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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]
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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.
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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
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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
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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.
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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
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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
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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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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)