- On 15 Oct 2002 at 14:25:54, "SK. Abdul Mohammed Jafar Sadik Basha" (h2002032.at.bits-pilani.ac.in) sent the message

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Dear all,

i would be glad to know the answers of the following questions

1) What is the difference between AUCall and AUC0-infinity in non

compartmental analysis by WinNonlin?

2) How to calculate the fraction of dose converted into metabolite by

non-compartmental analysis in case of iv bolus ( oral also)?

3) How to find out MRT incase of iv infusion for a definite period of

time?

Thanks in advance.

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

*SK.ABDUL MOHAMMED JAFAR SADIK BASHA*

*2002H108032 *

*Room No.: 230, Bhagirath Bhavan *

*BITS, Pilani *

*Rajasthan *

************************************* - On 15 Oct 2002 at 14:39:10, "Davies, Brian {CLIN~Nutley}" (BRIAN.DAVIES.-at-.ROCHE.COM) sent the message

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> 1) What is the difference between AUCall and AUC0-infinity in non

> compartmental analysis by WinNonlin?

AUCinf is the total AUC i.e. AUClast plus AUClast to inf (Clast/lambdaz)

AUCall is AUClast plus the area of the triangle assuming that the next

time point after Clast is zero.

> 2) How to calculate the fraction of dose converted into metabolite by

> non-compartmental analysis in case of iv bolus ( oral also)?

Fm = AUC'x/AUC', where AUC'x is the total area under the curve of

metabolite in plasma after IV drug and AUC' is the total area under the

curve of metabolite after an equimolar IV dose of metabolite.

> 3) How to find out MRT incase of iv infusion for a definite period of

> time?

MRTinfusion = MRT + (Infusion time/2)

Brian E. Davies

Clinical Director, PDMP

Hoffmann-La Roche, Nutley, NJ

* brian.davies.aaa.roche.com

* (973) 235-2053 - On 15 Oct 2002 at 14:46:46, Art Straughn (astraughn.aaa.utmem.edu) sent the message

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Abdul,

To make the correct calculation of MRT from in infusion of finite time

please see: Straughn, AB. "Model-independent steady-state volume of

distribution", J Pharm Sci 1982 May: 715):597-8. Note an original

paper

on this subject has an integration error in the proof and gives the

wrong

answer.

Art Straughn, Pharm.D.

Professor and Director

Drug Research Laboratory

University of Tennessee

874 Union Ave

Suite 5P

Memphis, TN 38163

E-mail: ASTRAUGHN.aaa.UTMEM.EDU - On 15 Oct 2002 at 22:40:46, "Aziz Karim" (aakari.at.msn.com) sent the message

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I have attached a graph (both as .pdf and .jpg format) which clearly

describes differences between AUC (all) and AUC (inf). Hope this helps.

Aziz Karim

[As attachments aren't possible on the PharmPK list I have put the jpeg

image on the PharmPK website at

http://www.boomer.org/pkin/pk/AUCinf.jpg - db] - On 17 Oct 2002 at 08:42:23, "Hans Proost" (j.h.proost.-at-.farm.rug.nl) sent the message

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Dear colleagues

In answer to the following question:

>> 3) How to find out MRT incase of iv infusion for a definite period of

>> time?

Brian Davies wrote:

> MRTinfusion = MRT + (Infusion time/2)

This is correct. However, it may be confusing. In non-compartmental

analysis, MRT is calculated as

MRT = AUMC/AUC

This value of MRT includes the term (Infusion time/2), and thus equals

the

MRTinfusion in your equation.

On the other hand, in compartmental analysis, MRT is usually calculated

as

MRT = Vss / CL

This value of MRT refers to a bolus dose administration.

So, if MRT is calculated from AUMC/AUC, addition of (Infusion time/2)

should

be omitted. The actual MRT is obtained by subtraction of (Infusion

time/2)

from MRTinfusion.

By the way, I do not know which MRT is provided by WinNonlin. Anyhow, it

should be made clear which value is reported. I would suggest to stick

to

the 'real' MRT, i.e. after a bolus dose administration. IMHO, the value

of

MRTinfusion does not make much sense.

Hans Proost

Johannes H. Proost

Dept. of Pharmacokinetics and Drug Delivery

University Centre for Pharmacy

Antonius Deusinglaan 1

9713 AV Groningen, The Netherlands

Email: j.h.proost.-a-.farm.rug.nl

[I'm not sure what real MRT means...MRT probably should always be

provided with a subscript... MRT(IV-Bolus), MRT(IV-Infusion), or

MRT(Oral) etc.

Thus, MRT(xxx) is 'always' = AUMC/AUC

and the calculations:

MRT(IV-infusion) - MRT(IV-bolus) = MIT (mean infusion time ;-) =

Duration/2 <- no new information

MRT(Oral) - MRT(IV-bolus) = MAT (mean absorption time) <- might be

useful

can/may be performed...do I have the right? - db] - On 17 Oct 2002 at 09:48:22, "Wolna, Peter" (Wolna.-at-.IKP.DE) sent the message

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Dear Aziz,

a graph using the original scale might be a better demonstration

of the phenomenon, since AUC calculation is based on non-transformed

data.

In addition, you cannot display points with concentration zero in

log-scale.

Regards

Peter

Peter Wolna

Inst. f. Klin. Pharmakologie

D-67269 Gruenstadt - On 17 Oct 2002 at 13:45:26, "Dr. Ibrahim Wasfi" (iawasfi.-a-.emirates.net.ae) sent the message

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Dear Aziz:

Congratulations. Perfect graph.

Dr. Ibrahim Wasfi

Forensic Science Laboratory

P O BOX 253, Abu Dhabi

United Arab Emirates - On 17 Oct 2002 at 17:37:57, Paul Collier (p.collier.-at-.qub.ac.uk) sent the message

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Aziz,

The graph that you have supplied is misleading. Because you have

labelled

the y-axis as being a log scale this is not the graph that represents

the

AUC that is required. You cannot plot zero on a log scale and therefore

this

does not give the correct visual representation of the relevant areas.

Paul

Dr Paul S. Collier

School of Pharmacy

Queen's University, Belfast

97 Lisburn Road

Belfast BT9 7BL

N. Ireland, UK - On 17 Oct 2002 at 15:02:14, "Davies, Brian {CLIN~Nutley}" (BRIAN.DAVIES.at.ROCHE.COM) sent the message

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Hans

The MRT given by WinNonlin is always the 'real' MRT because the program

automatically adjusts for the infusion time.

regards

Brian

Brian E. Davies

Clinical Director, PDMP

Hoffmann-La Roche, Nutley, NJ

* brian.davies.-a-.roche.com

* (973) 235-2053 - On 18 Oct 2002 at 10:54:51, Nick Holford (n.holford.aaa.auckland.ac.nz) sent the message

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>> MRTinfusion = MRT + (Infusion time/2)

>

> This is correct. However, it may be confusing. In non-compartmental

> analysis, MRT is calculated as

>

> MRT = AUMC/AUC

>

I think this is the most widespread actual use of MRT.

> By the way, I do not know which MRT is provided by WinNonlin. Anyhow,

> it

> should be made clear which value is reported. I would suggest to stick

> to

> the 'real' MRT, i.e. after a bolus dose administration. IMHO, the value

> of

> MRTinfusion does not make much sense.

I like to use the term Mean Disposition Time (MDT) to refer to Vss/CL

because it refers to the residence time attributable to disposition

(distribution and elimination) and excludes the input process which has

a Mean Input Time (MIT) (aka Mean Absorption Time MAT). They are simply

related like this:

MRT = MIT + MDT

The MDT is the same as MRT for a bolus input because MIT=0.

Nick

Nick Holford, Divn Pharmacology & Clinical Pharmacology

University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New

Zealand

email:n.holford.at.auckland.ac.nz

http://www.health.auckland.ac.nz/pharmacology/staff/nholford/ - On 18 Oct 2002 at 08:07:24, "Aziz Karim" (aakari.-at-.msn.com) sent the message

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Dear Paul:

You are absolutely right that you can not show zero value in the log

scale.

The graph was for illustrative purpose only. The problem with using the

linear scale would be that the terminal phase elimination phase would

not be

obvious because of the exponential decay. I should omit the zero value

from

the graph and just say value below lqc.

Again thanks for your comments.

Aziz - On 21 Oct 2002 at 11:01:47, Rostam Namdari (chista90.aaa.yahoo.com) sent the message

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Dear Hans,

You rather have an interesting opinion regarding

MRTinfusion. Would you please provide a little more

insight as to why do you think MRTinfusion does not

make much sense? What about slow release formulation?

Should do not be still meaningful/ useful if the

plasma concentration-time curve decline in a

mono-exponential manner?

Rostam - On 23 Oct 2002 at 10:52:16, "J.H.Proost" (J.H.Proost.aaa.farm.rug.nl) sent the message

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Dear Rostam,

Thank you for your response.

> Would you please provide a little more

> insight as to why do you think MRTinfusion does not

> make much sense?

I would say: the advocates of MRTinfusion should indicate what is the

use of this value.

MRTinfusion is the average time that drug molecules reside in the body

AND in the syringe (starting at time zero). To me, this makes no sense

because the drug in the syringe is not in the patient. We have full

control over the drug administration.

I welcome the suggestion by Nick Holford about Mean Residence Time =

AUMC/AUC and Mean Disposition Time = Vss/CL. Please note, however, that

in case of infusions, this definition of MRT cannot be translated to

the 'mean residence time in the body'. So, the confusion is not yet

solved completely.

> What about slow release formulation?

In this case the situation is different. In case we would know that the

release of drug obeys perfect zero-order over a defined time interval,

the situation is almost similar to that of an infusion, but the drug is

in the body (albeit not in the

'pharmacokinetic system') and is out of control. In real life, slow

release formulation are generally far from perfect

zero-order over a defined time interval, so the concept of a Mean Input

Time or Mean Absorption Time (as mentioned by Nick Holford) may be

applied.

> Should do not be still meaningful/ useful if the

> plasma concentration-time curve decline in a

> mono-exponential manner?

In case of a mono-exponential plasma concentration-time decline MRT and

MRTinfusion may be useful, but also may be considered superfluous,

since clearance and volume of distribution (two independent

characteristics of the system) describe the system exactly. Half-life

is useful for choosing an

appropriate dosing interval, and indicates how fast steady state is

reached. IMHO, that's enough, and we do not really need more parameters.

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

Email: j.h.proost.aaa.farm.rug.nl - On 25 Oct 2002 at 15:02:08, "Prof. Dr. Michael Weiss" (michael.weiss.-a-.medizin.uni-halle.de) sent the message

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Some remarks to the recent discussion on the meaning and usefulness of

MRT:

In view of a clear terminology I have proposed the names "mean

disposition residence time" (MDRT) for disposition curves after a bolus

iv dose and "mean body residence time" (MBRT) or "mean total residence

time" (MTRT) after noninstantaneous input, i.e.

MTRT = MDRT + MIT, where MIT= mean input time

MIT = T/2 for infusion time T (i.e., useful to calculate MDRT from

numerically estimated MTRT).

MIT = MDT + MAT (mean dissolution time + mean absorption time) after

oral administration.

Since MDT (mean dissolution time) is an already established term in

pharmacy and very useful for in vitro-in vivo correlation, the use MDT

instead of MDRT, as proposed by Nick, is open to question.

Regarding the information given by MDRT on the disposition system, the

following holds for linear systems and only assumes that the

elimination rate is proportional to C(t), but is independent of a

specific compartmental model.

Besides the fundamental relationship MDRT= Vss/CL, MDRT determines

the degree of accumulation: Ass /FDm = MDRT/tau

(Dm maintenance dose, tau dosing interval)

More than 90% of a bolus dose is eliminated in t90% (washout) and

following infusion more than 90% of Css a reached in t90%, where

t90% = 3.7 MDRT

Note that t63.2% =MDRT only holds for a one compartment model

(monoexponential function) !

Upper and lower bounds to the washout curves can be predicted when the

variance of RT is known after bolus injection or for log-concave curves

after oral administration.

e.g. ., time required for 63% of the total administered dose to be

eliminated (Rostam's question):

MDRT(1-CV^2)/2 < t63% < MDRT (where CV^2 = VDRT/MDRT^2) (< means: <

or =)

The following inequality is general valid V0 < Vss < Vz. (< means: <

or =)

Weiss, M.: Generalizations in linear pharmacokinetics using properties

of certain classes of residence time distributions. I. Log-convex drug

disposition curves. J. Pharmacokin. Biopharm. 14:635-657 (1986)

Weiss, M.: Generalizations in linear pharmacokinetics using properties

of certain classes of residence time distributions. II. Log-concave

curves following oral administration.J. Pharmacokin. Biopharm. 15:57-74

(1987)

Weiss, M.: Washout time versus mean residence time. Pharmazie

43:126-127 (1988)

Weiss, M.: The relevance of residence time theory to pharmacokinetics.

Eur. J. Clin. Pharmacol. 43:571-579 (1992)

The theory of residence time distributions also offers a method to

define measures of kinetics of drug distribution in the body (i.e.,

which are not influenced by elimination as t1/2,alpha): Weiss, M, Pang

KS.: The dynamics of drug distribution. I. Role of the second and third

curve moment. J. Pharmacokinet. Biopharm. 20: 253-278 (1992)

Best regards,

Michael Weiss

Martin Luther Univ.

Dep of Pharmacology

Section of Pharmacokinetics

D-06097 Halle/Saale

Germany

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