- On 27 Jun 2002 at 12:17:38, "Aqel Abu-Qare" (aabu-qare.aaa.neophrm.com) sent the message

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In doing non-compartmental pharmacokinetics analysis, is it possible

that AUC0-inf will be less than AUC0-last or AUC0-all.

Regards,

Aqel W. Abu-Qare, Ph.D

Research Scientist.

Pharmacokinetics,Metabolism

and Bioanalytical.

NeoPharm, Inc.

1850 Lakeside Drive

Waukegan, IL 60085 - On 27 Jun 2002 at 19:08:02, "Stephen Duffull" (sduffull.aaa.uqpharmacy.pharmacy.uq.edu.au) sent the message

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Aqel

> In doing non-compartmental pharmacokinetics analysis, is it possible

> that AUC0-inf will be less than AUC0-last or AUC0-all.

No. Assuming you are talking about a single dose study then since

AUC(0-inf) = AUC(0-last) + AUC(last-inf)

and AUC(last-inf) cannot be negative.

Regards

Steve

Steve Duffull

School of Pharmacy

University of Queensland

Brisbane QLD4072

Australia - On 28 Jun 2002 at 11:24:56, David Bourne (david.-at-.boomer.org) sent the message

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[Quite a few replies - db - see WDSOP message for my reply :-)]

From: "Aziz Karim"

Date: Thu, 27 Jun 2002 22:24:32 -0500

To: david.aaa.boomer.org

Subject: Re: PharmPK Re: AUC 0-inf

Status: U

Dear Aqel:

WinNonlin gives you the option of determining AUC (last), AUC (all) and AUC

(inf) As pointed out by Dr Duffel, AUC (last) can not be greater than

AUC (inf).

However there can be an artefact where by AUC (all) would end up

being greater than

AUC (inf).

We need to clearly define the AUC(last) and AUC (all) values:

1) AUC (last) would represent the AUC up to the last validated measurable

plasma concentration [C(last).

2) AUC up to the last point below the limit of quantitation [considered zero

in AUC calculation] represents AUC(all).

It is difficult describe in words the above distinction so I have attached a

figure which explains the differences between the two AUC values.

Please let me know if

you have difficulties in opening the attachment. If so I will send

you this figure by

fax or send you directly via your E-mail address.

[The attachment is not included - my attempt to resist the spread of

viruses - db]

AUC(last) by definition can not be greater than AUC(inf). However, as an

artefact, it is possible for AUC(all) to be larger than AUC(inf).

This occurs when

time span is large between the last validated plasma concentration

(Clast) in the

disposition phase and the next sample with concentration below the

limit of quantitation (see attached Figure for explanation).

As a note, I don't particularly like to use AUC(inf) for drugs with

short half lives (T1/2 = < 24 hours). The reason for this is one

single concentration [C(last)] in the beta phase has a high influence

on the AUC(inf) values since AUC(inf) = AUC(last) +

[C(last)/(0.693/T1/2)]. It is simply better to determine AUC(last)

with the most sensitive assay and taking blood samples for a time

period exceeding 4*T1/2.

AUC(inf) is more appropriate for drugs with long T1/2 (>48 hours)

provided that the ratio of [AUC(last)/AUC(inf) ]exceeds 0.80.

Regards,

Aziz Karim

---

From: daniel.martinez.at.beaufour-ipsen.com

Date: Fri, 28 Jun 2002 08:27:45 +0200

To: david.at.boomer.org

Subject: Re: PharmPK AUC 0-inf

Dear Abu-Qare,

I think that you have some problem when you do the Pharmacokinetics

analysis. I don't know any case where the AUCall is higher than the AUCinf.

If you think about the non-compartmental formulas of this parameters you

will see that:

AUCinf = AUClast + Clast / lz

so as minimum you can have an AUCinf = AUClast if Clast = 0.

I hope it helps.

Your Sincerely

Daniel Martínez

RIA Laboratory

Metabolism & Pharmacokinetics Service

Research & Development Department

IPSEN PHARMA, S.A.

Ctra. Laureŕ Miró 395

Sant Feliu de Llobregat, Barcelona, Spain

daniel.martinez.-at-.beaufour-ipsen.com

---

From: "Stephen Duffull"

Date: Fri, 28 Jun 2002 16:34:21 +1000

To: david.at.boomer.org

Subject: Re: PharmPK Re: AUC 0-inf

Aziz

So if I'm interpreting you correctly you have some conc value that is BLQ?

When you compute AUC(all) you include some estimate of the BQL conc value

but when you compute AUC(inf) you don't.

This is not really an artifact of the data - so much as an artifact of your

analysis. If you have

LOD > conc > BQL

then you can expect to get these results if you ignore this conc when doing

regression to compute AUC(inf).

Really, you should model your data (I realise that this does not help you).

Regards

Steve

Steve Duffull

School of Pharmacy

University of Queensland

Brisbane QLD4072

Australia

---

From: "Gregorio Encina"

Date: Fri, 28 Jun 2002 08:41:37 +0200

To: david.aaa.boomer.org

Subject: Re: PharmPK AUC 0-inf

It is impossible and illogical that AUC0-inf will be less than AUC0-last or

AUC0-all. But you must be carefull with some programs like WinNonlin,

because if you put in the worksheet sampling points of elimination phase

quantified LOQ as "0" , in some cases (fast elimination and wide sampling

time period), the AUC0-all obtained could be greater than AUC0-inf.

Gregorio Encina, Ph D.

Pharmacokinetics and Drug Metabolism Dpto

Laboratorios Dr. Esteve, S.A.

Avda Mare de Deu de Montserrat, 221

08041 Barcelona, Spain

gencina.-a-.esteve.es

---

From: "McBurney, Alan"

Date: Fri, 28 Jun 2002 08:14:52 +0100

To: david.-at-.boomer.org

Subject: Re: AUC0-inf

Sorry to disagree with an earlier reply on this but yes, it is possible to

obtain an AUCinf which is less than AUCt or AUCall. There has been previous

correspondence on this matter earlier this year.

The situation arises when the sampling period includes concentrations which

are BLQ towards the end of the sampling period. If these results are

entered as zero, then the trapezoidal rule can potentially calculate an area

between the last two sample points which is greater than the extrapolated

area.

Alan

HUNTINGDON LIFE.SCIENCES LIMITED

http://www.huntingdon.com

---

From: TOUBLANC_NATHALIE.-a-.Lilly.com

Date: Fri, 28 Jun 2002 14:06:43 +0100

To: david.-at-.boomer.org

Subject: Re: PharmPK Re: AUC 0-inf

Actually, when you do NCA, if your AUC0-inf is calculated using Clast

predicted and not Clast observed, and your Clast observed is higher

than your Clast predicted, you could end up having a higher

AUC(0-inf) (calculated using your Clast pred) than your AUClast using

your Clast obs.

Regards

Nathalie

Global PK/PD and Trial Simulation - On 28 Jun 2002 at 16:47:17, "Madhusudana Rao Chaluvadi" (mchaluvadi.-a-.hotmail.com) sent the message

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Dear Dr. Abu-Qare,

Could you please explain the possibility how AUC0-inf is less than

AUC0-last or AUC0-all in non-compartmental pharmacokinetics analysis. - On 28 Jun 2002 at 18:13:28, Michael.D.Karol.at.abbott.com sent the message

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Imagine that you have a sampling scheme where the last data point is zero

(actually BLQ and treated as zero) and the second to the last point is not

zero. If the time between the last and second to last data points is large,

the area of the last trapezoid may be greater than the extrapolated area using

the second to the last point and beta.

Greater sampling density in the tail end of the curve would alleviate this

discrepancy.

Michael

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