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 <http://www.wright-dose.com/>

-----Original Message-----
From: owner-nmusers_at_globomaxnm.com [mailto:owner-nmusers_at_globomaxnm.com]
On Behalf Of Bonate, Peter
Sent: 10 July 2007 18:01
To: nmusers_at_globomaxnm.com; PharmPK_at_boomer.org
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
peter.bonate_at_genzyme.com
phone: 210-949-8662
fax: 210-949-8219
blackberry cell: 210-315-2713
 



Received on Wed Jul 11 2007 - 05:24:44 EDT