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Hi Roger.
I didn't think it was that mysterious. Doesn't it boil down to the
amount of PK/PD variation that is manageable in human clinical use?
Having acquired the experience of many medications we attempt to
extrapolate back from that to animal models, trying to evolve useful
parameters for predicting the PK/PD behaviour of a novel molecule.
If we had some kind of register of this variation perhaps an alternative
would be to just rank a novel molecule amongst its potential peers
rather than relying on what I agree is a somewhat arbitrary statistic.
The non-parametric approach!
I guess we'd have a problem with a unique and uniquely useful treatment
like digoxin but how many of them are there nowadays?
Kind regards to all the Forum for this New Year, 2012
Andrew Sutton
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The following message was posted to: PharmPK
Dear David,
At the end of the message from Nimesh Patel, you wrote:
>Are your variations in Vd, kel and t(1/2) similar to what others report
>after
>iv or po administration? Vd will be Vd/F and could vary with F. This could
>cause differences in kel and t1/2.
Variability in F will indeed affect Vd/F, but it will cause variability in
CL/F to the same degree. The calculated kel, and thus t1/2, will not depend
on F, since the ratio (CL/F) / (Vd/F) is the same as the ratio CL/Vd. So,
variability in F cannot cause differences in kel and t1/2.
all the best for 2012,
Hans Proost
Johannes H. Proost
Dept. of Pharmacokinetics, Toxicology and Targeting
University Centre for Pharmacy
Antonius Deusinglaan 1
9713 AV Groningen, The Netherlands
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This issue appears to pop up frequently. The question, to my mind, is a
bit misleading. I can't think of a reason why Vd, kel or t1/2 would
change as a function of route of administration. The only reason for
change in these values is an interference caused by the rate of
absorption (and not the bioavailability).
Which Vd are we talking about here? For clarity, let's take the Vss.
Obviously variability in F changes the value of Vss/F, but it does not
change the Vss. There is only one way to calculate Vss/F. Determine the
Vss after IV administration and divide the value by F (I don't know why
one would want to do that, but that's the correct way). Calculation of
Vss/F is not possible from data obtained after non-IV administration
unless you know, a priori, that the disposition of that drug is best
described by one-compartment model after IV administration.
If interested, you can find further reading in J. Vet Pharmacol Ther.
2011 Oct;34(5):512-4.
Best regards and a very good 2012,
Stefan Soback
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The following message was posted to: PharmPK
Plasma drug concentration profile:
Sorry for the earlier sloppy mailing. My reply was to these messages:
"At the end of the message from Nimesh Patel, you wrote:
>Are your variations in Vd, kel and t(1/2) similar to what others report
>after
>iv or po administration? Vd will be Vd/F and could vary with F. This
could
>cause differences in kel and t1/2."
Hans Proost wrote:
"Variability in F will indeed affect Vd/F, but it will cause variability
in
CL/F to the same degree. The calculated kel, and thus t1/2, will not
depend
on F, since the ratio (CL/F) / (Vd/F) is the same as the ratio CL/Vd.
So,
variability in F cannot cause differences in kel and t1/2."
This issue appears to pop up frequently. The question, to my mind, is
a bit misleading. I can=92t think of a reason why Vd, kel or t1/2 would
change as a function of route of administration. The only reason for
change in these values is an interference caused by the rate of
absorption (and not the bioavailability).
Which Vd are we talking about here? For clarity, let=92s take the Vss.
Obviously variability in F changes the value of Vss/F, but it does not
change the Vss. There is only one way to calculate Vss/F. Determine
the Vss after IV administration and divide the value by F (I don=92t
know why one would want to do that, but that=92s the correct way).
Calculation of Vss/F is not possible from data obtained after non-IV
administration unless you know, a priori, that the disposition of that
drug is best described by one-compartment model after IV
administration.
If interested, you can find further reading in J. Vet Pharmacol Ther.
2011 Oct;34(5):512-4.
Best regards and a very good 2012,
Stefan Soback
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