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I was wondering if anyone has or knows of any useful references
discussing or studying the effects of sepsis/septic shock on
pharmacokinetics (animal models or human subjects). I would also
appreciate any other thoughtful coments.
Many thanks in advance.
Regards
Hussain Mulla
Snr Clinical Pharmacist/Research Associate Glenfield Hospital
England
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Dear Hussain Mulla:
It is generally known that patients with sepsis have larger volumes of
distribution for aminoglycosides that do general medical patients. Some
years ago, Marcus Haug, Pharm.D., at the Cleveland Clinic, and Peter
Slugg, M.D., noted that patients' Vds would get smaller - they called it
"Vd collapse", and showed that this occurs in patients who are getting
well. You can contact Dr. Haug there at 216-444-4302.
In 1991, through the courtesy of Evan Begg, M.D., in the Division of
Cliniical Pharmacology at Christchurch Hospital, New Zealand, we were
able to study a patient with a pyelonephritis who had appeared to be
doing well on tobramycin for about 6 days, and who then relapsed and
went into septic shock, and had a very eventful subsequent 3 weeks
before she recovered and was able to go home. Before the relapse, her Vd
was .19 L.kg. After, it was .55 L/kg. After recovery, it had come down
to about .2 L/kg again. All this shows that it is not just some
literature finding, but that individual patients themselves undergo such
changes.
Most methods for fitting data to date use the assumption that there is
one fixed set of parameter values that best fits the data. However, the
above patient has stimulated our group to develop tools to detect such
changes in parameter values when they are unsuspected, and when they
take place during the period of the data analysis. David Bayard has
implemented a sequential Interacting Multiple Model Bayesian approach to
do this. He presented this at the Society for Computer Simulation
meetings in Dan Diego about 2 years ago, and has validated it with
careful simulations of clinical scenarios in which such changes in
parameter values take place. His IMM method tracks the simulated changes
in behavior of a drug with about half the error of conventional maximum
aposteriori probability Bayesian methods of standard multiple model
Bayesian posteriors.
We have now incorporated this method into pour new multiple model
MM-USC*PACK software for planning, monitoring, and adjusting drug dosage
regimens for patients. We have beta versions of it now available for
evaluation by those who are interested. You can download these beta
versions from our web site www.lapk.org. We think this new software,
which also develops dosage regimens specifically to hit desired
therapeutic targets with maximum precision, will be a further step
forward in optimizing therapy for patients who must receive precise
dosage regimens of potentially toxic drugs.
Very best regards,
Roger Jelliffe
Roger W. Jelliffe, M.D. Professor of Medicine, USC USC Laboratory of
Applied Pharmacokinetics 2250 Alcazar St, Los Angeles CA 90033, USA
email= jelliffe.at.hsc.usc.edu Our
web site= http://www.usc.edu/hsc/lab_apk
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A poster covering some PK/PD data for LY315920 were presented at the
American Thoracic Society in 2001. See the abstract in the April 2001
supplement of Am J Respiratory and Crit Care Med. vol 163.
Inhibition of Secretory Phospholipase A2 by LY315920/S5920: Implications
for Sepsis-Related Multiple Organ Failure S. T. Forgue, J. Geiser, R.
Dean, B.P. Smith, D. Radtke, N. Farid, E. Abraham and W. Macias
S. Thomas Forgue, Ph.D., Senior Research Scientist Global PK/PD and
Trial Simulation
Eli Lilly & Company
550 North University Boulevard
Indianapolis IN 46202
317.277.7991 S.T.FORGUE.at.LILLY.COM
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Dear Roger,
Your observations are in a very good agreement with the data
reported by Mackowiak [Mackowiak, PA. Influence of fever on
pharmacokinetics and pharmacodynamics. In: Fever: Basic mechanisms and
menagement, (ed. P. Mackowiak), Raven Press, NY, 1991, pp.341-351]. I
have 2 questions: 1. Are there changes in clearance term of the drug
under consideration?, and 2. Are there some peculiarities depending upon
pathogens' biology, e.g. G(-) or G(+) and ana- or aerobic strains?
All the best,
Dim
Dimiter Terziivanov, MD,PhD,DSc, Professor Clinic for Therapeutics and
Clinical
Pharmacology, Univ Hosp "St. I.Rilsky",
15 D. Nestorov st, 1431 Sofia, Bulgaria
e-mal: terziiv.-a-.yahoo.com
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Dear Dim:
Thanks for your note, and the reference: I will look for it. Yes, there
are probably changes in clearance as well[?], as there are also changes
in the Kslope with aminoglycosides, or with our patient, at any rate.
Thanks so much,
Roger
Roger W. Jelliffe, M.D. Professor of Medicine, USC USC Laboratory of
Applied Pharmacokinetics 2250 Alcazar St, Los Angeles CA 90033, USA
email= jelliffe.at.hsc.usc.edu Our
web site= http://www.lapk.org
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)