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Dear Colleagues:
I would like some help and comments on a matter of terminology.
As some of you know, we have been developing a methodology that uses
noninvasive methods for measuring drugs at their target sites, followed by a
pharmacokinetic analysis of these raw data. We have proposed the name
of "PHARMACOKINETIC IMAGING" to designate these methods, which provide
temporal data on chemical species at clearly defined spatial sites
(see Pharm. Res.12:1821,1995 - "Imaging is much more than looking at
pretty pictures").
We are now struggling with another problem of definitions: what name should
we use to define the amount of a drug that becomes available at the target
site? Because noninvasive methods can now measure such amounts, a clear
definition of terms becomes urgent. But there is considerable confusion.
One possible term to use is "bioavailability". Goodman and Gillman (p. 4/5,
1996) states: "Bioavailability is a term used to indicate the extent to which
a drug reaches its site of action OR a biological fluid from which the drug
has access to its site of action". There is significant incompatibility
between these two sections of the above definition. The concentration of a
drug in a biological fluid measured at point X of the body does NOT
necessarily connote availability of that drug at its target site. And Gibaldi
and Perrier (Pharmacokinetics p. 411, 1982) state: "Bioavailability often
refers to the fraction (F) of an ORAL dose that actually reaches the SYSTEMIC
CIRCULATION". Hence, Gibaldi's definition (and I suspect in most people's
view) tends to the second part of Goodman and Gillman's above statement,
rather than the broader and more encompasing first part.
Let me propose two alternatives, and I would like comments from the
group:
1) To use the term "Bioavailability at the target site" [BTS] "to indicate
the extent to which a drug reaches its site of action"
Alternatively
2) To use a new term "Drug exposure at the target site" [DETS] "to indicate
the extent to which a drug reaches its site of action".
I look forward to all your comments.
=========================================================================| Professor Walter Wolf, Ph.D. E-Mail: wwolfw.aaa.hsc.usc.edu |
| Director, Pharmacokinetic Imaging Program |
| Department of Pharmaceutical Sciences Telephone: 213-342-1405 |
| University of Southern California Fax: 213-342-9804 |
| 1985 Zonal Ave., Los Angeles, CA 90033 |
| |
| Center for Noninvasive Pharmacology, Los Angeles Oncologic Institute |
| MRI at St. Vincent Medical Center Telephone: 213-484-7235 |
| 2131 Third St., Los Angeles, CA 90057 Fax: 213-484-7447 |
========================================================================------------------------------
Date: Wed, 9 Jul 1997 11:29:48 -0500
From: William Dager
Subject: Re: Adjusted weight-based dosing for LMWHs?
In reply to several questions on the use of LMW Heparin to treat DVT:
Several papers have addressed the use of LMW Heparin to treat DVT's.
1. Hull et al.Subcutaneous Low-Molecular Weight Heparin Compared with
Continuous Intravenous Heparin in the treatment of Proximal-Vein
Thrombosis. N Engl J Med 1992;326:975-82.
2. Lensing AWA et al. Treatment of deep vein thrombosis with low molecular
weight heparins, a meta analysis. Arch Intern Med. 1995;155:601-607
3. Tapson VF, Hull RD.Management of venous thrombotic disease: The impact
of Low-Molecular Weight Heparin. Clinics in Chest Medicine 1995 16(2):281
(6 differenr papers are reviewed on DVT tx with a LMW Hpearin)
2 years ago we deveploped a program for outpatient treatment of Deep Vein
Thrombosis with Enoxaparin 1mg/kg. We tend to adjust the dose down for
obese patients, but the original studies by Hull did not. I was part of a
discussion recently with Dr Hull, and they felt comfortable with the total
body weight being used, but data seems to be lacking on if adjusting the
dose reduces risk of bleeding with no change in treatment outcomes.
Getting back to our program, we have enrolled 40 patients to date, and
have had only 2 complications to date. 1 patient had a lower GI Bleed (The
patient had a rectal polyp removed 2 days prior), and 1 patient had a
recurrent DVT despite a therapeutic INR (She was eventually diagnosed with
cancer). The cost savings to our institution was around $200,000.00. Our
results were recently presented at the 4th annual anticoagulation form in
San Antonio, TX.
As for the question on when to start the warfarin, it is my understanding
that the hypercoagulable state that occurs post the first warfarin dose
secondary to inhibition of protein C & S (anticoagulant proteins) was a
significant concern when higher loading doses were used. No one seems to
know weither the clot will extend when doses are given prior to
establishing heparin anticoagulation first. The conserivative approach may
be to wait untill the APTT is above 50 prior to starting warfarin, but
many will initiated warfarin 6 hours after starting heparin. I have
noticed that INR values drawn within 8 hours after the first warfarin
dose will drop (around 10%), so I tend to wait for 8 hours post the
heparin bolus prior to starting the warfarin. The earlier I get the
warfarin dose in the more time I have between the dose and INR value the
next day, and thus better data to estimate the next dose.
I hope this helps address some of your questions.
William Dager, Pharm.D. FCSHP
Coordinator, Pharmacokinetics Consult Service
University of California, Davis Medical Center
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From: "Robert D. Phair, Ph.D."
To: "'PharmPK.-at-.pharm.cpb.uokhsc.edu'"
Subject: RE: What should we call the amount of a drug that reaches its target
Date: Wed, 9 Jul 1997 16:27:45 -0400
MIME-Version: 1.0
Walter-
I am impressed with the technology of pharmacokinetic imaging. I think it
speaks to the power of imaging to move beyond static pictures and reach for
dynamics. But unless you can distinguish among interstitial,
receptor-bound, internalized endosomal, lysosomal, cytosolic, nuclear and
organellar, it seems premature to attach an acronym such as BTS to your
noninvasive measurement. I would imagine your signal will often be a linear
or nonlinear combination of drug concentrations at these various sites.
Moreover, since the mechanism of action is not always known, it can be very
difficult to know with certainty which clearly defined spatial site is the
key one.
This is not to minimize the importance of your approach. I have followed
your posts on this subject with great interest. But from the point of view
of a physiological modeler, and a cell physiologist, it seems to me that
you should simply name your signal, [drug]_location, where _location is a
subscript identifying your "clearly defined spatial site".
You cannot be certain that this is the "target" or even the physical
location of the "target", but you *can* be sure that your measurement is
much *closer* to the target than is plasma, and for that reason alone it
makes a valuable contribution. Your approach will, of course, require
kinetic models that are substantially more complicated than classical PK,
but this is surely the wave of the future. Many people are excited about
Dedrick-descended PB-PK models, and data sets like yours will be essential
if we are to identify the parameters of many such models.
Just the thoughts of a cell physiologist/kineticist, but I am convinced
that the disciplines of PK/PD, PB-PK, and physiological modeling are about
to converge and synergize. That's why I subscribe to David's list.
Regards,
Bob
----------
Robert D. Phair, Ph.D. rphair.at.bioinformaticsservices.com
BioInformatics Services http://www.bioinformaticsservices.com
Partnering and Outsourcing for Computational Biology
-
From: "Gentry, Tom"
To: "PharmPK.aaa.pharm.cpb.uokhsc.edu"
Cc: "'Conolly, Rory'",
"Lands, William"
,
"'Nick Holford'"
,
"'Plapp, Bryce'"
Subject: RE: What should we call the amount of a drug that reaches its target
Date: Wed, 9 Jul 1997 16:52:19 -0400
Encoding: 115 TEXT
Dear Dr. Walter Wolf,
With an interest in the "bioavailability" of a drug with multiple sites
of action (ethyl alcohol) I appreciate the significance of your question,
and would like to hear the result of your Email inquiry. While I have used
"bioavailability" to refer to the proportion of an oral dose which reaches
systemic circulation, I readily acknowledge this would be irrelevant for
some important sites of alcohol's action, such as the stomach and the
liver.
I'd suggest that when we intend to refer to the biological action at a
certain site, we use the appropriate adjective. Thus, the "gastric
bioavailability", "hepatic bioavailability", and "CNS bioavailability", may
very well be different. Then the term "systemic availability", or simply
availability* can be used for the fraction of an oral dose that reaches
systemic circulation, reserving the prefix bio- for the implication of a
biological action.
* Please note the use of "availability" in the first column of the
60-page Table of Pharmacokinetic Data toward the back of G&G.
In any case, I'd like to know what you hear from our colleagues, and
would join in whatever consensus you come up with.
Sincerely yours,
Tom Gentry
======================================================R. Thomas Gentry
NIAAA / NIH
Willco Bldg., Suite 400, 6000 Executive Blvd.
Bethesda, MD, 20892-7003
tel. 301-443-6009 fax. 301-443-7043
Email: tgentry.at.willco.niaaa.nih.gov
=====================================================------------------------------
Date: 10 Jul 1997 08:08:08 EST
From: "Vladimir Piotrovskij"
Subject: What should we call the amount of a drug that reaches its target
To: wwolfw.aaa.hsc.usc.edu
Cc: PharmPK.-a-.pharm.cpb.uokhsc.edu
Comment: MEMO 07/10/97 08:06:00
Dear Dr. Wolf,
Why do you think you need a new term? "The amount of a drug that
becomes available at the target site" is OK if you mean "amount".
"Bioavailability at the target site" is something different since the
term "bioavailability" usually refers to the fraction, not to the
amount itself. "Drug exposure at the target site" seems also not
appropriate as "exposure" always implies a time factor (AUC, etc.)
--------
Vladimir Piotrovsky, Ph.D. Fax: +32-14-605834
Janssen Research Foundation Email: vpiotrov.at.janbe.jnj.com
Clinical Pharmacokinetics vpiotrov.aaa.janbelc1.ssw.jnj.com
B-2340 Beerse
Belgium
To: PharmPK.aaa.pharm.cpb.uokhsc.eduBack to the Top
Mime-Version: 1.0
Dear Dr. Wolf:
In my opinion, bioavailability would be an incorrect term to use. I believe
the etymology of the term Bioavailability is from the descriptive phrase,
biological availability of the drug for pharmacological action; usually the
amount of drug reaching systemic circulation, that is, not still bound
within the dosage form matrix, or released at a site in the GI tract where
it will not be absorbed. In non-systemic acting drugs, such as
sucralfate, the absorption phase is not a part of the bioavailability
equation. But bioavailability is still the term used to define the amount of
drug released from the dosage form, and that is available for action.
In my mind, for systemic acting drugs, the term bioavailable differentiates
between the amount of drug that is and is not absorbed. You wish to
differentiate between the amount of bioavailable drug that actually
reaches the site of action, or does not (ie not bound to plasma protein or
deactivated in some way). Is this not the biologically active amount?
Would the term "Bioactive" be appropriate. It would seem to be a logical
extension of the "bioavailable" concept. In the case of sucralfate,
bioavailability would be determined by measuring the "Bioactive" amount.
Perhaps a new, well defined term for your purposes, and a new
definition of bioavailable would be the best solution to your problem.
Regards
Peter Gingras
pgingras.-a-.apotex.ca
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Dear Dr. Wolf:
The term "bioavailability" seems to be imprecise and often misused. To
avoid any misunderstanding, in my own publications (on PBPK/PD
modeling applied to environmental/occupational scenarios), I use terms
"DELIVERED DOSE" or "DELIVERED LOCAL CONCENTRATION", as
opposed to "exposure dose" or "exposure concentration".
Physiologically based pharmacokinetic/pharmacodynamic models allow
us to define the delivered local concentration and verify it experimentally
(expressed per kg of some particular internal organ, expressed per L of
venous blood equilibrated with and leaving the internal organ, expressed
per L of cytosol, etc.) Moreover, for xenobiotics bioactivated by the
particular organ (e.g., the liver) essential is the "AMOUNT METABOLIZED
OVER TIME" rather than the concentration.
I hope, this will help you.
Sincerely,
Dr. Janusz Z. Byczkowski
Janusz Z. Byczkowski, Ph.D., D.Sc.
Project Scientist and Study Director,
Toxic Hazards Research,
ManTech Environmental Technology, Inc.
Dayton, OH 45437-0009
Phone/voice mail (937)255-5150 ext. 3121
E-mail: ByczkowskiJ.-a-.falcon.al.wpafb.af.mil
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Dear Dr Wolf,
We are reading the discussion on "What shall we call....." with great interest.
I agree with Tom Gentry that one estimate of tissue concentration can
hardly be called
"bioavailability" even though it does show the maximum amount of drug
available to the
tissue at that point. Perhaps we need a term less used for a quantity
available over time such
as "biopresence". This avoids the problem that we do not know how much of
it is actually
active, which to my mind makes the term bioactive, suggested by Peter
Gingras a little too
ambitious.
If your system can assess the concentration in plasma or blood as well as
tissue, there would
be another interesting concept to name, ie; the gradient or difference
between them.
Presumably there will be a negative gradient before Cmax plasma and a
positive gradient
afterwards. The point of zero gradient would be an interesting one to work
with and could
become a new way of defining the speed of bioavaialbilty from different
formulations of
drugs or the constancy of sustained release formulations.
Andrew Sutton.
ASutton.aaa.gcpl.co.uk.
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I have only recently read your inquiry asking what to name the amount of
drug that reaches the target site. I have a suggestion based upon
terminology that was introduced about 25 years ago. Why not use a form of
the term "biophase". The biophase was used to define the anatomical
location of the site of action. It usually was used in reference to a
pharmacological response or a receptor response whose actual location was
vague. With regard to your work, the target site could be referred to as
the "biophase" and "biophasic imaging" could refer to the technic.
"Biophasic concentration" would refer to the amount or conc. of drug at the
target site.
Ron Schoenwald
Professor, Pharmaceutics Division
The University of Iowa
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Ron:
The problem with using established terms to define a novel concept is that
people already have pre-determined ideas/definition and usages for that term.
Hence the -irritating- issue of "perfusion" and "blood-flow" that occurs
when discussing how antineoplastic drugs reach a solid tumor. Perfusion and
blood-flow are commonly used by basic researcher of many fields and
clinicians alike. Depending on each individuals background and interests
these words are used and misused.
Although I like the idea of biophase, particularly because it is established
and used in pharmacokinetic texts (e.g. Handbook of basic PK, by Ritschel) I
think an slight variation of it might be more appropriate.
Sadly I myself have been dealing with this issue exposed by Dr. Wolf for the
last few weeks with no clear suggestion.
Maybe someone else in this discussion group can provide ideas? Maybe we can
borrow concepts or language from other fields besides pure pk?
Alfredo R. Sancho,
USC PK Imaging Ctr.
Los Angeles, CA
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Dr. Wolf:
As a followup from all the accumulated emails on the issue of "What to
call..." First let me address the original two terms, followed by my
suggestion. Of course I am throwing a piece of meat to the lions den,
hopefully to stimulate discussion and a favorable and agreable outcome.
1) Bioavailabilty at the target site.
-- What level of the target site is this term referring to? Which method of
noninvasiveness is being used will preclude the level at which the
measurement is done. As you all are aware different methods of noninvasive
pk imaging provide slightly different information, e.g. NMR spectroscopy give
exquisite chemical information, while nuclear medicine give fine-tuned
spatial location.
-- Bioavailabity is a commonly used term within the pk group and it seems to
have slightly different meaning, leading to discordance. Moreover, from a
commoner's point of view, just because the drug is available it does not mean
it will be absorbed or used at the target site, particularly if the
bioavailability measurement was done from a systemic site (plasma).
-- The argument mentioned in favor of bioavailability that steady state will
be reached between the systemic plasma level and the drug levels within the
various tissues, hence the systemic levels being a clear representation of
the tissue levels does not always apply. Specifically, in the case of solid
tumors in which these tissues do not behave as any one single tissue found in
the body. Solid tumors have their own unique pathophysiological parameters
controlling what occurs within them, therefore a steady state may never truly
be reached for the tumors are bio-systems in constant flux, more so than any
other tissue in the body. Hence why chemotherapy is used, taking advantage of
the metabolic rate of the tumor and the surrounding tissues.
2) Drug Exposure at Target site.
-- To which fraction or species of the administeered drug is this term
referring to? Active, semi-active or innnactive fractions? You may find all
three or even more species at the target site, but which one is the one this
term is referring to?
-- What time frame or time point is the term referring to? Exposure is an
accumulative concepts, therefore is this term referring to all the drug that
reached the target, or only at it peak concentration or at a particular time
point?
----------------
About my suggestion... I conquer with most of the responders, the term has to
match the novel conept of noninvasiveness while still obtaining the necessary
functional and temporal information needed to formulate a PK model and
understanding to the drug behaviour and disposition within the body.
My suggestion is; Functional Target Drug Level
My reasoning is the following:
1) The word FUNCTIONAL due to that the drug measured at the target site is in
not only that of the effective species, it may be bound to proteins (low and
high molecular) or it may be "captured" by extracellular components. In
either case, all of these species will be at the target site as well as
elsewhere in the body. By using this term I try to inform the reader that
the measurement was done at the target site or region of interest, to a
certain level of accuracy and the drug measured included but not exclusively
the effective drug -free- as well as other species that may still be
effective.
2) The word LEVEL is not accumulative as "exposure" may be understood. It
also retains the temporal aspect while not limiting to a particular time span
nor a time point. It could include the drug concentration over a period of
time, it could include also the drug concentration at a peak -time or amount-
or it could even denote the amount of drug needed to obtain a response (e.g.
a threshold).
3) Althogh I was inclined to use the word biophase I ended up using TARGET.
Reason being that although biophase precisely denote the site of action of a
drug, not all drug mechanisms are understood or are clear. Target may be a
bit vague to some, it clearly states that it is the region of interest, which
is defined by the protocol of the study or the drug dosage.
4) Both "Drug Exposure" and "Bioavailability" denote a idea of rate and
level. Unless the observation of the biosystem is done in a temporal manner
(several consecutive time points) a rate term can not be used. The difference
between the systemic measurement and the target site drug levels is not
sufficient to justify creating a term that means rate. For within a target
site there are other factors influencing minute rate functions of metabolic
processes determining the fate of drug molecules. Moreover, when working
with trace doages or MTD's the metabolic processes may behave differently
then when given normal dose, e.g. due to saturabel compartments. Hence, a
single trace dose may provide only information as to did or did not the drug
reach the target site.
5) In lieu of functional, effective has been suggested. Unless the
noninvasive methodology used allows for chemical information of the the drug,
this word can not be used. Moreover, sometimes the mechanism of entrance of
the drug or the drugs mechanism of action are not always clearly understood.
Therefore how can the word effective be used when what and where exactly is
it referring to?
I hope this help either clear the issue or make the water muddier. In either
case I hope it is food for thought.
Alfredo R. Sancho,
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Dear colleagues,
As technology enables us, increasingly, to characterize the rate and extent
of drug appearance at the site of action, terminology (increasingly) must
keep pace. Obviously, the term "bioavailability" is no longer adequate.
Professor Wolf's alternative -- "bioavailability at the target site -- is
plausible, perhaps more so than "drug exposure at the target site", as long
as we are careful to differentiate between the rate and extent of drug
appearance at the target site. Just as the classical term
"bioavailability" is somewhat abstract and vague unless (1) defined in both
differential ("rate") and integral ("extent") ways; and (2) defined in
terms of the applicable reference value or context, we must also ensure
that these concerns are addressed in whatever newer terminology is promoted.
I am also concerned about the further misuse of the word "level" in this
context just as I have objected to its use in classical pharmacokinetics.
"Level" implies or connotes a plateau or constant concentration. When one
is concerned with molecules (primarily endogenous ones) maintained at a
relatively constant level by some homeostatic process, that may be
acceptable. But most xenobiotics are not maintained at a plateau or
constant concentration in fluids or tissues unless the delivery system or
formulation intervenes, i.e. when a zero-order delivery system (e.g.
constant rate i.v. infusion pump; ALZET=81 osmotic delivery system) is used.
When concentration varies with time, "level" won't do! This is a misnomer
that has been allowed to persist in the literature in spite of its
erroneous connotations. It was one thing for clinicians, in the past, to
speak of homeostatically-maintained levels of some endogenous species --
even there, "levels" are not necessarily appropriate any longer. It was
another thing to apply that terminology to xenobiotics (which are not
subject to physiologic regulation) or to endogenous compounds administered
in dosage forms or delivery systems...
Lawrence H. Block, Ph.D.
Professor of Pharmaceutics and Chair
Department of Medicinal Chemistry and
Pharmaceutics
Mylan School of Pharmacy
Duquesne University
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