- On 9 Apr 1998 at 11:36:59, "Gretler, Dan" (DGRETLER.-at-.corr.com) sent the message

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Does anyone have any information about comparing a 90 min continuous iv

infusions (rather than an iv bolus) with oral administration of a drug

to calculate absolute bioavailability? References, tips, pitfalls etc

would be appreciated.

Daniel Gretler, MD

COR Therapeutics Inc.

[db - make sure you collect samples during the infusion] - On 10 Apr 1998 at 10:07:41, "Garg, Varun" (VARUNG.aaa.MOCR.OAPI.COM) sent the message

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Using an infusion will have the advantage of not missing the Cmax which is a

problem with bolus when the first blood collection is not rapid enough to

capture the distribution phase. You need to sample throughout the infusion

period as Dr. Bourne has suggested. If clearance is nonlinear with

concentration, you need to make sure that the concentration ranges are

similar between oral and iv infusion (or bolus) by adjusting the dose.

Varun Garg, Ph.D.

Otsuka America Pharmaceutical, Inc. - On 10 Apr 1998 at 10:10:35, Maria Durisova (exfamadu.-at-.savba.savba.sk) sent the message

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Dear Daniel,

our article: CXT-MAIN a software package for determination of the analytical

form of the pharmacokinetic system weighting function, published in

Comput. Methods Programs Biomed., 51, 1996, 183-1992, presents a pro-

cedure for the determination of the extent and rate of bioavailability

even in situations when deconvolution methods cannot be used. In this acticle,

the application of the procedure is given, employing an example

similar to that in your question.

A version of this software is available at the home page of the

PharmPk group. The last version of it contains also a facility

for testing the similarity of two rates of bioavailability.

Best regards,

Maria

*******************************

Dipl.Engineer Maria Durisova, CSc.,

Institute of Experimental

Pharmacology, Slovak Academy of

Sciences, Phone/fax: 004217375928.

Bratislava, Slovak Republic - On 13 Apr 1998 at 15:38:35, Nick Holford (n.holford.-a-.auckland.ac.nz) sent the message

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Attempting to assess absolute bioavailability for a drug with concentraton

dependent clearance is not a simple task. It is not solved by adjusting the

dose. Bioavailability can only be assessed with a model dependent approach

that recognises the non-linearities. AUC wont cut it.

--

Nick Holford, Center for Drug Development Science

Georgetown University, 3900 Reservoir Rd NW, DC 20007-2197

email:n.holford.-a-.auckland.ac.nz tel:(202)687-1618 fax:687-0193

http://www.phm.auckland.ac.nz/Staff/NHolford/nholford.htm - On 14 Apr 1998 at 14:12:37, Maria Durisova (exfamadu.aaa.savba.savba.sk) sent the message

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The frequency responses of all the linear dynamic time

invariant systems and their models are continuous curves

(1). It follows then that if the points of the frequency

response of the system under study, calculated e.g. as the

ratio of the Fourier transforms of the system output and

input (2), can be considered to lie on a continuous curve,

the system can be sufficiently approximated by a linear

model. This property can be employed e.g. in a

bioavailability study, to decide whether

1.- the system describing the drug fate after a single oral

dose,

2.- the system describing the drug fate during and after an

intravenous infusion,

3.- the system describing the drug bioavailability

can be sufficiently approximated by linear models or not.

Sincerely,

Maria Durisova

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

Technology and Application, Pergamon Press, Oxford, 1987.

2. L. Dedik, M. Durisova, pharmacokinetics, J. Pharmacokin.

Biopharm., 22, 1994, 293-307. - On 16 Apr 1998 at 10:38:22, "Benjamin Sandoval Guzman" (benjamin.at.udgserv.cencar.udg.mx) sent the message

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Hi, everyone

Iuse a PC(windows 95), I have Adap, but I don't have Microsoft Fortran

PowerStation 4.0, I now hi is recomended, but it cost $750. Any helpul

ideas.

Benjamin Sandoval Guzman

UNIVERSIDAD DE GUADALAJARA

C.U.C.E.I Div CIENCIAS BASICAS

Depto Farmacobiologia Farmacia

Calz Gral Marcelino Garcia Barragan 1461 C.P o Z.C 44430 - On 20 Apr 1998 at 10:22:20, Maria Durisova (exfamadu.-a-.savba.savba.sk) sent the message

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Dear Olof,

Any part of the human environment can be considered an object

of study provided that a set of influences of this

environment affects the object so as to cause an observable

set of changes. If only one influence is selected, and if

only one of its effects is observed, then a single

input/single output system can be defined on the object.

The system approach provides the unified conceptual framework

for utilizing general strategies to formulate mathematical

models of various systems, for investigating phenomena

described by mathematical models, and for devising strategies

to control or exploit such phenomena.

From the point of view of system behavior after introducing

non-zero inputs, the systems can be classified as:

1) systems with deterministic behavior

2) systems with stochastic behavior. The output of a system

with deterministic behavior can be determined on the basis of

the known state and input of the given system. The

statistical characteristic of the output of a system with

stochastic behavior can be predicted on the basis of the

known statistical characteristic of the system input. The

systems with deterministic behavior can be classified as:

1) static systems, whose behavior is independent of the

system state

2) dynamic systems, whose behavior is dependent on the system

state. The latter systems can be classified as:

1) linear systems, satisfying the additivity and homogeneity

axiom

2) non-linear systems which can be defined by the simple

dichotomy, of being either linear or it is non-linear.

From the point of view of system behavior regardless the form

of the system input, the systems can be classified as:

1) time invariant systems, with properties constant over the

time interval of the study

2) time variant systems, with variable properties over the

time interval of the study. Properties of almost any real

system are represented by a combination of properties of the

systems outlined above. For system modeling, however, only

the dominant properties are taken into account, while the

remaining ones are ignored.

The system can be defined on the living body under study,

using the input/output relationship. The measurable input of

the system can be for example the drug administration through

any route. The system can respond to this input with

a measurable output, as for example by the drug concentration

in plasma, blood or in different parts of the living body, or

by the effect of the drug. The measured fate of the drug in

the body and the observed (measured) effect of the drug

depend on the system state. It follows then that, considered

from the point of view of the system theory, the systems

describing the drug fate and/or the systems describing the

drug effect are the dynamic systems (see above).

Since the systems defined in pharmacokinetics are

predominantly time invariant over the short interval of the

study, and since their behavior is linear or can be

linearized in a particular operation region, the theory of

linear dynamic time invariant systems (also the basis of

the linear compartment models) has been widely discussed in

pharmacokinetic literature.

The frequency domain method, one of the major tolls of this

theory, was mentioned in pharmacokinetics by Smolen in 1979,

however, it has not gained appreciable momentum among

pharmacokineticians yet. Although the understanding of the

principles of the frequency domain modeling requires an

abstract way of thinking for the biologically trained reader,

its rewards compensate for that initial inconvenience. The

main advantage of the applications of the system approach in

pharmacokinetics is that it enables to model different

systems, e.g. systems describing drug fate after different

routes of administration, systems describing drug

bioavailability, systems describing drug in-vitro and/or in

vivo dissolution, systems describing drug effect, etc., in

a methodologically uniform way.

One of the goals of our work is to expound on general

principles and methods of the system approach in

pharmacokinetics, with the aim uniformizing and clarifying

them and thus helping to render them more accessible to

medical, biological and pharmaceutical students, scientists,

clinicians, and drug marketing personnel. To help to overcome

the complexity of the mathematical concepts of the frequency

domain modeling method we published the CXT program. It is

written in a graphical mode, and it can help the user to

apply this method without exact knowledge of mathematical

techniques. The program can be run also in a tutorial way and

is suitable for a workshop presentation.

The details on the theory of the linear dynamic systems and

explanations of the concepts of that theory can be found in

specialized literature. A description of the frequency domain

modeling is given for example at:

http://rclsgi.eng.ohio-state.edu/matlab/freq/freq.html.

Sincerely,

Maria Durisova

Institute of Experimental Pharmacology

Slovak Academy of Sciences

Slovak Republic

Phone/Fax:004217375928 - On 21 Apr 1998 at 11:50:25, Olof.Borga.-at-.draco.se.astra.com sent the message

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Dear Dr Durisova:

Thank you for a clear description of this field, which is entirely new

to me. Thank you also for putting the effort into this lengthy answer. I

will look into it and find out how much I understand and whether I will

have the courage to dig deeper in this theory. I might come back to you

with more questions.

Thanks again,

sincerely

Olof Borg=E5, Ph.D.

Pharmacokinetic Expert

Kinetics and Metabolism

Preclinical R&D

Astra Draco AB, P.O. Box 34, S-221 00 Lund, Sweden

Tel: +46 46 33 60 00 Direct: +46 46 33 68 75

Fax: +46 46 33 66 66 Direct: +46 46 33 71 64

e-mail: olof.borga.-a-.draco.se.astra.com

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