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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
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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
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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.
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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
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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
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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
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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
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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
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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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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)