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Dear All,
Under what conditions the observed Css for a constant rate infusion
could be underestimated or overestimated from the equation of Css =
Rinf/Cl using the Cl value of a bolus dose exhibited a 2-cpt kinetics.
Thank you very much in advance for all the answers.
C Lau, Ph.D.
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Dr.Lau,
If the Ko/Cl calculation is equavalent to Ko/VbBeta, then
the estimated Css should be close to what is actually observed.
However, if the Cl term is estimated from plasma concentrations
during the distribution phase, then the calculated Css will
underestimate the observed plasma concentrations, since:
Ko/VcAlpha << Ko/VbBeta
VcAlpha >> VbBeta
In contrast, if there is an accumulation phase as in the case
of aminoglycosides, then the Css calculation will underestimate the
observed plasma concentrations at steady state. The difference would
probably not be significant in this later case.
Mike Leibold, PharmD, RPh
ML11439.at.goodnet.com
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If the Cl = Dose/AUC equation is used, both alpha and beta phases are
considered in the clearance calculation.
Nonlinearity in the drug's PK behavior may be one reason for a change in
Cl. If the drug is one of endogenous compounds or almost identical to any
endogenous compounds such as erythropoietin, the drug produced by the body
could interfere with the exogenous drug's PK behavior.
Sometimes, for the drugs eliminated via their pharmacological receptors,
the increase in the receptor population after repeated administration can
change the PK behavior as well as PD, which can cause changes in Cl.
Sunny Chapel, Ph.D. Candidate,
University of Iowa
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Elinore,
Estimations of Css may be under or overestimated for a drug which displays
circadian rhythm changes in Cl, depending on which time of the day the
original Cl value was estimated. Perhaps some others in this group with
experience in circadian changes can comment in more detail?
Bert L. Lum, Pharm.D.
Associate Director, Clinical Trials Office, Room H-3249
Clinical Cancer Center, Mail Code 5225
Stanford University Medical Center
Stanford, CA 94305-5225
Phone: 650-498-4536 Fax: 650-498-4696
E-mail: bert.lum.aaa.stanford.edu Page: 650-723-8222 # 25067
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The following message was posted to: PharmPK To further comment on
the circadian changes and calculating Cl from Css data:
Ceftazidime shows a pronounced circadian rhythm when administered as
a continuous infusion in CF patients. Clearance reduction overnight
with constant drug input may result in increased serum concentrations
(up to 30-40%) in the morning. Therefore, timing of drug
concentration as part of TDM or PK analysis of such renally cleared
drugs can be very critical.
Refs: Vinks et al. Ther Drug Monit 1994; 16:341-48 ; Mouton et al.
Antimicrob Agents Chemother 1997;41:733-8.
Sander Vinks, PharmD, PhD,
Research Professor of Pediatrics
Pharmacology Research Center & Clinical Trials Office
Children's Hospital Medical Center
3333 Burnet Avenue
Cincinnati, Ohio 45229-3039
***************************************************************************
Alexander A. Vinks, PharmD, PhD,
Research Professor of Pediatrics
Pharmacology Research Center & Clinical Trials Office
Children's Hospital Medical Center
3333 Burnet Avenue
Cincinnati, Ohio 45229-3039
Tel: (513) 636-0159; (513) 636-0160 (secretary).
Fax: (513) 636-0168.
CHMCC email: sander.vinks.-at-.chmcc.org
****************************************************************************
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Dear PharmPK Group:
Pascal Maire in Lyon has also shown circadian rhythms with
Amikacin, related to the change in CCr between day and night. It was
in
Bleyzac N, Allard-Latour B, Laffont A, Mouret J, Jelliffe R, and
Maire P: Diurnal Changes in the Pharmacokinetic Behavior of Amikacin.
Therap. Drug Monit. 22: 307-312, 2000.
Hope this helps,
Roger Jelliffe
Roger W. Jelliffe, M.D. Professor of Medicine, USC
USC Laboratory of Applied Pharmacokinetics
2250 Alcazar St, Los Angeles CA 90033, USA
Phone (323)442-1300, fax (323)442-1302, email= jelliffe.at.hsc.usc.edu
Our web site= http://www.usc.edu/hsc/lab_apk
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)