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Hi All,
I am comparing AUCs for subjects who each were in 4 treatment groups on
separate days - enzyme induced, enzyme inhibited, selective intestinal
inhibition, and controls. My sample times are the same for each enzyme
state, and using a noncompartmental analysis (NCA), I am extrapolating
approximately 30% of the AUCinf in the enzyme inhibited group. This
appears
to be giving me inflated AUCs, however when I deliberately limit my
data in
the NCA such that the AUC derived from the controls and other enzyme
states
is equally extrapolated (about 30%), I do not get inflated AUCs. The
last
sample time for the inhibited session is approximately equal to the
inhibited t1/2, and I limited the other enzyme state data to samples at
or
below the t1/2 as a test if the high % AUC extrapolated is the
explanation
for the inflated AUCs. This does not appear to be the case. I would
expect
the high % AUC extrapolated to result in more variance though not
necessarily bias, provided the kinetics are linear (they are). And why
did
the test run of limited data on the other enzyme data not produce the
same
bias? I believe the inhibited state AUCs to be inflated because when I
plot
all the AUC data (all 4 sessions) against a plasma concentration at a
single
sample time, all but the inhibited data falls on a line. Any thoughts?
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Dear Harshu,
I am a little confused about your statement that the kinetics of the
compound is linear on all the occasions, despite the fact that you
inhibit or induce the metabolism and thereby clearance, or manipulate
the absorption and thus bioavailability. Could you explain why you
think the kinetic is linear and what your criterias are for a linear or
non-linear kinetic? What are the relative changes in the AUCs compared
to the control group?
Toufigh Gordi
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Dear Harshu Chaobal,
You wrote:
>I am comparing AUCs for subjects who each were in 4 treatment groups on
>separate days - enzyme induced, enzyme inhibited, selective intestinal
>inhibition, and controls. My sample times are the same for each enzyme
>state, and using a noncompartmental analysis (NCA), I am extrapolating
>approximately 30% of the AUCinf in the enzyme inhibited group. This
appears
>to be giving me inflated AUCs, however when I deliberately limit my
data in
>the NCA such that the AUC derived from the controls and other enzyme
states
>is equally extrapolated (about 30%), I do not get inflated AUCs.
IHMO, your reasoning is incorrect:
1) The term 'inflated AUC' suggests that you assume that
the calculated value of AUC is overestimated due to the
extrapolation. If you have concerns that AUC is 'inflated'
by extrapolation, you cannot simply omit data points from
the other groups to get the same level of extrapolation.
You will not correct the inflated AUC, but, at best,
inflate the AUC in the other groups to the same level. But
in real practice it is more likely that you will increase
the error in your final results. You should focus on
improving the extrapolation of the 'problem' data, e.g. by
a more sophisticated way of estimating the terminal rate
constant.
2) 'Deliberately' omitting data sound like filling your
car with water instead of petrol. This will never work.
One should only omit data if there is a serious reason why
the data are not correct, or, perhaps, if the data do not
contribute to your results. But omitting data to increase
the degree of extrapolation is definitely bad practice.
Best regards,
Hans Proost
Johannes H. Proost
Dept. of Pharmacokinetics and Drug Delivery
University Centre for Pharmacy
Antonius Deusinglaan 1
9713 AV Groningen, The Netherlands
tel. 31-50 363 3292
fax 31-50 363 3247
Email: j.h.proost.-a-.farm.rug.nl
[Are the clearance values the same across groups? Has this be adjusted
for? How about truncated AUCs (or is this dropping data ;-) - db]
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Hi, I have a query for calculating of AUC0-inf
This is regarding calculating of AUC0-inf, during a bioequivalence
study with 36 hours time point as last sample; the concentration of
last sample (36 hours) is 0.00 ng/mL. What would be my last measurable
concentration for calculating AUC0-inf? Is it 0.00 or the concentration
found at 24.00 hours (second last sample)? In other words is AUC0-t and
AUC0-inf the same if the last sample concentration found is 0.00?
Thanks in advance
Bipin Patel
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The following message was posted to: PharmPK
Dear Bipin,
AUC (total) = AUC1+AUC2+AUC3+....AUCn
in your example
AUCn= (C(24)+C(36)/ 2) * (t (24) - t (36)) = ( (C(24) + 0)/2) * 12=
C(24) *
6
If your limit of quantification (LOQ) is well validated.
Dr Sadray
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In reply to
Hi, I have a query for calculating of AUC0-inf
This is regarding calculating of AUC0-inf, during a bioequivalence
study with 36 hours time point as last sample;
[SP] AS A RULE YOU MUST CONSIDER AS "LAST POINT" THE LAST QUANTIFICABLE
SAMPLE, I.E. THE LAST SAMPLE ABOVE LLQ (LOWER LIMIT OF QUANTIFICATION).
the concentration of[SP] last sample (36 hours) is 0.00 ng/mL. What
would be my last measurable concentration for calculating AUC0-inf? Is
it 0.00 or the concentration found at 24.00 hours (second last sample)?
In other words is AUC0-t and AUC0-inf the same if the last sample
concentration found is 0.00?
[SP] OBVIOUSLY AUC-t IS CALCULATED FROM TIME 0 TO THE TIME OF LAST
POINT >ABOVE LLQ AND AUC-inf IS CALCULATED AS AUC-t+(EXTRAPOLATED AREA
FROM LAST >POINT ABOVE THE LLQ AND INFINITY)
BEST REGARDS
STEFANO PORZIO
Pharmacokinetic and Tox. Dept.
Inpharzam Ricerche SA - ZAMBON-GROUP
Taverne - Switzerland
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The following message was posted to: PharmPK
Dear Bipian, Sida, and Stefano,
although statistics deals with probabilities, in PK we can be sure
(p=1),
that one particular concentration simply does not exist: zero ;-)
I would suggest to follow Stefano's advice, and calculate AUC until
the time point of the last quantifiable concentration by NCA-methods
(whatever you have stated in the protocol: in decreasing sequence of
regulatory acceptance - linear trapezoidal, log/linear trapezoidal,
Splines, Lagrange interpolation) and extrapolate from this time point
to infinity.
In the past there was a good deal of discussion around about the
"correct" calculation of AUC in NCA. It does make sense to include
the "absorption triangle" (since we know, that the pre-dose
concentration is sufficiently close to zero), but the "elimination
triangle" leading to something called "AUC-total" or "AUC-all"
simply does not make sense.
Please have a look at http://www.boomer.org/pkin/pk/AUCinf.jpg.
Example:
A drug with a half life of 12h, the last sampling time points
16h, 24h, and 36h.
Now imagine an infinitesimal difference in ka (or tlag) between
formulations (within the same subject). In one case you will get
a concentration at 24h just slightly above LOQ, whereas in the
other case you will not be able to quantify that concentration.
In the first case you will add a last "triangle" from 24h to 36h
(the "true" concentration at 36h is about LOQ/2, not zero!),
whereas your last triangle in the second case will cover 16h to 24h
(the "true" concentration at 24h is just slightly below LOQ, not
zero...).
best regards,
Helmut
--
Helmut Schutz
BEBAC
Consultancy Services for Bioequivalence and Bioavailability Studies
Neubaugasse 36/11
A-1070 Vienna/Austria
tel/fax +43 1 2311746
http://BEBAC.at Bioequivalence/Bioavailability Forum at
http://forum.bebac.at
http://www.goldmark.org/netrants/no-word/attach.html
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The following message was posted to: PharmPK
Dear Helmut
Even though
C(36)=LOQ/2=almost 0
the AREA of the last triangle can be whatever
C(24)x(36-24)/2
and may be a value not negligible. Or is there something I dont get
right?
Best regards
Otilia Lillin
MSc Scientific Computing
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DEAR OTLILLA,
I SUSPECT YOU HAVE NO EXPERIENCE TO CALCULATE NC PARAMETERS!
IF YOU LIKE YOU CAN FOLLOW THESE SUGGESTIONS:
1. PLACE THE PROFILE IN SEMILOG GRAPHIC I.E. LOG (CONECENTRATION)
VS. TIME
2. VERIFY THAT A MINIMUM OF 3 POINTS ARE AVAILABLE TO APPROXIMATE A
STRAIGHT-LINE IN THE LAST PART OF YOUR PROFILE (YOU MUST DEFINE THE
LAST POINT AS THE FAREST POINT ABOVE LOQ, THEN GET BACK TO OTHER
POINTS)
3. DESIGNE, MANUALLY OR BY LINEAR REGRESSION, A REGRESSION LINE IN
SEMILOG SCALE FOR SELECTED POINTS (A MINIMUM OF 3 POINTS ARE USUALLY
REQUIRED TO DEFINE AN ACCEPTABLE REGRESSION)
4. CALCULATE THE SLOPE OF THIS STRAGHT LINE (EQUATION IS
Concentration = -lambda x time + constant)
5. USE lamda TO CALCULATE THE AUC FROM LAST POINT TO INFINITY AS
[CONCENTRATION OF THE LAST POINT]/lamda
6. AS [CONCENTRATION OF THE LAST POINT]YOU CAN CONSIDER THE
[EXPERIMENTAL CONCENTRATION] OR THE [CALCULATED CONCENTRATION] AS BY
YOUR REGRESSION STRAIGHT LINE (I.E. [CALCULATED CONCENTRATION] =
-lambda x [LAST TIME]+ constant)
7. CALCULATE THE AUC 0-inf AS THE SUM OF AUC 0-last + AUC last-inf
BEST REGARDS
STEFANO PORZIO
INPHARZAM RICERCHE S.A.
ZAMBONGROUP
TAVERNE - SWITZERLAND
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The following message was posted to: PharmPK
Dear Otilla,
you wrote:
>Even though,
>C(36)=LOQ/2=almost 0
>the AREA of the last triangle can be whatever
>C(24)x(36-24)/2
>and may be a value not negligible.
>
I am afraid, you first line is not correct, since:
C(36) # LOQ/2 # 0!
We simply do not know the value of C(36);
the only thing we do know is:
LOQ > C(36) > 0.
It does not make sense to put so much effort in validating
the analytical method (and we are satisfied with 20% precision
and 20% inaccuracy at LOQ!), and then rather arbitrarily
setting the first value after the last quantifiable to LOQ/2
or - even worse - to zero.
Best regards,
Helmut
--
Helmut Schutz
BEBAC
Consultancy Services for Bioequivalence and Bioavailability Studies
Neubaugasse 36/11
A-1070 Vienna/Austria
tel/fax +43 1 2311746
http://BEBAC.at Bioequivalence/Bioavailability Forum at
http://forum.bebac.at
http://www.goldmark.org/netrants/no-word/attach.html
PharmPK Discussion List Archive Index page
Copyright 1995-2010 David W. A. Bourne (david@boomer.org)