- On 12 Mar 1999 at 22:45:17, Reynaldo Martina (r.martina.at.teknika.btl.akzonobel.nl) sent the message

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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 - On 19 Mar 1999 at 15:05:36, David_Bourne (david.aaa.pharm.cpb.uokhsc.edu) sent the message

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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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