Back to the Top
The following message was posted to: PharmPK
Dear all,
We had rats received single and multiple doses of a drug (let's say, 10 mg/kg qd
and 10 mg/kg qd x 7d), and PK parameters of AUC, clearance, and Vd were
statistically evaluated. The results showed that AUC significantly increased
after multiple doses, but clearance and Vd were not different when comparing in
single and multiple doses.
As NCA was used for calculating clearance from AUC (CL=Dose/AUC), I am confused
with the results. This may be just due to the mathematical calculations. But is
there any biological explanation for the increased AUC but constant clearance
(when doses remained the same)?
I appreciate anyone's comments.
Best regards,
Ralf
How are you ('the program' - what program?) calculating AUC (multiple dose). It should be from 0 to Tau not
infinity - db]
Back to the Top
The following message was posted to: PharmPK
Dear Ralf,
If the clearance remains constant, AUCtau at steady-state should
mathematically be equivalent to AUCinf after single dose. Indeed,
CL=Dose/AUCinf after single dose and CL=Dose/AUCtau at steady state.
Are you sure you are not comparing pears and apples? Especially, if you
compare the same kind of AUC (AUCtau or AUCinf) between multiple and single
dosing, it is expected to have an increase after multiple dosing simply
because of the accumulation.
--
Fabrice Nollevaux,
Pharmacometrics and Statistics Team Manager
www.arlenda.com
Back to the Top
The following message was posted to: PharmPK
Ralf,
What is the half-life of the drug? Has all of the previous dose been
substantially cleared before the next dose is administered?
Best regards,
Walt
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (NASDAQ: SLP)
42505 10th Street West
Lancaster, CA 93534-7059
U.S.A.
http://www.simulations-plus.com
Back to the Top
[Maybe repeat - db]
The following message was posted to: PharmPK
Dear Walt and Nollevaux,
Many thanks for your kind replies.
To Walt,
The half-life is about 2.5 hr, and the drug is administered once daily.
Therefore it is likely no accumulation during the multiple dosing regimen. The
pre-dose blood samples from multiple-dose group also showed only trace amount
(nearly BQL) presented before the consecutive dose.
To Nollevaux,
Since the drug is almost eliminated before the next dose administered, comparing
AUCinf of single dose with AUCtau or AUCinf of multiple dose did not result in
different conclusions (AUC_%Extrap < 0.5%).
I would like to illustrate the experiment more detailed. Male and female rats
were grouped to receive 2 dose of the drug (10 and 20 mg/kg), and grouped to
receive the drug in single and multiple does. I suppose there are three factors
(gender-male and female, dose-10 and 20, and treatment-single and multiple ),
and three-way anova was used for the statistical evaluation. As previously
mentioned, in female rats AUC significantly increased after multiple doses, but
clearance and Vss were not different. In contrast, no difference in AUC,
clearance, and Vss in male rats.
It is interesting that the statistical results reflect what we observed--
decreased food consumption and body weight loss were found in female rats after
multiple doses, but no abnormal findings in male rats. It seems that the toxic
effect in female rats is correlated with the increased AUC. Yet I am wondering
why the clearance remained constant when AUC significantly increased?
Best regards,
Ralf
Back to the Top
Ralf:
My two cents;
1. Since there is a gender difference, most likely your drug is metabolized by CYP3A (in
rats there is gender difference)
2. Inhibition of CYP3A could be a time-dependent/conc dependent
3.If the metabolism is CYP3A mediated, please check the effect of transporters if you
havent already looked, transporter/DME inhibition can lead to increased AUC
Another scenario:
In females, a Phase II metabolite most likely a glucuronide is produced more than in
males, that falls off in the mass spec source, giving you the increase in AUC of the
parent but no changes in CL. Please check if there are any glucuronides, what they, and
how they behave in the mass spec source. This could be an analytical artifact.
Regards
Parnali Chatterjee
E-mail: Parnalic.-a-.hotmail.com
parnali_chatterjee.-at-.yahoo.com
Back to the Top
Dear Ralph,
with respect to difference between male and female rat, you can have a look of one of our
recent paper related to drug metabolism enzyme activity in both gender. This may help you.
http://www.ncbi.nlm.nih.gov/pubmed/22321050
Henri
Back to the Top
The following message was posted to: PharmPK
Dear Ralf,
Before extending the discussion to biology, I just want to be sure that the underlying
maths are correct ;-)
You wrote " Since the drug is almost eliminated before the next dose administered,
comparing AUCinf of single dose with AUCtau or AUCinf of multiple dose did not result in
different conclusions (AUC_%Extrap < 0.5%).".
Indeed, if the drug elimination from the body between each successive dose is virtually
complete, you are right that it makes not a big difference comparing AUCtau or AUCinf.
But then, I still miss the point on how your clearance can be different between single and
repeated dosing: If AUCtau(repeated)=AUCinf(single), then
CL(repeated)=Dose/AUCtau(repeated)=Dose/AUCinf(single)=CL(single).
For a better understanding, maybe coud you indicate how (software, formulas...) CLs have
been calculated?
Another thought is that the apparent discrepancy in your results could be an artefact of
your statistical analysis.
As you probably know, the assumption of a normal distribution does not hold for PK
parameters (first, simply because a PK parameter can not be negative). PK parameters are
generally considered as log-normally distributed and therefore should be analyzed using a
multiplicative model instead of an additive model. For an ANOVA, this can be achived by
applying the statistical model to the log-transformed data rather than on the raw data. As
the clearance is only a (rescaled) inverse of the AUC, the statistical results obtained on
log(CL) or on log(AUC) should then be identical.
Fabrice
--
Fabrice Nollevaux,
Pharmacometrics and Statistics Team Manager
www.arlenda.com
|
Want to post a follow-up message on this topic?
If this link does not work with your browser send a follow-up message to PharmPK@boomer.org with "Increased AUC but constant clearance after multiple doses" as the subject | Support PharmPK by using the |
Copyright 1995-2011 David W. A. Bourne (david@boomer.org)