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Dear colleague,
We are planning to infuse drug intravenously to maintain three Css
levels (0.1, 0.2, and 0.4 =B5g/ml) in rats. Which is a better or
correct way of doing this from physiological point of view, varying
drug concentration or infusion rate? Thank you for your help and
time.
C. Elinore Lau, Ph.D.
Psychology Department
Rutgers University
New Brunswick, NJ
[If the drug exhibits 'multi-compartment/distribution' kinetics you may
want to consider a fast/slow infusion combination...some simulations might
help - db]
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[A couple of replies - db]
Date: Wed, 5 Aug 1998 12:01:15 +0200 (MET DST)
From: Maria Durisova
To: PharmPK.aaa.pharm.cpb.uokhsc.edu
Subject: Re: PharmPK Re: way of establishing Css
Dear Elinore,
We would recommend to use the procedure A or B:
A.
1. In a pilot experiment, to determine the drug clearance
(Cl) after a single bolus intravenous dose. In the
experiment, the sufficient drug dose and sampling schedule
can be estimated according to the knowledge about the drug
kinetics available in the literature. After that, to
calculate the necessary rate of the infusion (IR) according
to the equation:
IR = Cl. Css,
where Css is the requested steady-state level and
Cl= Dose/AUC.
If time to reach the Css level is rather long, in agreement
with David's comments, you can use the procedure B consisting
of the following steps:
B.
1. In a pilot experiment, to determine the drug
concentration-time profile after a single bolus intravenous
dose, or during and after an intravenous infusion.
2. To identify a model of the system describing the drug fate
in the body on the basis of the drug input and measured
concentration-time profile.
3. Using the system model identified in the second step and
a model of the requested drug concentration-time profile, to
determine the model of the necessary drug input.
Both procedures can be used if the drug kinetics can be
sufficiently approximated by linear models in the dosage
range of your interest.
If you need our help please do not hesitate and contact us.
Good luck,
Maria Durisova
and
Ladislav Dedik
---
Date: Wed, 05 Aug 1998 07:26:15 -0400
From: Nabil B. Darwazeh
To: PharmPK.at.pharm.cpb.uokhsc.edu
Subject: PharmPK Re: way of establishing Css -Reply
Mime-Version: 1.0
varying the infusion rate might introduce large volume of the drug
solution to the blood unless within the limit of the rat system can handle
without changing the rate of renal filtration and / or volume of
distribution. Varying drug concentration to a higher concentrations to
reach Css might introduce some toxicity if the concentration is high
enough to alter the systemic clearance or the biotransformation which
make end up with a non linear kinetics.
Nabil Darwazeh
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Dear Dr. Lau:
Your problem is an interesting one. We dealt with it when we were
developing lidocaine infusion regimens to achieve and maintain desired
target concentrations in patients. This was described by Rodman et al in
Clinical Studies with Computer-Assisted Initial Lidocaine Therapy, in Arch.
Int. Med., 144: 703-709, 1984.
The software to do this has been part of the USC*PACK programs
since then.
You enter your population PK parameter values and store them as a
population PK model. You enter the patient's age, gender, height, weight,
etc. You enter your desired target goal, and the format of the infusion
regimen - that is, the duration of each step of the stepwise changing
infusion regimen. It usually consists of something like a 5 min loading
infusion, followed by, for example, one or two steps of 15 min, then one or
two steps of 30 min, then hourly steps after that. For rats, the infusion
steps would probably be more rapid, something like 1,2,4,8,15, 30 min,
perhaps. You must see. The general idea is the same, for such a drug having
both a central and a preipheral compartment.
The infusion rate to go from the concentration present at the start of
that particular infusion to the desired target value at the end of that
step is computed and shown. We used conventional infusion apparatus for
patients at the time, and also developed smart infusion pumps to do this,
but commercial interest was not present for smart pumps for general medical
uses in 1976, when we first did this.
The software could be used, I believe, to help you develop the types of
infusion regimens you have in mind. We also are having a workshop on the
more general aspects of population PK/PD modeling, which also mught
interest you, on September 22, in San Diego. You can get more information
about it at our web site, which is given below.
Very best regards,
Roger Jelliffe
************************************************
Roger W. Jelliffe, M.D.
USC Lab of Applied Pharmacokinetics
CSC 134-B, 2250 Alcazar St, Los Angeles CA 90033
**Note our new area codes below, since 6/15/98!**
Phone **(NOTE NEW AREA CODE AND PREFIX)** (323)442-1300, Fax (323)442-1302
email=3Djelliffe.-at-.hsc.usc.edu
************************************************
You might also look at our Web page for announcements of
new software and upcoming workshops and events. It is
http://www.usc.edu/hsc/lab_apk/
************************************************
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