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The following message was posted to: PharmPK
Blood (Serum) Half Lives versus Target Tissue Half Lives
In the recent discussion about half life, half lives in target sites of
action were not considered - or did I miss it? Do we not need
information about half lives in specific sites of deposition and
binding through direct measurement with sensitive and high resolution
approaches, - not just with routine low-resolution ADME cut and count
radioassays and whole body imaging, - both known for false negatives?
Blood half life determination certainly is important. It reflects blood
bioavailability, absorption (Kavanagh), and elimination - but not at
the level of targets. In the Effective Half Life in the Body (mentioned
by Ayyappa), different organs are lumped together. Is that useful when
low capacity-high specificity sites remain undetected?
Which blood half life segment corresponds to site(s) of action, i.e. to
the half lives of the different individual targets of the same
compound? Is it reasonable to make a general time- and dose-related
extrapolation from blood levels to target levels? Individual target
tissues may have quite different and much longer half lives compared to
that of blood or serum.
Evidence indicates that bioavailability and half life in targets can
NOT be determined through extrapolation from blood measurements, unless
specific evidence is provided that blood and target half lives are
identical or related to each other in a certain ratio. Binding
properties of plasma and target proteins are different.
Assumptions of identity between blood and target half lives most likely
are fallacious.
Walter E. Stumpf
University of North Carolina at Chapel Hill
2612 Damascus Church Rd
Chapel Hill, NC 27516
www.walterstumpf.com
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The following message was posted to: PharmPK
Walter,
You've hit on a subject that is dear to both of us!
Indirect models are often required to fit PD effects to plasma
concentrations. Why? Because of the point you make so well - target
tissue
concentrations do not necessarily follow plasma (Cp) concentrations. So
various empirical models that incorporate hysteresis and other effects
have
been devised to find functions that correlate effect-time with Cp-time.
These are useful models, but I think they can mask the underlying
mechanistic effects that we'd really like to understand.
PBPK/PD modeling attempts to get around this by fitting effect models to
(usually predicted) concentrations in individual tissues. Modern PBPK
models
appear complex, but they are constrained by the observations (Cp-time
and
other data), as well as estimated values for individual tissue volumes,
blood flows, and partition coefficients (Kps). These constraints keep
the
models from straying too far from reality.
We've seen consistent success using PBPK models to predict human Cp-time
with good results using only data that would be available prior to
dosing in
human - sometimes only what would be available prior to animal dosing.
But
predicting Cp-time is not predicting tissue concentration-time.
For a number of drugs, measured Kps are available in rat, and those
values
can be used in human predictions for those drugs. This approach can
provide
good estimates for human plasma concentration-time (e.g.,
terbinafine). It
also provides estimates for tissue concentrations, but without
verification,
we can only hope they're in the right ballpark.
Whether the PBPK model is done with measured Kps (rare) or with
calculated
Kps (common), fitting PD models to predicted target tissue
concentrations
can then be attempted, and when the models are good, they should be more
direct and informative than indirect models based on plasma
concentrations.
Unfortunately, measuring tissue concentrations in human is not possible
unless it can be done as you propose - with accurate imaging methods.
Let's
hope that someday PBPK modeling combined with cost-effective, accurate
tissue measurements will become common practice.
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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I couldn't agree more that it is essential to know target tissue
concentrations. Empirical data (e.g. high-resolution imaging) may be
the "Holy Grail" but till then, and in particular for drug screening
in early (earlier) drug development, we may have to rely on models.
We have been working for many years in this area in the context of
tumour tissue. In a recent paper (J Natl Cancer Inst 2006;98: 1118 -
28) we describe and validate a model that takes into account drug
gradients and concentrations within the tumour tissue (and oxygen
gradients and concentrations for that matter) to predict drug- and
irradiation-induced cell killing. We show in Fig. 6 of this paper that
without taking drug gradients into account (i.e. using the plasma
concentrations instead) meaningless data are obtained.
Best 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 1142
New Zealand
E-mail: f.pruijn.at.auckland.ac.nz
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Even if you knew the total concentration at a given tissue, to my best
knowledge you would get the "total" concentration (free + tissue
bound). The particular pharmacology under observation may depend on
the total or (according to the free drug hypothesis) only the free
fraction of a drug the receptor is exposed to.
So, if you are looking at "time-course" aspects for one specific
compound, you may be ok with a relative measure of drug concentration
in a given tissue versus blood, and free or bound concentrations might
lead to equivalent conclusions. However, if you are trying to compare
characteristics of different drugs, with different free fractions in a
given tissue, the comparison might not hold all that well...
My 2 cents -
Dario
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The following message was posted to: PharmPK
Dario,
You are correct - the unbound concentration is important. In PBPK
modeling
we do our best to estimate both Fup (fraction unbound in plasma) and Fut
(fraction unbound in tissue). Of course, if experimental data exist
then the
actual values are used.
For imaging studies such as Dr. Stumpf has proposed, combining PBPK
modeling
with the imaging data and estimates (or measurements if available) of
binding in various tissues and plasma should often provide useful
models.
("All models are wrong, some models are useful" - G. Box).
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
Dear Dario,
In our models it is the free drug that is diffusing. We take 'reaction
terms' into account. For example, to model oxygen
gradients/concentrations you obviously have to know the oxygen
metabolism (consumption) terms.
For other molecules reversible (e.g. non-specific or specific saturable
binding) and irreversible (e.g. first-order or saturable metabolism)
reaction terms are parameterised as required.
Plasma protein binding is also measured.
Not all terms have a huge influence on the biological effect (PD
endpoint) and depending on the compound (s) under study, but all things
being equal tissue diffusion MUST be taken into consideration or else
pseudo-scientific nonsense is obtained.
This approach works really well, and was in fact developed, for lead
optimisation studies. The JNCI study (2006, 98: 1118 - 28) deals with
the lead compound tirapazamine and 15 analogues.
Best 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 1142
New Zealand
E-mail: f.pruijn.aaa.auckland.ac.nz
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Dear Colleagues:
I am absolutely delighted that there is a growing number within the PK
community that recognize and agree that for many drugs the key
information that is needed is the PK of a drug at its target site(s)
and that information on such PK/PD can be obtained best or in many
cases only, by the use of noninvasive imaging methods. While nuclear
imaging is probably the molecular imaging method with the highest
sensitivity, nuclear magnetic resonance spectroscopy (MRS) can provide
the greatest degree of chemical information, whereas MRI is together
with nuclear imaging excellent for measuring PD effects. And we are
also now seeing the emergence of optical methods that will expand and
complement the above techniques.
Having said that, there are still many roadblocks that limit the wider
use of noninvasive imaging methods in PK/PD studies. We held a
workshop a year ago at USC that identified these roadblocks, and a
report of the recommendations has been published. See Wolf, W,
Atkinson, DJ and Colletti, PM: Enhancing Drug Development and Drug
Monitoring: Academia, Industry and Government Chart Common Goals,
Pharmaceutical Research, 24:2025-2027, 2007.
Charged with implementing these recommendations is a new organization,
the Multidisciplinary Advisory Council on Noninvasive Imaging Studies
- MACNIS - that is actively pursuing the goal of expanding the ability
to effectively use noninvasive imaging in PK/PD studies. MACNIS is a
consortium of members from the FDA, the NIH, the pharmaceutical and
the imaging industries and academia, and will take the leading role in
the development and implementation of PK/PD studies based on
noninvasive imaging methods. The specific activities that MACNIS will
undertake will be announced at our website http://www.macnis.org, and
we look forward to greater participation in this collective effort by
many members of the PK community.
--
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.usc.edu/schools/pharmacy/faculty_directory/detail.php?id=59
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The following message was posted to: PharmPK
Information about drug targets is essential. That includes target
identification, characterization, and pharmacokinetics.
Walter Wolf is right, of course: to understand mechanisms of drug
action we need to know about target pharmacokinetics. We cannot get
that information from drug blood levels. Extrapolations from blood
levels or from ground-up organs (L.J. Roth: "don't homogenize the
brain; the brain you are homogenizing may be your own.") are misleading
(with few exceptions). Drug availability to target tissues and cells
and target pharmacokinetics are different from that of blood, - and may
vary even among targets.
Noninvasive imaging methods for target pharmacokinetics are helpful
and, when applicable, can be essential. Current methods, however,
provide limited resolution and may not recognize important HIGH
SPECIFICITY-LOW CAPACIITY sites. Available evidence indicates that
preclinical high resolution methods may be needed to complement
noninvasive imaging - especially for important lead compounds.
I discussed this topic with evidence in a recent MEMORANDUM to the FDA
and ICH (Drug Discovery Today, Volume 12, Number 15/16, August 2007)
and in a monograph DRUG LOCALIZATION in TISSUES and CELLS (Chapel Hill,
2003).
P.S.: High resolution methods may be viewed as 'non-expedient', but "we
learn from history that expediency has rarely proved expedient" (B.H.
Liddell Hart in "The shortsightedness of expediency.")
--
Walter E Stumpf
Dr.med., Ph.D., Dr.hc.
Prof. Cell biology and Pharmacology em.
University of North Carolina
2612 Damascus Church Rd
Chapel Hill, NC 27516
Tel/Fax: 919 942 8646
www.walterstumpf.com
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The following message was posted to: PharmPK
Drs. Stumpf and Wolf argue an important issue, which is knowing what
happens at the drug target(s).
Is there anybody on this forum who uses imaging mass spectrometry (IMS)
at all and particularly in drug development?
The reason I ask is that this appears to be a very promising (invasive)
imaging technique that has the potential of giving high sensitivity,
high resolution, and high specificity.
Best 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 1142
New Zealand
E-mail: f.pruijn.at.auckland.ac.nz
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The following message was posted to: PharmPK
Dear Dr. Pruijn
You asked this question:
"Is there anybody on this forum who uses imaging mass spectrometry (IMS)
at all and particularly in drug development?"
Did you get an answer? I have not seen any yet.
And - would there be any alternate means for the IDENTIFICATION and
CHARACTERIZATION of in vivo(!) TARGETS in drug research and development?
If there is, I like to know and see the evidence. THE PICTURE IS THE
EVIDENCE!
This means representation of compound within cellular-subcellular
detail in the context of clear tissues and organ structure.
Resolution, sensitivity, and authentic in vivo representation are
critical.
To my knowledge, presently there is no alternate method available,
none that matches the information provided with Receptor Microscopic
Autoradiography.
This method is available and tested. Its utility and superiority over
other methods has been demonstrated many times and for many compounds.
(Not just any autoradiography method is applicable for drugs. There
are wrong methods that produce artifacts, useless, with misleading
data published in the literature.)
Like any high resolution method, it requires attention to detail, it
is "labor intensive" (in some minds)and not "expedient" (in some
minds) - although it is highly result-expedient, informative, and
ultimately cost saving.
This is a long and recurrent story, frequently not understood by
chemists and pharmacists, and profit-guided administrators, - all with
different perspectives.
Target pharmacology is essential - as you stated. However, it requires
knowledge in cell biology-histology and pharmacology, in addition
specific method expertise and experience.
Best regards, Walter
--
Walter E Stumpf
Dr.med.,Ph.D., Dr.hc.
Professor of Cell Biology and Pharmacology em.
University of North Carolina
2612 Damascus Church Rd
Chapel Hill, NC 27516
www.walterstumpf.com
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Dear Dr. Stumpf,
Thank you for your post.
So far I have not seen any replies to my question.
Although I am not an expert in imaging mass spectrometry (far from
it!) I'd like to take this chance to pitch for it.
In my mind there is no question that imaging mass spectrometry, and
nano-SIMS in particular, can achieve the same things (?) and produce a
similar "picture" as, for example, Receptor Microscopic
Autoradiography. There certainly is a growing amount of literature and
a thriving community of enthusiastic scientists out there that seem to
support my notion.
For the interested & inquisitive minds amongst us (and who have time
to read these):
http://www.cameca.fr/html/publications.html#ns50_bio
http://www.cameca.fr/doc_en_pdf/jb2006_5_lechene.pdf
It is/was not my intention to start a comparison between (the)
different technology platforms; the intention is/was to highlight the
importance of knowing the drug target(s) and drug concentration(s) at
the target. This is the key information that is often unavailable and
any technology that may be used to obtain it deserves to get our
attention. I am keen to explore the possibilities to use imaging mass
spectrometry in our research, hence the question in my previous post.
Best 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 1142
New Zealand
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The following message was posted to: PharmPK
Dear Dr. Pruijn,
You stated:
"In my mind there is no question that imaging mass spectrometry, and
nano-SIMS in particular, can achieve the same things (?) and produce
a similar "picture" as, for example, Receptor Microscopic
Autoradiography."
Such a statement requires support by evidence which I have not yet seen.
Introducing a method for imaging requires testing and documentation -
not just with any compound. Together with L.J. Roth (during the
mid-1960s) we postulated that claims for the localization of
diffusible compounds can be made ONLY AFTER TESTING with two compounds
for which localization is known. We did just that with estradiol and
mesobilirubinogen, BEFORE we recommended our Thaw-mount and Dry-mount
Autoradiographic methods - later modified and called Receptor
Microscopic Autoradiography.
Unfortunately, methods have been and still are recommended without
such prior testing, simply using any compound for claims of the
utility of the method.
For instance, we know well the target cell distribution of estradiol
and vitamin D in brain, spinal cord, pituitary, etc. We published maps
of steroid hormone distribution. These compounds can easily be used.
With such evidence provided, a claim as made above could be supported
and justified.
Too many false and unsupported claims have been made in the past. Too
many related artifacts have been published in the literature.
Yes, imaging mass spectometry and similar procedures will be able to
contribute to drug localization and targeting, characterization of
localized compounds; - but probably will not be able to replace low
and high resolution autoradiography that provide convenient high
resolution and surveys simultaneously.
You stated further:
"any technology that may be used to obtain it (target identification}
deserves to get our attention." Why then not paying attention to the
well tested high resolution autoradiography?
Each method has limitations. Therefore various correlative methods may
have to be employed to complement each other, - depending on type of
compound. Validation of method and data are paramount.
Here I can only hint at some problems and implications. This is a wide
topic. Investigators can easily be mislead through unqualified
statements and claims.
Best regards,
Walter E Stumpf
--
University of North Carolina
2612 Damascus Church Rd
Chapel Hill, NC 27516
www.walterstumpf.com
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