Dear Sir,Back to the Top
How the absolute bioavailability of a orally adminstered drug should be
tested? Normally, the AUC of the blood-time profile of drug
administered orally will be compared with the drug (at the same dose)
via intravenous adminstration.
The question is how to administer the drugs via intravenous route? Is
it through infusion or bolus injection? If it is infusion, what is the
the total
time of infusion? If it is i.v injection, the sampling points are the
critical factor, which determines the AUC in the initial portion of the
blood level profile. What is the exact sampling points to be employed
in the case of i.v. injection
The backround of this question is that, rifampicin shows absolute
bioavailbility of 93% as compred to i.v. infusion given for 3h. But the
absolute bioavailbility was only 50%, when it was administered by i.v.
infusion given for 30 min or by i.v injection.
Expecting the earliest reply
T. Thanga Mariappan
T. THANGA MARIAPPAN,
DEPT. OF PHARMACEUTICAL ANALYSIS,
NATIONAL INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH (NIPER),
PHASE-10, SECTOR-67, MOHALI-160 062,
PUNJAB, INDIA
e.mail: ttmariappan.-at-.yahoo.co.in
[Is the elimination linear? Samples should be collected immediately at
the end of infusion and others, maybe one or two during would help (as
well as the usual samples after the infusion) - db]
Dear Thanga,Back to the Top
You can use several different time intervals for an infusion dosing.
A good way to determine an appropriate sampling schedule during both the
infusion and the post-infusion phase is to perform a pilot study.
In the case that a drug is administered intravenously by an infusion and
orally by an instantaneous dose, the rate of the absolute bioavailability
cannot be determined using a deconvolution method and the concentration-time
profiles of the drug resulting from the intravenous and oral drug administration.
In the given case, the rate of the absolute bioavailability can be determined
employing the technique introduced in the study:
http://www.uef.sav.sk/weighting_function.pdf
Regards,
Maria Durisova, PhD, DSc (Math/Phys)
Vice Director of Institute of Experimental Pharmacology
Slovak Academy of Sciences
and
Head of Department of Pharmacokinetics
D\0x02D9bravska cesta 9
841 04 Bratislava
Slovak Republic
Tel./Fax: +421 2 54775928
http://www.uef.sav.sk/durisova.htm
Back to the Top
Dear Maria,
In your reply to Thanga you wrote:
"In the case that a drug is administered intravenously by an infusion
and orally
by an instantaneous dose, the rate of the absolute bioavailability
cannot be determined
using a deconvolution method and the concentration-time profiles of the
drug
resulting from the intravenous and oral drug administration.
"
This is not completely true. There are several possibilities to do so:
1) by analytical deconvolution, using a fitted function to a model
taking into account the infusion administration (e.g. a classical
compartmental model); a drawback is that the model-indepence is lost.
2) by numerical deconvolution. In my thesis I have described a
procedure to use data from an intravenous infusion administration as a
reference. Actually this method is more accurate than using a bolus
administration, since the estimation of partial AUCs is avoided. If you
are interested, I can send you a copy.
This procedure has been implemented in the program KinBes, a program
for the assessment
of bioavailability and bioequivalence. The program is commercially
available from Mediware. Please
contact Mr. Eddy van Essen at vanessene.-a-.cs.com if you are interested.
Best regards,
Hans Proost
Johannes H. Proost
Dept. of Pharmacokinetics and Drug Delivery
University Centre for Pharmacy
Antonius Deusinglaan 1
9713 AV Groningen, The Netherlands
tel. 31-50 363 3292
fax 31-50 363 3247
Email: j.h.proost.-at-.farm.rug.nl
Back to the Top
The following message was posted to: PharmPK Maria,
GastroPlus(tm) is used routinely for such analyses. It allows
simultaneous fitting of as many oral and iv doses as you have data for,
including nonlinear metabolism in both gut wall and liver, and
gastrointestinal exsorption. It employs the methods you and I know are
the most general - numerical solution of differential equations that
represent each of the interacting phenomena in absorption,
distribution, metabolism, and elimination, within a physiological model
that is as realistic as we know how to make it at this time.
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (SIMU)
1220 W. Avenue J
Lancaster, CA 93534-2902
U.S.A.
http://www.simulations-plus.com
Phone: (661) 723-7723
FAX: (661) 723-5524
E-mail: walt.-at-.simulations-plus.com
Dear Hans,Back to the Top
Did you publish your approach to deconvoluntion using the i.v. infusion
as the reference?
I will be very interested to find out more.
radu
Radu D. Pop
Vice President, Scientific Affairs
Pharma Medica Research Inc.
966 Pantera Drive
Mississauga, Ontario
Canada, L4W 2S1
Back to the Top
Dear Thanga,
You wrote:
"The question is how to administer the drugs via intravenous route? Is
it through infusion or bolus injection? If it is infusion, what is the
the total time of infusion?
"
The crucial point is that the reference administration delivers the
total
dose of the drug to the general circulation. One would not expect a
difference in AUC after intravenous bolus administration or after an
infusion of any duration.
"If it is i.v injection, the sampling points are the
critical factor, which determines the AUC in the initial portion of the
blood level profile. What is the exact sampling points to be employed
in the case of i.v. injection
"
Indeed the sampling points after bolus injection are crucial. As a rule
of
thumb, measurements within two minutes after administration cannot be
used
since mixing over the vascular bed is not yet completed (in humans; in
small
laboratory animals one minute is more appropriate). If the decline of
the
concentration is very rapid even after a few minutes, one might
question if
an iv bolus is suited as a reference.
"The backround of this question is that, rifampicin shows absolute
bioavailbility of 93% as compred to i.v. infusion given for 3h. But the
absolute bioavailbility was only 50%, when it was administered by i.v.
infusion given for 30 min or by i.v injection.
"
This is a remarkable finding. You should know what is the reason of this
apparent discrepancy of the behaviour expected for linear
pharmacokinetics.
Assuming that the AUC has been determined appropriately, i.e. with a
sufficient number of measurements, and extrapolated to infinity, there
must
be a different reason. Rifampicin is a well-known enzyme inducer, and
might
affect its own clearance, thus resulting in erroneous estimates of
bioavailability, since any usual method for the estimation of
bioavailability is based on a constant clearance. Another factor is the
biliary excretion and enterohepatic recirculation, which may result in
irregular concentration profiles and hamper the estimation of AUC.
Best regards,
Hans Proost
Johannes H. Proost
Dept. of Pharmacokinetics and Drug Delivery
University Centre for Pharmacy
Antonius Deusinglaan 1
9713 AV Groningen, The Netherlands
tel. 31-50 363 3292
fax 31-50 363 3247
Email: j.h.proost.-a-.farm.rug.nl
Back to the Top
Dear Hans and Walt,
Thanks for your replies. An explanation to my previous message
is as follows: Our study: L. Dedik, M. Durisova, Comput.
Methods Programs Biomed.:
http://www.uef.sav.sk/weighting_function.pdf uses the general
formula that can be employed to determine a model of a dynamic
system that represents a drug bioavailability, regardless whether
forms of intravenous and extravascular drug inputs into the body
are identical or different. Thereafter, based on such a model,
an estimate of the rate of a drug bioavailability can be obtained.
On the other hand, in a specific case, i.e. if the forms of intravenous
and extravacular drug inputs into the body are identical, i.e.
Y_iv(t)= k.Y_ex(t),
where k is a constant k>0, the general formula mentioned above
can be simplified and expressed using the convolution integral
in the time domain. Thereafter, the rate of the drug bioavailability
can be determined directly by deconvolving concentration-time profiles
that result from intravenous and extravascular drug inputs into the
body.
This is what I had in mind on writing my previous message to the
PharmPK,
not the procedure employed e.g. in the study by D.R. Drover et al.
Anesthesiology 2002, 97, 827-836.
The procedure described in our study mentioned in the first paragraph
of this message exhibits the following properties:
1. The selection of an optimal model of a dynamic system that represents
a drug bioavailability and the determination of interval estimates of
model parameters start with a non-iterative method,
i.e. the method which does not require initial estimates of model
parameters and which runs very rapidly. In the next step, the model
is refined by iterative methods and interval estimates of
model parameters are determined.
2. Based on a such model an estimate of the rate of bioavailability
can be determined in a numerical or in an analytical form without
any a priori assumption about a particular form of the rate
of bioavailability, regardless whether forms of intravenous
and extravascular drug inputs into the body are identical or different.
This can be done even if drug bioavailability is a rather complex
dynamic process with several time delays.
3. The procedure can be used to determine a mechanism-based
model of a bioavailability process and to identify and quantify
several fractions of a drug that obey different pathways
in a bioavailability process, see the study by M. Durisova et al.
Bull. Math. Biol. 1995, 57, 787-808.
The procedure can be run under Windows,
employing the software package CTDB, a version of
which is available here:
http://www.uef.sav.sk/advanced.htm
Yes Hans, I would greatly appreciate receiving
a copy of your study mentioned in your reply.
Regards,
Maria Durisova
Maria Durisova, PhD, DSc (Math/Phys)
Vice Director of Institute of Experimental Pharmacology
Slovak Academy of Sciences
and
Head of Department of Pharmacokinetics
D\0x02D9bravska cesta 9
841 04 Bratislava
Slovak Republic
Tel./Fax: +421 2 54775928
http://www.uef.sav.sk/durisova.htm
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)