RE: mid-infusion higher than end of infusion
Hi Pete
I assume that this compound is NOT a biologic, owing to the plans for oral
formulation, but can you give any information on the general class of agent
that you are dealing with? That can provide some information on possible
causes of this sort of behavior such as what Bruce suggests below. You
could also get extravasation or some local inflammation that is causing
altered PK in the case of anti-neoplastic agents
Diane
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Quoted reply history
From: [EMAIL PROTECTED] [mailto:[EMAIL PROTECTED] On
Behalf Of Bruce Charles
Sent: Tuesday, July 10, 2007 8:06 PM
To: Bonate, Peter; [email protected]; [EMAIL PROTECTED]
Subject: RE: [NMusers] mid-infusion higher than end of infusion
We saw this behavior with doxorubicin infused over 20 min to parrots and it
seems to be quite reproducible (Gilbert et al. Aust Vet J 2004; 82:769-772)
. We put it down to mid-infusion fluctuations in serum levels as a result of
altered cardiac output from the concentrated infused drug, based on the
papers by Richard Upton (Br J Anaesth 2004; 92:475-484 ; Intensive Care Med
2001; 27: 276-282).
Cheers
BC
Bruce CHARLES, PhD
Associate Professor
School of Pharmacy
The University of Queensland, 4072 Australia
[University Provider Number: 00025B]
TEL: +61 7 336 53194
FAX: +61 7 336 51688
[EMAIL PROTECTED]
http://www.uq.edu.au/pharmacy/brucecharles/charles.html
From: [EMAIL PROTECTED] [mailto:[EMAIL PROTECTED] On
Behalf Of Bonate, Peter
Sent: Wednesday, July 11, 2007 3:01 AM
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