Distribution of Simulated Cmax

From: Partha Nandy partha.nandy@bms.com Subject: [NMusers] Distribution of Simulated Cmax Date: Sat, 19 Nov 2005 11:45:15 -0500 Hi All, I am kindly seeking your opinion regarding an observation that I have made on a number of occasions. Here's the scenario: First I first fit a PK model (1-, 2- or 3-compartment & covariates) to the data and after validating the model, use the model to predict the concentration-time profiles. I then take the simulated concentration-time data to compute AUCt, AUCINF, and Cmax, via. non-compartmental approach. Even though the distribution of the PK parameter estimates generated from boot-strap data are similar to the parameter distributions from the original data set, and PPC (posterior predictive check) do not show obvious flaws in the model; most often the distribution of Cmax estimated from the Simulated data sets are quite different from that of the observed/experimental data set (I have used Chi-square and Kolmogorov-smirnov 2-sample test to compare distribution). In fact it appears that the the observed distribution and simulated distribution came from very different populations. In this situation, if one wants to compare treatments using 90% confidence-intervals (80-125%), how valid is the comparison when it appears that the simulated data is from a different population and the observed data from a different population, moreover the CIs from the observed Cmax was not within 80-125%. Have any one faced this dilemma and if so, can any one share their experiences? Any suggestions from the group is appreciated. Kind Regards, Partha