Simulation settgin in the precence of Shrinkage in PK when doing PK-PD analysis

Hi nonmem users, I have a question related to shrinkage in PK when doing a sequential PK-PD analysis. Consider a situation with substantial shrinkage in the estimated individual PK (e.g. CL). When simulating PD based on dose from the model, it seems to me that variability in PD will be over-predicted if the estimated variability in CL (omega) is used. Would it then be appropriate to apply shrinkage to the variability in CL prior to simulating the PD? Does this have any practical consequences, and is meaningful to consider? I have mostly seen examples of consequences of shrinkage in the context of covariate analyses. Are there any examples relating to PK-PD analyses. E.g simultaneous, versus sequential? Consider for example the situations below: I.e. analysis performed by: 1. Derive individual PK parameters. 2. Relate posthoc plasma conc to PD If doing the analysis based on dose, any variability in PK will show up as variability in the dose-PD relationship. When doing the analysis based on plasma concentration (E.g. AUC), the PK-variability is accounted for by the PK-model and will not influence the variability in exposure response. However in the presence of shrinkage in the PK parameters, the situation should be somewhere in-between these two scenarios and some of the variability in PK will still show up as variability in PD. Hence when simulating based on the estimated variability in CL the variability in pd should theoretically be exaggerated. Regards, Matts Kågedal Senior Pharmacometrician AstraZeneca -------------------------------------------------------------------------- Confidentiality Notice: This message is private and may contain confidential and proprietary information. If you have received this message in error, please notify us and remove it from your system and note that you must not copy, distribute or take any action in reliance on it. Any unauthorized use or disclosure of the contents of this message is not permitted and may be unlawful.