Re: Time of day as a covariate

From: "Bonate, Peter" - pbonate@ilexonc.com Subject: Re: [NMusers] Time of day as a covariate Date: 2/10/2004 2:15 AM Dear Peter, There are many possible reasons, to be considered after Nick's comments bout clinical significance of course. I would consider: - Protein binding, since tissue partition, Kp, is a function of Kp for he unbound drug (Kpu) and fu. Kpu is often assumed to be invariant even across species (it depends upon what the particular drug binds to in the tissue though). - Blood cell distribution, which would affect fu - Since I note your are in an oncology company, perhaps comedications which could affect tissue distribution through the above mentioned mechanisms, plus perhaps interaction with tissue transporters. - Components of food could affect many of these mechanisms. - If the drug is not delivered parenterally, is the V1 you are considering really V/F, therefore the variation could be due to F? Best regards, Phil. Philip Lowe PhD Head of Modelling and Systems Biology Clinical Development & Medical Affairs Novartis Pharmaceuticals AG CH-4002 Basel Switzerland