RE: mid-infusion higher than end of infusion

-----Original Message----- From: [EMAIL PROTECTED] [mailto:[EMAIL PROTECTED] Behalf Of Rene Bruno Sent: Wednesday, July 11, 2007 8:50 AM To: James G Wright; [email protected] 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: [EMAIL PROTECTED] [mailto:[EMAIL PROTECTED] On Behalf Of James G Wright Sent: Wednesday, July 11, 2007 11:25 AM To: [email protected] 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: [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