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 - 08:50:14 EDT