MM elimination vs dose

From: "Bonate, Peter" Peter.Bonate@genzyme.com Subject: [NMusers] MM elimination vs dose Date: Fri, 30 Sep 2005 12:25:03 -0400 Dear all, I am having trouble with something and I was hoping that someone would have some brilliant solution for me. I am fitting a 3-compartment model IV in 95 patients with rich data using FO-approximation. My base model has BSA and Age on CL as power functions. When I include dose on clearance as a power model, the OFV decreases from 13620.35 to 13516.61. The power term (SE) was -0.341 (0.152). Further, if I plot AUC(0-infinity) vs dose there is evidence of nonlinearity based on a power model. A 2-fold increase in dose results in a ~2.3 fold increase in AUC. The next model I tried was a Michaelis-Menten model where BSA and Age was included on Vmax. The OFV was 13619.24. No change from the base model. I also tried different starting values for Vmax and Km and get around the same solution each time, so local minima I don't apply here. Even when I compare a 3-compartment model with no covariates to a 3-compartment model with MM elimimation the OFV does not change (14138.61 vs. 14138.79, respectively). But as soon as a put Dose on CL (OFV=13560.37), BSA on CL (OFV=13651.29), and AGE on CL (OFV = 13942.51), the OFV decreases from the base model of 14138.61. Even taking into account the problems with the distribution of the likelihood ratio test and FO-approximation, these seem to be real decreases. So has anyone any ideas for why dose drops the OFV in a linear compartmental model but a MM elimination model won't work. All models minimized successfully without any singularities. Is the nonlinearity so mild that it can't be supported by a nonlinear compartmental model? Thanks for your help, Pete Bonate Peter L. Bonate, PhD, FCP Director, Pharmacokinetics Genzyme Corporation 4545 Horizon Hill Blvd San Antonio, TX 78229 phone: 210-949-8662 fax: 210-949-8219 email: peter.bonate@genzyme.com