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Dear all,
I am currently working on a study involving the administration of a
muscle relaxant using a target controlled infusion device (1). There
are two groups (say A and B, each with there own set of rate
constants). The target concentration is set at 2 ng/ml. I understand
classical pharmacokinetic modeling is not appropriate when a
TCI-device is used.
I am particularly interested in calculating the fast and slow
distribution half-lives. My preliminary idea was to calculate the
average time (and infusion rate) upto the moment the target
concentration is reached, and calculating the average time (and
infusion rate) until the end of infusion. Using these two calculated
times (and infusion rates), I wonder if classical PK modeling may
still be applied:
using the plasma concentration data calculated by the TCI-device and
these calculated times and infusion rates, a classical PK model may be
used to calculate the elimination rate constants and thus the
(theoretical) half-values. Is there a reason why this would be
incorrect?
If you have other suggestions, please let me know.
Kind regards,
Reynaldo Martina
r.martina.-at-.teknika.btl.akzonobel.nl
(1) STANPUMP
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[Two replies - db]
From: "Hans Proost"
Organization: Pharmacy Dept Groningen University
To: r.martina.aaa.teknika.btl.akzonobel.nl, PharmPK.-at-.pharm.cpb.uokhsc.edu
Date: Mon, 15 Mar 1999 09:17:13 MET
Subject: Re: PharmPK question regarding PK modeling using a TCI devi
X-Confirm-Reading-To: "Hans Proost"
X-pmrqc: 1
Priority: normal
Dear Dr. Martina,
You wrote:
> I am currently working on a study involving the administration of a
> muscle relaxant using a target controlled infusion device (1). There
> are two groups (say A and B, each with there own set of rate
> constants). The target concentration is set at 2 ng/ml. I understand
> classical pharmacokinetic modeling is not appropriate when a
> TCI-device is used.
Classical pharmacokinetic modeling is appropriate when a TCI-device
is used; TCI is based on classical pharmacokinetic modeling!
Of course, you have to take into account the exact dosage regimen
produced by the TCI device.
(Note: I presume that the target concentration was set at 2000 ng/ml;
I am not aware of any muscle relaxant showing activity at 2 ng/ml).
> I am particularly interested in calculating the fast and slow
> distribution half-lives. My preliminary idea was to calculate the
> average time (and infusion rate) upto the moment the target
> concentration is reached, and calculating the average time (and
> infusion rate) until the end of infusion. Using these two calculated
> times (and infusion rates), I wonder if classical PK modeling may
> still be applied:
> using the plasma concentration data calculated by the TCI-device and
> these calculated times and infusion rates, a classical PK model may be
> used to calculate the elimination rate constants and thus the
> (theoretical) half-values. Is there a reason why this would be
> incorrect?
Using average time and average infusion rate would, at best, yield an
estimate of the half-lives. The main problem is that you don't know
whether or not the estimates are reasonably accurate.
> If you have other suggestions, please let me know.
The best method to obtain the distribution and elimination half-lives
is to calculate them directly from the model parameters (i.e. the rate
constants) used for the TCI device . This gives you the 'exact'
half-lives of the model.
Best regards,
Johannes H. Proost
Dept. of Pharmacokinetics and Drug Delivery
University Centre for Pharmacy
Groningen, The Netherlands
tel. 31-50 363 3292
fax 31-50 363 3247
Email: j.h.proost.-a-.farm.rug.nl
---
X-Sender: jelliffe.-at-.hsc.usc.edu
Date: Mon, 15 Mar 1999 09:30:37 -0800
To: PharmPK.-a-.pharm.cpb.uokhsc.edu
From: Roger Jelliffe
Subject: Re: PharmPK question regarding PK modeling using a TCI device
Mime-Version: 1.0
Dear Reynaldo:
I do not understand why you say that classical PK modeling may not be
appropriate when a TCI device is used. You have a desired target
concentration. You wish to design an infusion regimen to achieve and
maintain that target concentration. You will need to use usually a stepwise
constant infusion format, with changing infusion rates during the
distribution phase of the drug, followed by a maintenance rate after that.
You might look at Rodman J et al: Clinical Studies with Computer-Assisted
Initial Lidocaine Therapy, Arch. Int. Med. 144: 703-709, 1984, and Rodman
J: Lidocaine, in Applied Pharmacokinetics, ed by Evans W, Schentag J, and
Jusko W, pp.350-391, 1980, ISBN 0-915486-03-2.
You can use many different programs to calculate the fast and slow
half-lives or rate constsnts. Among others, the iterative 2-stage Bayesian
and the NPEM programs can do this from any type of infusion regimen.
Nonlinear models can also be used if needed. Those models can then be put
into clinical software such as the USC*PACK programs to develop the above
dosage regimens to give to patients. Steve Shafer at Stanford has also used
his Stanpump for just such purposes.
Hope this helps,
Roger Jelliffe
Roger W. Jelliffe, M.D. Professor of Medicine, USC
USC Lab 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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