Plcebo Corrected PK/PD

From: "MANOJ KHURANA" manoj2570@yahoo.com Subject: [NMusers] Plcebo Corrected PK/PD Date: Wed, March 2, 2005 12:07 pm Dear Group, I am trying to understand the way and need of doing placebo correction for PD response in PK/PD modeling. I went through NONMEM archives but couldn't find much. One reference that I came accross was "P. Mortin et al. Pharmacodynamic and Pharmacokinetic profile of S17092, a new orally active prolyl endopeptidase inhibitor, in elderly healthy volunteers. A phase I study. BJCP, 50, 350-359" and they looked at %inhibition of prolyl endopeptidase for escalating dose cohorts having 9 subjects per cohort (3 placebos + 6 treatment) and placebo correction was done by subtracting the average response at each time point. I need to know if this averaging method is the ideal and acceptable way of doing it when we know that there is intersubject variability in the response in the placebo group other than the assay variability. Is there a way to handle this in the model itself in NONMEM. My next question is vvery general. Can someone explain me under what circumstances do we need a placebo correction and how it is done for different PD responses. What should be our criteria to decide if we need a placebo correction while looking at the placebo response data. I would appreciate if someone could provide me references and guidance for that. Thanks in advance for your time Manoj Khurana