Non-linear CL

From: "Gordi, Toufigh" Toufigh.Gordi@cvt.com Subject: [NMusers] Non-linear CL Date: Thu, 6 Oct 2005 13:01:28 -0700 Jing, Scrolling through your control stream, I find at least 3 possible sources of error. The first one is the large number of ETAs you have. All your parameters are associated with a variability terms, i.e. 6 ETAs! Do you really have enough information in your data to be able to estimate these parameters? In my limited experience, 1-3 ETAs are normally sufficient in most models. The second is the lack of infusion instructions to NONMEM. If your compound is given as infusion, you need to tell NONMEM about it. Third problem is with your $DES. The way it is written now, your drug lives the first compartment through elimination and transfer to compartment 2. Nothing comes back to it. However, in the next line, the drug leaves compartment 2 by going back to comp 1. The mass balance is not preserved. Also, you have a third compartment that is in contact with comp 2 but not the central compartment (comp 1). I think you will have issues with the ability to identify the model parameters, unless you have observations in compartments 2 or 3. Is this supported by other knowledge you have about how your compound is distributed and eliminated? I also have a question. When you state that CL in nonlinear, is it concentration- or time-dependent? In other words, does clearance change with a single dose or from one dose to the next? Toufigh Gordi P.s. There seems to be something wrong with the server. I sent this message this morning and it never got through, while I get double copies of other people's mails. I have had similar experience before. Associate Director of Clinical Pharmacology CV Therapeutics Inc. 3172 Porter Dr. Palo Alto, CA 94304 Tel.: 650-384-8929