- On 27 Jan 2003 at 11:28:53, Toublanc Nathalie (Nathalie.Toublanc.aaa.UCB-Group.com) sent the message

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Dear All,

I would like to conduct a little survey.

To calculate the extrapolated AUC (C(t)/lambda_z) in an NCA, do you use

for C(t) the observed concentration or the predicted one?

Also, for AUC calculation, do you use the linear method, log-lin method

or mixed log-lin?

Thanks in adance for your input

Nathalie Toublanc

UCB pharma - On 27 Jan 2003 at 13:16:27, David Bourne (david.-a-.boomer.org) sent the message

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[Two replies - db]

From: Garry Boswell

Date: Mon, 27 Jan 2003 10:42:40 -0800

To: david.-a-.boomer.org

Subject: Re: NCA calculation

C(t)observed and linear

---

From: "Brian Sadler"

Date: Mon Jan 27, 2003 12:51:48 PM US/Central

To: david.-a-.boomer.org

Subject: Re: NCA calculation

The following message was posted to: PharmPK

Bonsoir Nathalie,

I typically use the observed C(t) to extrapolate AUC. I know of no

regulatory preference for either the observed or predicted value. My key

recommendation is that you choose one and use it consistently. Special

consideration may need to be given to the case in which the observed

value

of C(t) is NOT used in the estimation of lambda_z. This can be important

when C(t) is at or near the lower limit of quantification or when it is

considerably higher than the predicted value. If the observed and

predicted

values are very different then my best advise is to rely on your

understanding of the possible reasons underlying the discrepancy and

choose

the method that minimizes any potential bias.

With regard to the trapezoidal method, I recommend linear up to Cmax and

logarithmic after.

Brian

Strategic PK Consulting, LLC

bsadler1.-a-.nc.rr.com - On 27 Jan 2003 at 13:29:44, "Rob Ariano" (RARIANO.aaa.sbgh.mb.ca) sent the message

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The following message was posted to: PharmPK

Dear Nathalie:

For extrapolated AUC, I use observed C(t),

where AUC last is C(t)/lambda_z, which in fact is log-linear by

definition. - On 27 Jan 2003 at 17:13:21, RPop.aaa.pharmamedica.com sent the message

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In BE studies the regulations are as follows:

FDA - use the last measured concentration

Canada and EU - use the predicted concentration at the time of

the last measurable analyte level. The prediction should be based on

the regression line estimated on at

least 4 or 3 data points from the terminal linear disposition phase.

Use of the predicted concentration may have the advantage of diminished

errors since the extrapolated AUC will not be based on one single

measurement, the C(t).

AUCo-t should be calculated in BE studies by the trapezoidal method

applied to the raw data.

There are papers in the literature showing that the best approach (less

errors) is the log-lin method.

radu

Radu D. Pop

Director Biopharmaceutics

Pharma Medica Research Inc.

966 Pantera Drive

Mississauga, Ontario

Canada, L4W 2S1 - On 28 Jan 2003 at 00:05:17, =?ISO-8859-9?Q?"=DDlbeyi_A=F0abeyo=F0lu"?= (ilbeyi.aaa.tr.net) sent the message

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The following message was posted to: PharmPK

Dear Nathalie,

To calculate the extrapolated AUC, you can use both experimental and

predicted Cz. Experimental point can hold some error, since it is

already a low concentration point. You are also calculating an area

depending on a single point. On the other hand, employing the estimated

Cz for this calculation has the backing up of at least several points.

Cz is estimated with the help of the terminal line.

Ylbeyi Aoabeyoolu

ilbeyi.aaa.tr.net - On 28 Jan 2003 at 00:11:29, =?ISO-8859-9?Q?"=DDlbeyi_A=F0abeyo=F0lu"?= (ilbeyi.-a-.tr.net) sent the message

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The following message was posted to: PharmPK

As regarding AUC method to employ, it is best to consider the sign of

the second derivative, in order to use logarithmic or linear AUC

calculation, based on the suggestion by Proust and not by Chiou.

Ylbeyi Aoabeyoolu

ilbeyi.at.tr.net - On 28 Jan 2003 at 20:07:39, =?ISO-8859-1?Q?Helmut_Sch=FCtz?= (helmut.schuetz.aaa.chello.at) sent the message

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The following message was posted to: PharmPK

C(calc) and linear.

BTW (in order to compare BE guidelines): C(calc) is mandatory in the EU

and

Canada, C(obs) in the USA...

Helmut Schütz

Head Biostatistics

Biokinet GmbH

Nattergasse 4

A-1170 Vienna/Austria

Tel +43(0)1 4856969 77

Fax +43(0)1 4856970 90

mailto:helmut.schuetz.-a-.chello.at - On 29 Jan 2003 at 22:57:05, =?ISO-8859-1?Q?Helmut_Sch=FCtz?= (helmut.schuetz.-a-.chello.at) sent the message

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The following message was posted to: PharmPK

fabrice_nollevaux.-at-.sgs.com wrote:

> Dear Dr. Schütz,

>

> May I ask you any reference regarding the mandatory use of C(calc) in

> the EU ?

> I do not find anything about it in the "Note for Guidance on the

> Investigation of Bioavailability and Bioequivalence" (CPMP, 2000).

>

> Many thanks in advance,

>

> Fabrice Nollevaux,

> Senior Biostatistician

> SGS Biopharma - Biometrics Department

> Tel: ++32 (0)10 421 149

> Fax: ++32 (0)10 402 018

Dear All,

mea culpa, mea maxima culpa...

Fabrice is right, mandatory is wrong!

Since about twenty years C(calc) is of widespread use throughout

Europe, maybe one of the earliest

references is

STEINIJANS, V.W. and E. DILETTI;

Statistical Analysis of Bioavailability Studies: Parametric and

Nonparametric Confidence Intervals

Eur. J. Clin. Pharmacol. 24, 127-136 (1983)

The guideline (CPMP/EWP/QWP/1401/98 26 July 2001, available at EMEA's

site as 140198en.pdf) only

states at

3.3 Reporting of results

[...] The method used to derive the pharmacokinetic parameters from the

raw data should be

specified. [...]

If adhering to good statistical practice (i.e., laying down in the

protocol what we're intending to

do) I experienced no problems even with "tough" authorities (e.g.,

Brasil's ANVISA).

Best regards

Helmut Schütz

Head Biostatistics

Biokinet GmbH

Nattergasse 4

A-1170 Vienna/Austria

Tel +43(0)1 4856969 77

Fax +43(0)1 4856970 90

mailto:helmut.schuetz.-at-.chello.at - On 3 Feb 2003 at 11:34:24, "Durisova Maria" (exfamadu.-at-.savba.sk) sent the message

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The following message was posted to: PharmPK

AUC_res = C_calc/k_el should be used, not AUC_res = C_obs/k_el.

The difference between the AUC_res from the last sampling point to

infinity

calculated on the basis of C_calc or C_obs can be explained as follows:

The figure available at http://www.uef.sav.sk/AUC_res.ppt

illustrates an example in which the three last sampling points

of the measured drug concentration-time profile

were used to estimate the exponential function (the full black line)

which approximated the measured drug concentration-time profile

to infinity. The elimination rate constant k_el was estimated

on the basis of the given exponential function.

AUC_res = C_calc/k_el is the area form the last sampling point

to infinity under the given exponential function, i.e. under the full

black

line.

On the contrary, AUC_res = C_obs/k_el is the area form the last

sampling

point to infinity under the dotted red line. As seen in the given

example,

AUC_res = C_obs/k_el overestimates AUC_res= C_calc/k_el, determined

on the

basis of the

exponential function which was used to estimate the elimination rate

constant k_el.

Analogously, AUC_res=C_obs/k_el can also underestimate

AUC_res = C_calc/k_el, i.e. the area based on the exponential function

which was used to estimate the elimination rate constant k_el.

Maria Durisova, PhD, DSc,

Head of Department of Pharmacokinetics

and Scientific Secretary

Institute of Experimental Pharmacology

Slovak Academy of Sciences

841 04 Bratislava 4

Slovak Republic

Phone/Fax: +421 2 54775928

http://www.uef.sav.sk/durisova.htm

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