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I am seeking information concerning theophylline
clearance (population kinetics). I am building a kinetic module
for use at the hospital I work. Any information would be
greatly appreciated.
Thank You,
Doug Kidder R.Ph.
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Their are several factors that can influence the calculation of a
patients theophylline clearance in clinical practice. Drug interactions
can have abrupt (ie cimetidine after 24 hours) or delayed (e-mycin,
starting or stopping tobacco) onset. Factors such as liver disease or
heart failure depend on the severity and presence of symptoms. This can
some times change on a daily basis. If the patient received a flu
vaccination or has been recently under or over compliant (Some patients
will double up prior to arriving to the ER to avoid being tubed). Severe
COPD/Asthma requiring ventilation may depend on the presence of PEEP
>10mmhg (or presence of autoPEEP)(decreased cardiac output secondary to
depressed venous return) or changes in ABG's.
Infusion rates (was the rate equivalent to the total amount givin in the
past 24 hours) due to incompatibilities or administration error. Time of
level draw and the method used, especially if not at steady-state,
to calculate the clearance can also influence your predictions (ie Koup
vs Chu vs PK Bayesian software).
I hope this gives you a starting point and some things to consider. Feel
free to contact me if you have any questions.
William Dager, Pharm.D.,FCSHP
Coordinator, Pharmacokinetic Consult Service
UC Davis Medical Center
e-mail: wedager.at.ucdavis.edu
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Due to the many factors which affect theophylline clearance, it is very
difficult to develop a population model which can include all cofactors and
accurate predict the effect of each cofactor on theophylline clearance. The
best method is to just measure a serum concentration. However, numerous
articles are published on the effect of various factors on theophylline
clearance. They are:
Jusko WJ, et al. Factors affecting theophylline clearances: Age, tobacco,
marijuana, cirrhosis, congestive heart failure, obesity, oral contraceptives,
benzodiazepine, barbiturates, and ethanol. J Pharm Sci 1979; 68 (11):
1358-66.
This article is widely quoted and used in development of several already
available pharmacokinetic dosing software programs.
Reigelman S., et al. Factors affecting the pharmacokinetics of theophylline.
Eur J Respir Dis. 1980; 61 (Suppl 109): 67-82.
Richer M, et al. Hypoxia, arterial pH and theophylline disposition. Clin
Pharmacokinet. 1993; 25: 283-99.
How well do these models work?
Casner PR, et al. A randomized controlled trial of computerized
pharmacokinetics theophylline dosing versus empiric physician dosing. Clin
Pharmacol Ther. 1993; 53: 684-90.
My experience with a similar unpublished study was the same; a population
kinetic model combined with dosage individualization based on serum
concentrations does not improve outcome of patients receiving theophylline as
measured by length of hospitalization and toxicity.
There are numerous studies in the literature on population theophylline
pharmacokinetics, primarily in the late 1970's and 1980's. Good luck!!
-------
Date: Wed, 7 Feb 1996 11:28:27 -0600
From: "John E. Murphy, Pharm.D."
Subject: Creatinine Clearance
It seems to me that any estimate of renal function without age in the
equation would discount the fairly well established effect of age on
renal function. You might wish to focus on studies that have
measured creatinine clearance and a drugs clearance and separated out
the age factor in that manner. That is, is there any difference in
clearance of a drug in a 20 year old and an 80 year old who both have
measured creatinine clearance of 90 ml/min? I know there are such
studies but don't have them readily available.
John E. Murphy, Pharm.D.
Professor and Head
Department of Pharmacy Practice and Science
(520) 626-5730 (P), (520) 626-7355 (FAX)
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We have experience with a population based Bayesian forecasting model that
does a pretty good job taking in to account the various factors that alter
theophyllne clearance. The advantage of using this type of model is that
it utilizes available serum concentrations as well as population data. In
the absence of serum concentration data, it gives a very good first estimate
of the likely clearance value.
Art Harralson, Pharm.D., BCPS
Professor and Vice-Chairman
University of the Pacific
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Applied Pharmacokinetics, (Evans, Schentag, and Jusko, eds.) has a very
complete compilation of theophylline pharmacokinetic values in various
populations. The tables are all completely referenced so you can review
the original literature and make up your own mind. The discussion of
various parameters in the text is also interesting.
Art Harralson
Professor and Vice-Chairman
University of the Pacific
School of Pharmacy
AHARRALSON.at.UOP.edu
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Dear Doug,
From the sound of your question, the responses youv'e gotten our pretty
abstract. I, too, am a pharmacist in a hospital which routinely screens all
patients on theo for estimated levels and confirm them via actual levels.
we use very simple equations to determine estimates because like most
hospitals we have a lot of patients. This simple strait forward estimate may
be used if you like:
1. estimate Clearance in L/hr by:
using Ideal Body Wt x .05 x disease states
Here you'd factor in specific disease adjustments
examples: asthma = 1.0 smokers use 1.4 see applied therapeutics for a
complete list of factors associated w/variation in theophylline elimination.
2. Next calculate Vd using ABW * 0.5
3. Knowing the relationship b/w VD and cl we can
determine t 1/2 = vd/cl * 0.693 (usu 8hrs)
4. estimate Cpss using:
Cpss = (dose/24hr) divided by CL = mg/l
Hope this is what your after. It's fairly accurate and quick. Applied
therapeutics also discusses expected changes in levels when certain drugs
which interfere w/clearance are added.
Anna
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