- On 5 Jan 1998 at 12:02:59, "Zutshi, Anup" (zutshi.-a-.BATTELLE.ORG) sent the message

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Greetings

Does anyone have a literature citation on using variable rate IV

infusions (typically a linear accelerated infusion) as a means to

determine dose linearity of a test compound?

Anup Zutshi - On 12 Jan 1998 at 13:25:30, Maria Durisova (exfamadu.at.savba.savba.sk) sent the message

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Dear colleague,

Using the dynamic system approach, the solution of this

problem can be performed according to the procedure

consisting from the following three steps:

1. Definition of the system (1) by the measured input

function I(t) and the measured output function C(t).

2. Calculation of the frequency response of this system

under the conditions:

a) The input function I(t) is represented by any measured

variable rate IV infusion:

I(t) = R(t) for time t from the interval [0, T1]

= 0 for time > T1,

where R(t) is any function, having the value 0 for t<=0 from

below, e.g. the ramp function (to get some information on the

ramp function see e.g.

http://www.astro.virginia.edu/~eww6n/math/),

and T1 is the duration of the infusion.

b) C(t) is the drug concentration time profile. It is

measured in the time interval [0,T2], where T2>T1, and the

residual area under the C(t) profile from the last sampling

point to infinity is less than 10% of the area under the

C(t) profile from time T1 to infinity.

3. Plotting the calculated frequency response in the complex

plane.

According to one of the inherent properties of the linear

dynamic time invariant systems, if the points of the

calculated frequency response of the system under study can

be considered to lie on a continuous curve, the system can

be sufficiently approximated by a linear model (2,1). It

follows then that, the system approach offers the

possibility to answer your question even after one single

dose of the drug.

This procedure can be sufficiently performed using our

software CXT (3,4). CXT requires a fair degree of modeling

expertise in the frequency domain. If you are interested, we

can help you in the evaluation of your data.

Maria Durisova

and

Ladislav Dedik

1. L. Dedik, M. Durisova, Frequency response method in

pharmacokinetics, J. Pharmacokin. Biopharm., 22, (1994)

293-307.

2. M.G. Singh, Systems and Control Encyclopedia, Theory,

Technology and Application, Pergamon Press, Oxford UK, 1987.

3. L. Dedik , M. Durisova, CXT - A programme for analysis of

linear dynamic systems in the frequency domain, Int. J.

Bio-Med. Comput., 39, (1995) 231-241.

4. L. Dedik, M. Durisova, CXT-MAIN: A software package for

determination of the analytical form of the pharmacokinetic

system weighting function, Comput. Methods Programs

Biomed.,f 51 (1996) 183-192.

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