- On 4 Mar 2004 at 16:53:35, Thanga Mariappan (ttmariappan.aaa.yahoo.co.in) sent the message
Dear Sir,

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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] - On 8 Mar 2004 at 15:18:52, "Durisova Maria" (exfamadu.-at-.savba.sk) sent the message
Dear Thanga,

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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 - On 9 Mar 2004 at 14:28:26, "J.H.Proost" (J.H.Proost.-a-.farm.rug.nl) sent the message

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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 - On 9 Mar 2004 at 09:53:53, Walt Woltosz (walt.at.simulations-plus.com) sent the message

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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 - On 9 Mar 2004 at 17:45:08, RPop.aaa.pharmamedica.com sent the message
Dear Hans,

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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 - On 10 Mar 2004 at 12:37:23, "Hans Proost" (j.h.proost.-at-.farm.rug.nl) sent the message

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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 - On 10 Mar 2004 at 15:29:39, "Durisova Maria" (exfamadu.-a-.savba.sk) sent the message

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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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