RE: Simulations

From: "HUTMACHER, MATTHEW" <MATTHEW.HUTMACHER@chi.monsanto.com> Subject: RE: Simulations Date: Mon, 15 Nov 1999 09:50:26 -0600 Elaine, I am a little confused after reading your comparison of the NONMEM and Pharsight softwares on how you modeled the variability in NONMEM. On page 2 you sate "The variability in Ka, CL/F and V/F between subjects was modeled as proportional to the parameter and reported as a coefficient of variation (CV).". I translate this to mean you modeled, e.g. CL as CL=TVCLx(1+ETA(1)). Yet on page 5 in Table I, the table of PK parameter estimates, you report the model as "xexp(ETA(1))". These two models are not the same in terms of simulation. Estimation is a different matter. It is true under the first-order (FO) estimation scheme that these two models are equivalent in that the estimates of OMEGA for the two models should be within round-off error. If one uses the first-order conditional estimation method (FOCE), then these models will yield different estimates of OMEGA, especially for large intersubject variability. If you are interested in assessing the difference in simulated individual PK parameters by the two software packages, a more direct comparison can be made using a Q-Q plot. To construct a Q-Q plot, one could output the simulated individual parameters to a file. Then for each parameter, e.g. CL, one could sort the simulated CLs in ascending order (to obtain the order statistics) for both software types. The two sets of CLs could then be paired by their order statistics and plotted, e.g. Pharsight's on the x-axis and NONMEM's on the y-axis. If the method of simulation between the two softwares is the same, the distribution of points should lie very close to the line of identity (y=x). If the points deviate from this line, how they deviate should provide information as to the nature of the discrepancy. Hopefully this helps. Matt