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Can anyone help please?
A patient over 70 year is taking sustained release theophylline (Neulin
R) 250mg bd orally. She weighs about 60 kilos and her serum creatinine
is normal.
Can we predict her theophylline levels?...are there any equations which
are useful in this situation for sustained relase products? Are blood
level determinations essential in the calculations?
thank you
Janet Mifsud
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[Quite a few replies - db]
Date: Fri, 10 Dec 1999 03:13:57 -0700 (MST)
X-Sender: ml11439.-at-.pop.goodnet.com
To: PharmPK.aaa.boomer.org
From: ml11439.aaa.goodnet.com (Michael J. Leibold)
Subject: Re: PharmPK Theophylline sustained release TDM
Hello Janet,
There are calculations to predict theophylline serum levels in
various patient populations, based on population pharmacokinetic
parameters and standard pharmacokinetic equations.
Population Volume of Distribution Total body Clearance
(L/Kg) (ml/min/kg) L/hr/kg
Adults
Smokers 0.3-0.7 1.2 .072
Nonsmokers 0.3-0.7 0.9 .054**
Congestive Heart
Failure 0.48-1.2 0.36 .0216
Cirrhosis 0.45-0.64 0.36 .0216
** your patient
The above average pharmacokinetic parameter values can be used to
predict serum concentrations in a given patient when provided with
the essential demographics, in this case:
Patient age: 70 years
Patient wt: 60 kg
Nonsmoker?: assume yes
CHF?: assume no
Cirrhosis?: assume no
Dose: 250mg po every 12 hours
The pharmacokinetic formula useful for calculating theophylline
serum levels when using sustained release oral preparations is the
zero order absorption model. The fluctuation in serum levels during
a Q8 or Q12 hour interval with sustained release theophyline preparations
is small enough that little error may be incurred with this method
Css(ave)= [FSD]/[TauCl]
Css(ave)= Average Steady State Serum Concentration
F= fraction absorbed (90%)
S= content of theophylline in salt form (1)
D= dose (250mg)
Tau= dosage interval (12hrs)
Cl= Clearance in liters/hr= .054(60kg)= 3.24 liters/hr
Css(ave)= [(.9)(1)(250mg)]/[(12hrs)(3.24 liters/hr)]=
=*** 5.79 mg/liter ***
Ke= CL/Vd= 3.24 liters/hr/[(.5 L/Kg)(60kg)]= .108 hr-1
T1/2= .693/Ke= 6.42 hours
Time to steady state= 5(T1/2)= 5(6.42)= 32.1 hours
This is low in the therapeutic range of 5-20mg/liter, or ug/ml. Some
patients with asthma respond to serum theophylline concentrations in the
area of 5-10ug/ml, while others require hiher concentrations in the area
of 10-15ug/ml or even up to 20ug/ml. That is, vital capacity and FEV1 may
only increase in a given asthmatic if the serum concentrations are either in
the 5-10ug/ml range or higher.
Serum levels to guide therapy would be advisable due to the
large amount of interpatient varability in pharmacokinetic parameters
as well as in the therapeutic/toxic response to various theophylline
serum levels. In addition, there is a potential for reduced absorption
of sustained release oral theophylline preparations, and there are
numerous drug interactions which can influence theophylline elimination
half-life.
After an estimated 5 t1/2's (32 hours), obtain a trough theophylline
level just before the next scheduled dose. The following equation can
be used to calculate a dose:
Cl= [FSD]/[TauCss(observed)]
D= [(Cl)(Tau)(Css(desired)]/[(FS)]
So, if you were to obtain a theophylline trough of 5ug/ml and you
determine that the patient's FEV1 and vital capacity are not improving,
the Css desired would be 10ug/ml.
Cl= [(0.9)(250mg)/[(12hrs)(5mg/L)]= 3.75 liters/hr
D= [(3.75 L/hr)(12hrs)(10mg/L)]/(0.9)= 500mg q12hrs
Alternatively, is you use the *same oral theophyline product*, and
the *same dosage interval*, the above calculation can be further simplified:
(Dose Desired)= (Dose given)(Css Desired)/(Css observed)
Dose Desired= (250mg)(10/5)=500mg q12hrs
However, if you increase the dose, you should monitor for the adverse
effects of theophylline such as tachycardia, cardiac arrhythmias, tremors,
nausea, vomiting, and seizures.
I hope this is of some help!!
Mike Leibold, PharmD, RPh
ML11439.-a-.goodnet.com
References:
1) Schumacher, G.E., Therapeutic Drug Monitoring, Appleton& Lange,
Norwalk 1995
2) Mungall, D.R., Applied Clincal Pharmacokinetics, Raven Press,
New York 1983
---
Date: Fri, 10 Dec 1999 06:26:01 -0500
From: Nick Holford
X-Accept-Language: en
To: PharmPK.-a-.boomer.org
Subject: Re: PharmPK Theophylline sustained release TDM
Css=RateIn/Clearance
RateIn=500mg/24=20.8 mg/h (assume F=1)
Clearance=60*0.04 L/h/kg=2.4 L/h
Css=20.8/2.4 mg/L=8.7 mg/L
Predicted conc at steady state is about 9 mg/L. This is pretty close
to the target concentration (10 mg/L ) for theophylline. A blood
sample drawn in the middle of the dosing interval should give a conc
that reflects the average steady state conc and could be used to
estimate clearance in this individual and perhaps a dose change might
be warranted. The patient's response to theophylline (benefits and
adverse effects) should be considered as well as the concentration.
--
Nick Holford, Center for Drug Development Science
Georgetown University, 3900 Reservoir Rd NW, DC 20007-2197
email:n.holford.aaa.auckland.ac.nz tel:(202)687-1618 fax:687-0193
http://www.phm.auckland.ac.nz/Staff/NHolford/nholford.htm
---
X-Sender: dkisor.-a-.postoffice.onu.edu
Date: Fri, 10 Dec 1999 07:57:42 -0500
To: PharmPK.-at-.boomer.org
From: "Kisor, David"
Subject: Re: PharmPK Theophylline sustained release TDM
Janet,
There are ways to estimate the average concentration of theophylline, with
many assumptions.
First, if you assume that the sustained release product acts like a
continuous infusion, you can apply the following equation Css = (Ko/CL),
where Css is the average steady state concentration, Ko is the "infusion",
or here, dose rate (250mg/12hr), and CL is the clearance estimate of
theophylline based on population estimates, e.g., here ~0.04 L/hr/kg. Now
this value could be quite different for many reasons in this patient. You
need to consider dominant characteristics, for instance the clearance of
theophylline is increased (~60%) in patients who smoke, related to CYP1A2.
CHF decreases the clearance. There are other factors that effect the
clearance. Renal clearance is minimal for theophylline.
Of course, the patient should be monitored for response and toxicity. If
the response is adequate and toxicity is not an issue, whatever
concentration is present, is fine. If you need to alter the dose for some
reason, and want to have a "feeling" of where things are at on the regimen
you described, then you may apply the "very rough" approach mentioned
above. I suggest you read Applied Pharmacokinetics: Principles of
Therapeutic Drug Monitoring. Evans WE, Schentag JJ, and Jusko WJ eds.,
Chapter 13 by Edwards DJ, Zarowitz BJ, and Slaughter RL.
Dave Kisor
Dave Kisor
Ohio Northern University
College of Pharmacy
---
X-Sender: dkisor.aaa.postoffice.onu.edu
Date: Fri, 10 Dec 1999 08:06:01 -0500
To: PharmPK.at.boomer.org
From: "Kisor, David"
Subject: Re: PharmPK Theophylline sustained release TDM
Janet,
As a follow-up, if you get a blood concentration and have some confidence
that this represents an "average" value, then rearrange the equation, Css =
(Ko/CL) to solve for CL, i.e., CL = (Ko/Css), where Css is your "average"
concentration in this patient. Now that you have the CL calculated in this
patient, you can utilize this value to calculate a new dose rate (Ko), if
needed...Ko = Css desired x CL. The concentration in this individual
should represent the influence of any patient characteristics, e.g., CHF,
smoking, ect., therefore, you do not need to correct for these factors if
you have concentration data from the patient.
Again, there are many assumptions made here, including bioavailability and
the "trueness" of the sustained release product to provide a "zero
order-like" continuous infusion.
DK
Dave Kisor
Ohio Northern University
College of Pharmacy
---
Date: Fri, 10 Dec 1999 08:16:23 -0500
From: Steven Gelone
Reply-To: sgelone.-a-.thunder.ocis.temple.edu
X-Accept-Language: en
To: PharmPK.-a-.boomer.org
Subject: Re: PharmPK Theophylline sustained release TDM
Dear Janet,
The answer to your question is yes. Theophylline is a classic linear
compound at concentration within the therapeutic range. There are a variety
of refernces that would be useful. Here a just a couple.
Winter ME . Basic CLinical Pharmacokinetics. Theophylline chapter pp.
405-445. (Very practical with example problems included).
Bertino JS. Theophylline pp. 553-586. in Schumacher GE. Therapeutic Drug
Monitoring. (very well written and throrough. A good resource).
Best of luck
Steven Gelone, Pharm.D.
Associate Professor of Pharmacy and Medicine
Temple University Schools of Pharmacy and Medicine
Philadlephia, PA 19140
---
X-Sender: jelliffe.-a-.hsc.usc.edu
Date: Fri, 10 Dec 1999 10:36:02 -0800
To: PharmPK.-a-.boomer.org
From: Roger Jelliffe
Subject: Re: PharmPK Theophylline sustained release TDM
Dear Janet:
Dr. Agneta Hurst at our School of Pharmacy has obtained population
parameter values for theophylline, sustained release, from the literature.
We have put these in the USC*PACK programs. The Vd is 0.55 L/kg, the Fa is
0.18 hr-1, and the Ke is 0.079 hr-1. T1/2 is about 8.7 hr. CCr is about 55
ml/min/1.73 SqM.
Using these parameter values, and the above model in the USC*PACK
programs, she reached a steady state after about 4 days, with predicted
peak levels of 8.5 and troughs of 6.7 ug/ml. Of course, one would always
like to
1. Look at the patient and see how she is doing clinically, and
2. Get a serum level, if indicated, and begin to make a Bayesian
individualized model of the behavior of the drug in her. Then you will be
able to
3. Evaluate her cllinical sensitivity to the drug by comparing
her behavior
with that of her individualized model (or with the population predictions
of you do not wish to get a serum level).
4. Decide what target serum level peak wou would wish to achieve, as an
individualized target goal FOR HER,
5. Conmpute the regimen to achieve the goal as precisely as possible.
Does this help?
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
Phone (323)442-1300, fax (323)442-1302, email= jelliffe.aaa.hsc.usc.edu
Our web site= http://www.usc.edu/hsc/lab_apk
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thank you all for your help
janet mifsud
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