RE: [NMusers] mid-infusion higher than end of infusion

I saw similar problems because of operation procedures for compounds =
with rapid decay after the end of infusion. Therefore it is essential to =
make sure the PK sample at the end of infusion is collected right before =
the end of infusion rather than post the end of infusion.
 
Just curious about the binding issue. Could anyone describe a little bit =
more about this? Will this happen for a 30-minute infusion? How about =
for a 6-hour infusion or 24-hour continuous infusion? That is, is there =
a time scale/limit to observe this phenomenon (because of the binding =
variation with time)? Is this also dependent on the infusion rate and =
concentration?
 
Alan

-----Original Message-----
From: owner-nmusers_at_globomaxnm.com =
[mailto:owner-nmusers_at_globomaxnm.com]On Behalf Of Rene Bruno
Sent: Wednesday, July 11, 2007 8:50 AM
To: James G Wright; nmusers_at_globomaxnm.com
Subject: RE: [NMusers] mid-infusion higher than end of infusion



Hi everybody,

 

Of course poor control of the infusion rate can be an issue and also =
make sure that the end of infusion sample is performed just before the =
end of infusion rather than just (or some time) after. If these issues =
are clarified then binding of the drug to circulating cells or receptors =
could be an explanation... for example, this phenomenon is pretty common =
with monoclonal antibodies that bind to circulating receptors.

 

Rene

 


  _____


From: owner-nmusers_at_globomaxnm.com [mailto:owner-nmusers_at_globomaxnm.com] =
On Behalf Of James G Wright
Sent: Wednesday, July 11, 2007 11:25 AM
To: nmusers_at_globomaxnm.com
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 <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 - 11:32:06 EDT