simple linear correlation. The literature is full of examples, where
the effect of the compound is observed long after its plasma levels have
gone below the LOQ. Successful PK/PD models have been constructed in
these situations, which enable the investigator to propose more optimal
dose/dosing regime. I think it is time for us to start appreciating the
complexity of the biological systems and move away from simplification
such as "no linear correlation between AUC and effect", or "short
half-life equals short effect duration and is thus not suitable".
I agree with some of the contributors that plasma might not be a good
site for measuring drug levels when trying to establish a PK/PD
relation. However, that does not mean that there is no relation between
the kinetics of the drug and its effect! To my understanding, PK is not
the same as the time-course of a compound in plasma only. Plasma has
conventionally been used for PK studies because of its ease of
collection and the fact that many times, its levels are in a
(pseudo-)equilibration with the site of action of the drug. Many times,
other body fluids can be used. Personally, I have been lucky enough with
"my compound" being distributed to saliva and we have been able to
establish a PK/PD relation between drug levels in saliva and its
antiparasitic effect.
Toufigh Gordi
Back to the Top
The following message was posted to: PharmPK
Dear all,
I couldn't agree more with Prof Wolf's reply. We are developing
anticancer drugs that specifically target hypoxic tumour cells, which
are distant from blood vessels. To predict hypoxic cell kill within the
tumour upon drug administration using PK/PD modeling it is essential to
take into account the drug diffusion in the extravascular tumour
compartment (tissue diffusion). We 'measure' tissue diffusion in a 3D
cell culture model (multicellular layer model) and use a 3D-map of the
tumour (micro)vascular network that together with plasma PK (and the
appropriate PD model, of course) are combined in a spatially resolved
PK/PD model. Without the tissue diffusion component (i.e., using only
plasma PK) the model falls over.
Kind regards,
Frederik Pruijn
--
Frederik B. Pruijn PhD MSc (Senior Research Fellow)
Experimental Oncology Group
Auckland Cancer Society Research Centre
Faculty of Medical and Health Sciences
The University of Auckland
Private Bag 92019
Auckland
New Zealand
Phone: +64-9-3737 599 x86939 or x86090
Fax: +64-9-3737 571
E-mail: f.pruijn.-a-.auckland.ac.nz
Back to the Top
The following message was posted to: PharmPK
Frederik,
Would you please be more specific about what you mean by 'the model
falls over' when you use plasma PK only? Are you referring to
predictions based on the naive assumption that effects are immediately
related to plasma concentration? Have you tested other models that can
predict delayed effects based on plasma PK as the driver (e.g. effect
compartment model, turnover models)?
If there is a dissociation between predictions driven from plasma PK
compared with predicted tissue spatial diffusion then it suggests some
non-linearity in the way that drug gets to its target. Is this
non-linearity part of your model?
Nick
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
email:n.holford.at.auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
Back to the Top
The following message was posted to: PharmPK
Dear Nick,
see below for my reply. It will probably raise more questions.
Kind regards,
Frederik
--
Frederik B. Pruijn PhD MSc (Senior Research Fellow)
Experimental Oncology Group
Auckland Cancer Society Research Centre
Faculty of Medical and Health Sciences
The University of Auckland
Private Bag 92019
Auckland
New Zealand
Phone: +64-9-3737 599 x86939 or x86090
Fax: +64-9-3737 571
E-mail: f.pruijn.-a-.auckland.ac.nz
Nick Holford wrote:
>
> Frederik,
>
> Would you please be more specific about what you mean by 'the model
> falls over' when you use plasma PK only? Are you referring to
> predictions based on the naive assumption that effects are immediately
> related to plasma concentration?
Our PD model relates cell kill to drug exposure (a function of
concentration and time). Actually, it is the amount of the drug that is
metabolized to a toxic species (a radical) that causes DNA damage. This
metabolism is oxygen dependent and follows, in a non-linear fashion, the
oxygen gradient in the tumour tissue. Particularly with poor diffusers
(e.g., strong DNA binders) "naively" using the plasma concentration-time
profile greatly overestimates the cell kill in the hypoxic regions in
the tumour (the model falls over).
> Have you tested other models that can predict delayed effects based on
> plasma PK as the driver (e.g. effect compartment model, turnover
models)?
No, we haven't. One of the reasons we like our model is because it
allows us to measure the tissue diffusion coefficient using the
multicellular model. Furthermore, we have developed an algorithm that
successfully predicts the diffusion coefficient and it can, therefore,
be used to predict this critical parameter for hypothetical compounds
(e.g., before chemical synthesis).
>
> If there is a dissociation between predictions driven from plasma PK
> compared with predicted tissue spatial diffusion then it suggests some
> non-linearity in the way that drug gets to its target. Is this
> non-linearity part of your model?
Yes! I should add that the aforementioned metabolism can contain both a
first-order and a Michaelis-Menten component. In addition, the oxygen
gradient in tumour tissue is also non-linear. The 3D-map of the
(micro)vascular tumour network incorporates different vessel diameters
and flow rates and, consequently, different oxygen concentrations. We
have undertaken a validation of our model and so far the predictive
power has been excellent and it has become an integral part of drug
development program.
Regardless of our model, there is accumulating evidence that poor drug
diffusion can be a major reason for drug resistance in cancer
chemotherapy.
Back to the Top
The following message was posted to: PharmPK
Frederik Pruijnwrote:
"... Actually, it is the amount of the drug that is metabolized to a
toxic species (a radical) that causes DNA damage..."
Dear Frederik:
From my experience in modeling the interaction of free radical species
with tissues (for example, see LPOTCE and LPOXLIV models at <
http://members.aol.com/JanuszB/pbpk.htm >), additional nonlinearities
and even discontinuities may be introduced by the depletion of natural
scavengers (especially, Glutathione-SH and vitamin E). Moreover, the
model should include a "feedback" inactivation of metabolic activator
by the free radicals formed (non-linear inhibition by product of the
enzymatic reaction).
Best wishes.
Janusz Z. Byczkowski, Ph.D.,D.Sc.,D.A.B.T.
Consultant
212 N. Central Ave.
Fairborn, OH 45324
voice (937)878-5531
e-mail januszb.at.AOL.com
homepage: http://members.aol.com/JanuszB/index.html
JZB Consulting web site: http://members.aol.com/JanuszB/consult.htm
Back to the Top
The following message was posted to: PharmPK
thank you all for this discussion, as a student i am learning a lot
from this discussion,
i have a subquestion:
there are natural products which often follow this unrelated pk pd
one of the active ingredient of spice, curcumin isolated from curcuma
longa, maximum references on activity done in-vitro use a dose range of
1-100ug and the pk studies done with 12gm (12000mg) dose says the
highest level of curcumin in plasma is 2-4ug/ml with Cmax at 3hrs
(2-4hrs)..i doubt if there are any pk-pd studies on this drug..can any
body resonably explain pd activity of this drug..its a lipophilic drug
with high first pass converted to tetrahydrocurcumin which is a water
soluble active metabolite..which approach can be taken up to study the
pd activity of this drug..
thanking you
regards
Back to the Top
The following message was posted to: PharmPK
Dear colleagues,
Rachell Mandell wrote:
> In the drug Lipitor drug dosage rather than systemic drug levels
> correlate better with LDL cholesterol reduction.
As stated by James Wright and Toufigh Gordi, there can be many reasons
why
plasma drug levels 'do not correlate to drug effect'. An appropriate
PK-PD
analysis may provide a better insight in the relationship between dose,
plasma concentration - time profile, drug concentration - time profile
at
the effect site, and drug effect. However, a statement that dose
correlates
bettter to effect than concentration does not bring us further (although
this is probably the ideal end point from an industrial point of view:
every
patient the same dose for optimal effect!). Except for some special
cases,
one knows that plasma concentration is at least one step closer to the
effect site than dose. Using dose rather than plasma concentration is a
step
into the wrong direction.
In reply, Henri Benech wrote:
> Plasma levels of antiretroviral drugs such as nucleoside reverse
> transcriptase inhibitors (AZT and co) are not related to efficacy
and/or
> toxicity.
Of course I understand that there are more factors than plasma
concentration
determining the efficacy and/or toxicity of antiviral drugs, but I do
not
agree with this general statement. It is likely that a higher
concentration
results in a better efficacy and higher toxicity, if all other
conditions
are the same. So, concentration must be a factor determining, directly
or
indirectly, simply or complex, drug efficacy and toxicity. In my view
this
is a fundamental concept in PK-PD, and one needs very strong evidence to
reject this hypothesis. The observation that one is not able to assess
this
relationship does not mean that there is no relationship.
And Walter Wolf wrote:
> For the great majority of anticancer drugs, perhaps even all, systemic
> drug levels do not correlate with their drug levels in tumors.
Same comment.
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.aaa.rug.nl
PharmPK Discussion List Archive Index page
Copyright 1995-2010 David W. A. Bourne (david@boomer.org)