Fw: mid-infusion higher than end of infusion
Although physiological explanations can not be completely discarded, by
the principles of Occam's Razor, one should look for simple explanations
first. I agree with James that infusion variability may be a likely
cause. In my experience infusion pumps are not nearly as precise as you'd
think they'd be.
----- Forwarded by Michael J Fossler/PharmRD/GSK on 07/11/2007 08:38 AM
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"James G Wright" <[EMAIL PROTECTED]>
Sent by: [EMAIL PROTECTED]
11-Jul-2007 05:24
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Subject
RE: [NMusers] mid-infusion higher than end of infusion
Hi Peter,
A difference of substantial magnitude in a 30-minute infusion would
suggest to me that the rate of input or time of sampling is not precisely
controlled. Sorry to be boring, but every time I have seen this so far it
has been explained by the administration or sampling procedure. That the
phenomenon is not necessarily reproducible in the same subject partially
supports this interpretation, as an explanation requires substantial
within-subject variation (which is actually why the netrophil-binding idea
is particularly clever).
It is common in studies for the end-of-infusion sample to in fact be just
after the end of the infusion (when concentration is falling, usually
rapidly) even when your protocol specifically disallows this.
Best regards, James
James G Wright PhD
Scientist
Wright Dose Ltd
Tel: 44 (0) 772 5636914
www.wright-dose.com
Quoted reply history
-----Original Message-----
From: [EMAIL PROTECTED] [mailto:[EMAIL PROTECTED]
On Behalf Of Bonate, Peter
Sent: 10 July 2007 18:01
To: [email protected]; [EMAIL PROTECTED]
Subject: [NMusers] mid-infusion higher than end of infusion
Dear all,
I have a very unusual situation and wanted to see about getting the
collective opinion on the group regarding the best way to handle this
modeling problem. I have a drug that is given by 30 minute infusion.
Samples were collected at predose, mid-infusion, end of infusion, and
serial thereafter for 8 halflives. In about a third of the samples the
mid-infusion sample had a considerably higher concentration (25 to
50%)than the end of infusion concentration. This phenomenon occurred
across multiple studies, on multiple days (although not always in the same
subject twice), and across multiple analytical runs. I have ruled out
switched tubes and analytical error. For a variety of reasons this
appears to be a valid phenomenon.
Now, how best to model it or even explain it. The best I have been able
to come up with is it is a distribution phenomenon. In discussions with
another modeler I was informed that he just reviewed a paper having the
same phenomenon and in that paper the authors discarded the midinfusion
data. I have tried using time-dependent volumes using continuous and
change-point functions. I get modest improvements in goodness of fit
compared to completely ignoring the phenomenon which has a residual
variability of about 30% using a 3-C model.
As a company we have decided to pursue an oral formulation of this drug so
it seems to me that modeling the iv data to the point of completely
capturing the phenomenon may be a modeling exercise and not of any real
value any longer.
Any opinions on the validity of throwing out the data, just running with
the model that ignores the phenomenon and has high residual variability,
or something else I haven't been able to think of would be appreciated.
Thanks,
pete bonate
Peter L. Bonate, PhD, FCP
Genzyme Corporation
Senior Director, Pharmacokinetics
4545 Horizon Hill Blvd
San Antonio, TX 78229 USA
[EMAIL PROTECTED]
phone: 210-949-8662
fax: 210-949-8219
blackberry cell: 210-315-2713
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