RE: Approximate effect compartment

From: "Kowalski, Ken" Subject: RE: [NMusers] Approximate effect compartment Date: Fri, 22 Mar 2002 08:15:48 -0500 Daren, You might want to take a look at my paper: Kowalski, K.G. and Karim, A. "A Semicompartmental Modeling Approach for Pharmacodynamic Data Assessment," JPB 23:307-322 (1995). In this paper I derive what I call a semicompartmental solution to the effect-site concentration (Ce) where the only kinetic parameter that is estimated is keo. I assume a piecewise linear model for Cp (like doing the trapezoidal AUC) and using the effect site link dCe/dt = keo(Cp - Ce), I derive a recursive solution for Ce that only requires "noncompartmental-like" calculations. Using this solution for Ce requires one to use the observed Cp as a covariate and then one can estimate, keo and the PD parameters without having to specify a compartmental model for Cp. Now the bad news. This approach was developed for single subject data with fairly dense sampling...enough for doing noncompartmental calculations. Since you have sparse population data I don't think this approach will work for you. Moreover, even if you had dense sampling, some very special programming using verbatim code would be needed if you wanted to implement this method in NONMEM and plan to put an eta on keo. It turns out that one cannot "simply" specify recursive models using $PRED if those recursive models involve etas because NONMEM won't calculate the derivatives properly. Nevertheless, my paper might give you some additional insight. Regards, Ken