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The following message was posted to: PharmPK
Hello everyone:
I have a question regarding to calculate AUC in extented time period. I
have the plasma concentrations till 12 hours after dose, however, I need
to calculate AUC to 24 hours according to the protocol. The
concentrations at 12 hour point were either zero or very small. When I
tried to calculate AUC to 24 hour by predicted 24 hour concentration. It
turned out that the AUC to 24 hour was greater than AUC infinity. I
wonder whether anybody has experienced the same situation. How did you
do with it? Should I go with the AUC 24 hour that greater than the AUC
infinity? Thank you very much. Any information will be greatly
appreciated.
Have a great weekend!
Weijiang Zhang
Department of Pharmaceutical and Biomedical Sciences College of Pharmacy
The University of Georgia
Athens, GA 30602
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[You might want to look at http://www.boomer.org/c/p3/c02/c0210.html and
the two references - db]
From: Stephen Day
Date: Sat, 2 Feb 2002 23:33:43 -0500 (EST) To: david.aaa.boomer.org
Subject: Re: PharmPK Questions regarding AUC
The following message was posted to: PharmPK
Hello,
It sounds like your software is using the "linear trapezoid" method for
AUC calculation. If you switch to the "log-linear" method, the AUC(0-24
hr) should be smaller than the AUC(0-infinity). While this may fix your
funny AUC result, it may not be the best way to calculate the
AUC(0-24hr), because it places a lot of weight on your, very low, 12
hour data point. Then again... if your AUC is not very sensitive to
changes in the 12 hour data point, which is probably the case here, why
get more complicated? :-)
Steve
---
From: "Sam Liao"Date: Sat, 2 Feb 2002
23:38:57 -0500
To: david.-at-.boomer.org
Subject: RE: PharmPK Questions regarding AUC
The following message was posted to: PharmPK
Hi Weijiang:
Question is how you calculate the AUC. If it is calculated by linear
trapezoidal AUC, AUC-24 will be over-esitmated because drug
concentration decay exponentially in theory.
Best regards,
Sam Liao, Ph.D.
PharMax Research
270 Kerry Lane,
Blue Bell, PA 19422
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[Two replies - db]
From: David_Critchley.at.eisai.net
Date: Mon, 4 Feb 2002 08:46:05 +0000
To: david.-a-.boomer.org
Subject: Re: PharmPK Questions regarding AUC
The following message was posted to: PharmPK
Hi,
I have come across this issue before and it is not because of the method
of trapezoids used, as one gets the same result using either method (ie
AUC24
>AUCinfinity). It has occurred because you have a no measurable
concentration at 24hr, thus in order to calculate the AUC to 24hr the
programme draws a line from the 12hr concentration to the 0
concentration the 24hr point , thus adding a considerable triangle to
the area. If the terminal rate constant (k) predicts that the area after
the 12hr time point is smaller than this triangle (AUC extrapolation =
C12hr/k) the anomaly you desribe will occur. I guess once you understand
what's going on with the programme you can decide the best way to handle
it in context. In my situation I used the AUC24hr as I was not worried
by a slight overestimation (I was comparing AUCs from a clinical study
with AUCs from tox studies in order to help determine dose-escalation,
thus I was erring on the side of caution). However, the 'correct' answer
is probably to use the AUCinfinity, as the AUC24 for subjects where
there is no 24hr concentration is an artifact. I guess the only
difficulty that could arise is if the situation occurs where the k value
predicts a measurable level at 24hr and there is none to be found (ie
AUCinfinity>AUC24 but zero concentration observed at 24hr).
Note, the AUC24 is equivalent to the AUCall using WinNonlin (when zero
conc at 24hr), and the AUClast is the concentration up to the last
measurable concentration (12hr).
Hope this is helpful.
Regards,
Dave
Clinical Pharmacologist
Eisai Limited
---
From: Dimiter Terziivanov
Subject: PharmPK Questions regarding AUC To: david.aaa.boomer.org
MIME-Version: 1.0
Dear Weijiang Zhang,
It is not unexpected since according to the analytical method you
have used your 12 hour level is zero (or about LOQ), i.e. your AUC0->12
should be almost equal to AUC0->00.
I guess that the t1/2 of your drug is about 1.5-2h.
Kind regards,
Dimiter Terziivanov, MD,PhD,DSc
Clinic for Therapeutics and Clinical
Pharmacology, Univ Hosp "St. I.Rilsky",
15 D. Nestorov st, 1431 Sofia, Bulgaria
e-mal: terziiv.aaa.yahoo.com
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The following message was posted to: PharmPK
Thank you all for your help.
The problem I have is exactly as Dave said in his email. I've decided to
use AUCinfinity as AUC24 in this case, and provide additional
information about predicted 24 hour concentration using terminal phase
lambada z and last measurable concentration. Since all the predicted 24
hour concentrations are below LOQ, AUCinf can be used as AUC 24. BTW,
you are right, Dr. Terziivanov. The half-life of my compound is about
1.5 hour, and it's an oral dose.
Thank you again.
Best Regards,
Weijiang Zhang
Department of Pharmaceutical and Biomedical Sciences College of Pharmacy
The University of Georgia
Athens, GA 30602
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The following message was posted to: PharmPK
Another 2 cents...
For this problem one should NOT get AUC24 > AUCinfinity when the
log-trapezoidal method is used, provided: 1)the same kel value is used
for the calculation of the 24 hr concentration and the AUCinfinity; 2)
the actual 12 hour data point is used as a starting point for
AUCinfinity determination, as opposed to the "predicted" Clast that is
an option in Win-nonlin; 3) the calculated 24 hr concentration must not
be rounded to zero (even if it is ridiculously lower than the LOQ); and
4) The first 12 hours of the AUC are calculated the same way!.
The log-trapezoidal method works every time here because it is based on
the same model as the AUCinfinity calculation.
Steve
Stephen Day
Merck-Frosst Centre for Therapeutic Research Kirkland, QC CANADA
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Dear Weijiang Zhang,
I would like to express some concerns as regards your statement
"Since all the predicted 24 hour concentrations are below LOQ, AUCinf
can be used as AUC 24."
My concerns arise from the fact that your REAL concentrations are
zero or about LOQ long before the 24 hour. Your estimates of Cav(ss)
will be consistently overestimated and so will be the dosage regimen
predictions. I really don't know the therapeutic width of the drug under
consideration neither the target population(s) intended for it's use.
According to my experience, however, it is more safety if the protocol
includes 2(3) additional check-points, that is, at the 14h and at the
16h. This will allow you to hit on REAL zero or below LOQ levels and not
to use the predicted ones.
Kind regards,
Dimiter Terziivanov
Dimiter Terziivanov, MD,PhD,DSc, Professor Clinic for Therapeutics and
Clinical
Pharmacology, Univ Hosp "St. I.Rilsky",
15 D. Nestorov st, 1431 Sofia, Bulgaria
e-mal: terziiv.at.yahoo.com
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