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To all,
Unfortunately, the free online journal "Journal of Pharmacy &
Pharmaceutical Sciences" is not read by a good deal of the PK
community. When I posted information on a publication of mine on
"flip-flop" pharmacokinetics, I had about 100 reprint requests.
"Flip-flop" kinetics is a very important subject, since any drug which
is suitable for formulation into a SR product, where the SR product is
a good one, exhibits flip-flop kinetics (essentially a system where
absorption is rate-limiting). In flip-flop models, the plasma
concentration-time curve is proportional to rate of absorption. It's
that simple! You don't need expensive absorption rate programs (one of
which has an internal algorithm simultaneously solving 19 differential
equations) to analyze your data. Just look at it, and think about it.
I often use the phrase "visual inspection of the data indicates ...,"
and interestingly, no one has complained yet. The art of looking at
data, and figuring out just what is going on, is becoming a lost art.
With the advent of fast and inexpensive PK data analysis programs, the
temptation is simply to calculate parameters and transcribe them to
hyperspace and/or paper documents, without "ensouling" the data or the
parameters into a"synthesis of thought."
A "synthesis of thought" is a short, pithy statement characterizingany
system. For example, here is one synthesis of thought: although about
50% of marketed drugs exhibit some form of nonlinear pharmacokinetics,
the degree of nonlinearity is unimportant, and treating the drug as
thought it exhibited linear kinetics will often suffice for clinical
purposes.
Please find below a hyperlink to anotherarticle of mine which deals
withthe in vivo determination of Ki values. Or, if it does not work,
write me for a copy [Not to the list please - db].
http://www.ualberta.ca/~csps/JPPS2(2)/H.Boxenbaum3/Cytochrome-
Boxenbaum.pdf
The original methodwas developed by Rowland and Matin decades ago,
butalas, it was too far ahead of its times.
A few years ago, mibefradil (Posicor/Roche) came onto the market. When
combined with certain statin cholesterol lowering drugs, there were
deaths due to statin toxicity. Interestingly, these deaths appeared
only to occur in patients on Mevacor (mevastatin) and Zocor
(simvastatin). Relative to other statin drugs, these are high
clearance. The article on Ki which I wrote, illustrates the dangers of
drug interactions with high clearance drugs. When the metabolism of
high clearance drugs is inhibited, their plasma concentrations increase
to a much greater extent that low clearance drugs. So, you want to
develop new chemical entities (NCEs) with low clearance to get once
daily or once weekly dosing, but also to minimize the dangers of
potential drug metabolism interactions.
So, how do you select a low clearance drug from a library of hundreds
or thousands. Easy -- I like the ones with very high protein binding.
These are likely to be low clearance drugs. Extrapolating from
microsomal incubate half-lives (per Pfizer and others) and allometric
methods (per Boxenbaum, Mahmood, etc.) can be useful, but tend to be
too unreliable. And, how many drugs with 99% or higher plasma protein
binding do you know that are not low clearance? Some call this
simplistic, but maybe it qualifies for another synthesis of thought:
drugs which are highly, reversiblyprotein bound (greater than 99%)
will tend to be low clearance drugs, suitable for once daily or less
frequent administration (assuming intact drug activity only). And,
contrary to the thinking of some, these drugs are less likely to have
clinically significant drug metabolism interactions. Drug displacement
from plasma proteins for low clearance drugs is almost always without
clinical consequence. And please, do not cite warfarin-phenybutazone,
since the mechanism of this interaction is phenylbutazone's inhibition
of S-warfarin metabolism. If S-warfarin were a high clearance drug
(and not the low clearance drug it is), this drug interaction would be
much worse.
As an old-timer, I long for the old days when we had to plot our data
by hand, think about it, understand it, etc. Today, too many of us
(especially the CROs)employ the easy way out.Knock out the
parameterusingfast NCA program modules, dobioequivalence
testing(regardless of the nature of the study, e.g., looking for
"bioequivalence" of PK parameters in normal vs. hepatic failure
subjects), and get it out quickly.The current trendof prostituting
statistics into theservice of PK data analysis is the CRO leitmotif of
our times, where laziness of real thinking is subjugated tothe making
of a quick buck.
I personally identify with Einstein in the 4 quotes below:
In Faraday's day, there did not yet exist the dull specialization that
stares with self‑conceit through hornrimmed glasses and destroys
poetry.
Everything should be made as simple as possible, but not simpler.
Beware of trying to understand the whole by the arbitrary isolation of
the separate components or by hazy or forced abstractions.
Perfection of means and confusion of goals seem ‑ in my opinion ‑ to
characterize our age.
Best wishes. Harold.
Harold Boxenbaum, Ph.D.
Pharmaceutical Consultant
Arishel Inc.
14621 Settlers Landing Way
North Potomac, MD 20878-4305
(P) 301-424-2806
(F) 301-424-8563
Emails: harold.aaa.arishel.com
Website: www.arishel.com
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At 02:51 PM 6/19/2003, Harold Boxenbaum wrote:
"You don't need expensive absorption rate programs (one of
which has an internal algorithm simultaneously solving 19 differential
equations) to analyze your data. Just look at it, and think about it.
I often use the phrase "visual inspection of the data indicates ...,"
and interestingly, no one has complained yet."
I wholeheartedly agree with the concept of standing back and looking at
the big picture.
And I agree that you don't need 19 differential equations. We use
nearly 90.
There are some problems that yield to eyeball pharmacokinetics. But
there are many that do not. To assume that the top scientists around
the world who use sophisticated tools are simply lazy or perhaps naive
is wrong.
I have had the opportunity to visit most of the major and medium-size
research centers in the world over the past 6 years. I have worked
closely in problem-solving sessions where such things as active
transport (influx or efflux), regionally dependent solubility and/or
permeability, precipitation, etc. were the underlying mechanisms
involved in producing data that does not yield to eyeball
pharmacokinetics. I don't care how good someone is, there are certain
problems that cannot be solved by hand plotting the data and scratching
your head (and there are some than can). Having worked with some of the
sharpest scientists in the world, I can tell you that the really good
ones always stand back and consider the big picture. And they use
sophisticated tools as well when appropriate.
To imply that all pharmacokinetics and absorption problems can be
solved with eyeball pharmacokinetics is naive. To deny the usefulness
of state-of-the-art tools is a sign of "old-timer" syndrome. (I'm an
old-timer, too, but I try to avoid the syndrome!)
So let's advocate the proper use of tools, methods, and critical
thinking skills, and avoid bashing approaches that may be different
than what we would use or understand.
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (SIMU)
1220 W. Avenue J
Lancaster, CA 93534-2902
U.S.A.
http://www.simulations-plus.com
Phone: (661) 723-7723
FAX: (661) 723-5524
E-mail: walt.at.simulations-plus.com
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The following message was posted to: PharmPK
There is a term that I really like (and may use some day - the term
that is)
- "eyeball pharmacokinetics". It is somewhat illogical to me to take a
science based on math and chemistry and subject it to eyeball
examination -
troubleshooting problems maybe but not providing data and conclusions.
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The following message was posted to: PharmPK
There is nothing wrong in "Eyeball examination" of Pharmacokinetics, you
can't simply throw the numbers in a computer, take whatever output you
get
and submit the output. We do double blind studies but we don't submit
blind
data.
Cheers.
Prasad NV Tata, M.Pharm., Ph.D.
Manager-Pharmacokinetics
Mallinckrodt, Inc.
675 McDonnell Blvd.
Saint Louis, MO 63134-5840
Tel: (314) 654-5325
Fax: (314) 654-9325
e-mail: prasad.tata.aaa.tycohealthcare.com
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At 07:51 AM 6/26/2003, Tata, Prasad N wrote:
There is nothing wrong in "Eyeball examination" of Pharmacokinetics, you
can't simply throw the numbers in a computer, take whatever output you
get
and submit the output. We do double blind studies but we don't submit
blind
data.
Of course, and that's exactly what I said. One should always stand back
and look at the big picture. But to think that all problems can be
solved that way is naive.
Is a double blind study one where you use eyeball pharmacokinetics
twice - once with each eye covered? : )
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (SIMU)
1220 W. Avenue J
Lancaster, CA 93534-2902
U.S.A.
http://www.simulations-plus.com
Phone: (661) 723-7723
FAX: (661) 723-5524
E-mail: walt.at.simulations-plus.com
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The following message was posted to: PharmPK
Dear All
I believe this getting too much beyond limits.
I firmly believe no approach towards achieving basic goals of
studying pharmacokinetics is complete in itself.
Basically we should not forget why are we doing all this - writing
complex models, complex computer programs, advocation for and
against them, dosing volunteers, taking pains to do bioanalytical
work.
So period my dear frinds.
I hope my request is clear.
with regards
Prashant
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)