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I feel that I have to make a couple of points about the pulse dosing of
I take exception to the assertion that the current ODA practice has
no scientific basis and no rational monitoring criteria.
We do not give the same dose to every patient, nor do we use the same
dosing interval. In fact the dosing interval may be much shorter than
what the ODA designation suggests. I have recently summarized these
issues in a short consensus document (see june issue of the
international journal of clinical pharmacology and therapeutics or
It is difficult to understand the sort of scientific evidence t hat
be provided to support the pulse dosing of aminoglycosides. Are we to
make a distinction between evidence derived from clinical trials and
evidence derived from basic science (laboratory / vitro / animal)
research? What constitutes a scientific basis? Dr. Duffull admits that
at the present time there is no evidence to support the need for
AUC-based dosing. In fact he suggests that at some point we should
into " .. whether the AUC is important or not ...". However,
there is plenty of clinical evidence to support the need for a high
peak level to maximize efficacy as well as the need for a drug-free
interval to minimize toxicity.
Associate Prof of Pharmacology and Physiology
University of Rochester Medical Center
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On Thu, 6 Nov 1997 12:04:06 -0600 "Anaizi, Nasr"
> I take exception to the assertion that the current ODA practice has
> no scientific basis and no rational monitoring criteria.
The point I am trying to make about a scientific basis rests on
understanding the difference between a mechanistic understanding
(rational science) and a trial and error (emirical) approach. I
agree that the use of ODA has been triggered by some science e.g.
post-antibiotic effect. But we have only empirical data to show that
ODA has (perhaps) a marginal improvement in the therapeutic index
compared with 8 hourly dosing. Nobody know if every 36 h or every 72
h or even a single dose would be better based on any scientific
understanding of the processes connecting the conc-time profile of an
AG in humans to the subsequent cure of an infection or development of
>. It is difficult to
> understand the sort of scientific evidence t hat must
> be provided to support the pulse dosing of aminoglycosides. Are we
> to make a distinction between evidence derived from clinical trials
> and evidence derived from basic science (laboratory / vitro / animal)
YES! They are quite distinct.
Clinical trials (with design and analysis like those used to compare
ODA with q8h) can offer only empirical confirmation/refutation of a
particular strategy. They do not designed to provide the rationale
for understanding the scientific basis for the true optimum conc
profile for AG use.
Rutherford (a Nobel prize winning New Zealander) once said "Science
is either stamp collecting or physics". Empirical clinical trials are
at the stamp collecting end of science. What is needed are clinical
trials interpreted using PKPD models which can move our knowledge
towards the physics end of the scientific continuum.
"Physics" oriented clinical trials could for instance randomise
patients to very different conc profiles and be analysed by relating
efficacy and toxicity to the *time* course of conc as well as the
conc itself. AUC based methods to understand this issue are doomed to
failure because AUC explicitly remove the shape (time course) of the
profile from the information available to understand what is
Similar comments can be made about optimising treatment of other
schedule dependent drugs e.g. anti-cancer agents.
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, Private Bag 92019, Auckland, New Zealand
email:n.holford.-a-.auckland.ac.nz tel:+64(9)373-7599x6730 fax:373-7556
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Dear Drs. Anaizi and Dear Nick:
About ODA. It is interesting to me to see that what we have learned in
recent years about the apparent need for high peaks and lower troughs has
now been codified into the ODA mind set. Patients with good renal function,
and those with CF, who have really good renal function, are known, I
believe, to require more frequent dosing in order to prevent regrowth, as
the post antibiotic effect is not infinite. Similarly, those with reduced
renal functiojn are known to need even less frequent dosing. Further, high
peaks help prevent emergence of resistance.
What I would like to see is that the attention be paid to the GOALS of
therapy, such as the specific desired peak and trough levels which one
would choose, for EACH patient according to his/her perceived need, and
that the regimen be individualized to best hit these target goals. This is
goal - oriented, model - based individualized therapy. Then we can develop
regimens best adjusted to each patient's needs, not just look for the
single most likely dose interval for most people. I think that is a
scientific approach which is better for patients than simply looking for
something that works most of the time in many patients.
Roger W. Jelliffe, M.D.
USC Lab of Applied Pharmacokinetics
CSC 134-B, 2250 Alcazar St, Los Angeles CA 90033
Phone (213)342-1300, Fax (213)342-1302
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