From: Nick Holford <*n.holford*>

Date: Sun, 22 Mar 2009 08:28:00 +0200

Sorry -- this sentence need a 'not' as follows:

"This estimate is of course a shrinkage estimate which will typically be

biased towards the population CL but I have NOT realized that there is

also EBE bias from the choice of transformation used in parameter

estimation."

Nick Holford wrote:

*> Mats,
*

*>
*

*> This is an interesting idea but it seems to be more complicated than
*

*> just a consideration of the residual variability (RV%) when using log
*

*> transformation with transform both sides (TBS) estimation.
*

*>
*

*> First of all you appear to assume that the RV% is only a proportional
*

*> residual error but if could also include an additive component when
*

*> using TBS so that there is not a single RV% that would describe a
*

*> particular situation because it would change with concentration.
*

*>
*

*> A model based estimate of AUC would typically be based on an empirical
*

*> Bayes estimate (EBE) of CL. This estimate is of course a shrinkage
*

*> estimate which will typically be biased towards the population CL but
*

*> I have realized that there is also EBE bias from the choice of
*

*> transformation used in parameter estimation. Thus I would not expect
*

*> the model based estimate to be additionally biased because of using
*

*> EBEs with TBS. This is probably something you have thought about so
*

*> please inform me.
*

*>
*

*> Turning to the NCA method - I dont know if a bias is expected from the
*

*> NCA calculated AUC but I would naively assume that the trapezoidal
*

*> part would not be biased. I am ready to learn if there is a bias
*

*> expected with trapezoidal NCA. I expect this has been investigated and
*

*> reported but I am not familiar with it. The extrapolated portion
*

*> typically relies on a log linear transformation to estimate the
*

*> elimination rate constant which so in this respect the log transformed
*

*> model based and NCA based methods would seem to be similar.
*

*>
*

*> Another source of difference between model and NCA based AUCs might
*

*> arise from the use of different statistics to describe the central
*

*> tendency of the indidual estimates. NCA estimates could be based on
*

*> the arithmetic mean of the individual AUC sor on the geometric mean
*

*> (most commonly used for bioequivalence analysis). The model based
*

*> estimates based on the arithmetic mean of the EBE predicted AUCs would
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*> be biased towards the geometric mean because the population value
*

*> would typically be estimated with an exponential ETA.
*

*>
*

*> If you have the time would you expand on the details of your assertion
*

*> so that I and others can understand the basis more clearly? It seems
*

*> to me that comparison of model based AUCs with NCA based AUCs is more
*

*> complicated than just a consideration of the typical value of the
*

*> residual error.
*

*>
*

*> Nick
*

*>
*

*>
*

*> Mats Karlsson wrote:
*

*>>
*

*>> Dear Ethan,
*

*>>
*

*>>
*

*>>
*

*>> Just a caution when comparing model-based AUCs with NCA calculated
*

*>> AUCs. If you have done your modeling using log-transformation of
*

*>> observations and model predictions and then compared AUCs on the
*

*>> linear scale, you should not expect a perfect agreement between the
*

*>> two. The reason is that the mean of an exponentiated distribution of
*

*>> epsilons is not the same as the median, but higher. Thus, the AUCs of
*

*>> model-predicted individual profiles will be expected to be lower than
*

*>> either simulated or observed. The magnitude of the difference will
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*>> depend on the residual error magnitude and will typically be:
*

*>>
*

*>>
*

*>>
*

*>> %RV expected AUC difference
*

*>>
*

*>> 10 0.50%
*

*>>
*

*>> 20 2%
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*>>
*

*>> 30 5%
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*>>
*

*>> 40 9%
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*>>
*

*>> 50 14%
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*>>
*

*>> 70 29%
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*>>
*

*>>
*

*>>
*

*>> Best regards,
*

*>>
*

*>> Mats
*

*>>
*

*>>
*

*>>
*

*>> Mats Karlsson, PhD
*

*>>
*

*>> Professor of Pharmacometrics
*

*>>
*

*>> Dept of Pharmaceutical Biosciences
*

*>>
*

*>> Uppsala University
*

*>>
*

*>> Box 591
*

*>>
*

*>> 751 24 Uppsala Sweden
*

*>>
*

*>> phone: +46 18 4714105
*

*>>
*

*>> fax: +46 18 471 4003
*

*>>
*

*>>
*

*>>
*

*>> *From:* owner-nmusers *

*>> [mailto:owner-nmusers *

*>> *Sent:* Friday, March 20, 2009 6:52 PM
*

*>> *To:* Michael.J.Fossler *

*>> *Subject:* Re: [NMusers] calculation of AUC
*

*>>
*

*>>
*

*>>
*

*>> sorry for being lazy this morning and wish relying on others knowledge
*

*>>
*

*>> just to share, I used DADT=C method, and it didn't depend on sampling
*

*>> after I tried with my model (which took quite a while to get results)
*

*>>
*

*>> -- I could do as Bill suggested setting up some small dataset and
*

*>> simple model to check first, then would share with the group ealier :-)
*

*>>
*

*>>
*

*>>
*

*>>
*

*>>
*

*>>
*

*>> ------------------------------------------------------------------------
*

*>>
*

*>> *From:* "Michael.J.Fossler *

*>> *To:* nmusers *

*>> *Sent:* Friday, March 20, 2009 9:42:59 AM
*

*>> *Subject:* Fw: [NMusers] calculation of AUC
*

*>>
*

*>>
*

*>> I second Bill's suggestion to work this out on your own for your
*

*>> specific problem. This forum can help you with general questions and
*

*>> overall approaches, but very specific queries like this are for you
*

*>> and your colleagues to hash out.
*

*>>
*

*>> *Error! Filename not specified.*
*

*>> ----- Forwarded by Michael J Fossler/PharmRD/GSK on 03/20/2009 09:40
*

*>> AM -----
*

*>>
*

*>> *"Bill Bachman" <bachmanw *

*>> Sent by: owner-nmusers *

*>>
*

*>> 20-Mar-2009 09:17
*

*>>
*

*>>
*

*>>
*

*>>
*

*>> To
*

*>>
*

*>>
*

*>>
*

*>> "'Martin Bergstrand'" <martin.bergstrand *

*>> <ethan.wu75 *

*>>
*

*>> cc
*

*>>
*

*>>
*

*>>
*

*>> Subject
*

*>>
*

*>>
*

*>>
*

*>> RE: [NMusers] calculation of AUC
*

*>>
*

*>>
*

*>>
*

*>>
*

*>>
*

*>>
*

*>>
*

*>>
*

*>>
*

*>> The easiest answer is to work it out. Do some simulations (without
*

*>> variability) with multiple subjects with identical PK parameters BUT
*

*>> different sampling times. Tabulate your AUCs and compare the results
*

*>> for different sampling times!
*

*>>
*

*>>
*

*>>
*

*>>
*

*>> ------------------------------------------------------------------------
*

*>>
*

*>>
*

*>> *From:* owner-nmusers *

*>> [mailto:owner-nmusers *

*>> Sent:* Friday, March 20, 2009 8:45 AM*
*

*>> To:* 'Ethan Wu'; nmusers *

*>> Subject:* RE: [NMusers] calculation of AUC
*

*>>
*

*>> Dear Ethan,
*

*>>
*

*>> You need to provide more information on how you plan to calculate AUC
*

*>> otherwise the question canâ€™t be answered. It is of course possible to
*

*>> calculate the AUC without any influence of the sampling frequency.
*

*>> You should be able to find examples of how to do this in the NMusers
*

*>> archive. See for example the answer from Mats Karlsson in this thread
*

*>> (http://nonmem..org/nonmem/nm/98apr032002.html
*

*>> <http://nonmem.org/nonmem/nm/98apr032002.html>).
*

*>>
*

*>> Kind regards,
*

*>>
*

*>> Martin Bergstrand, MSc, PhD student
*

*>> -----------------------------------------------
*

*>> Department of Pharmaceutical Biosciences,
*

*>> Uppsala University
*

*>> -----------------------------------------------
*

*>> P.O. Box 591
*

*>> SE-751 24 Uppsala
*

*>> Sweden
*

*>> -----------------------------------------------
*

*>> martin.bergstrand *

*>> -----------------------------------------------
*

*>> Work: +46 18 471 4639
*

*>> Mobile: +46 709 994 396
*

*>> Fax: +46 18 471 4003
*

*>>
*

*>>
*

*>> *From:* owner-nmusers *

*>> [mailto:owner-nmusers *

*>> Sent:* den 20 mars 2009 13:05*
*

*>> To:* nmusers *

*>> Subject:* [NMusers] calculation of AUC
*

*>>
*

*>> Hi all, to calculate AUC of one of the compartments using ADVAN6, if
*

*>> it is a fixed time interval, will the AUC be influenced by the
*

*>> frequncy of sampling of the dataset within this interval or not?
*

*>> thanks
*

*>>
*

*>>
*

*>> ------------------------------------------------------------------------
*

*>>
*

*>> No viruses found in this incoming message
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*>> Scanned by *iolo AntiVirus 1.5.6.4*_
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*>> _http://www.iolo.com <http://www.iolo.com/iav/iavpop3>
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*>>
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*>>
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*>>
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*>
*

--

Nick Holford, Dept Pharmacology & Clinical Pharmacology

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

n.holford

http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford

Received on Sun Mar 22 2009 - 02:28:00 EDT

Date: Sun, 22 Mar 2009 08:28:00 +0200

Sorry -- this sentence need a 'not' as follows:

"This estimate is of course a shrinkage estimate which will typically be

biased towards the population CL but I have NOT realized that there is

also EBE bias from the choice of transformation used in parameter

estimation."

Nick Holford wrote:

--

Nick Holford, Dept Pharmacology & Clinical Pharmacology

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

n.holford

http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford

Received on Sun Mar 22 2009 - 02:28:00 EDT