Carl: You may want to try a couple of things. First, NONMEM 7.3 should be used, as improvements on IMP are always made.
Next, after the SAEM step, try $EST METHOD=IMP MAPITER=0 EONLY=1 NITER=20 Where MAPITER=0 has NONMEM not perform a MAP step even on the first iteration, but borrows conditional means and variances as proposal density information from the previous SAEM step. If this still does not work, then go in the opposite direction and have MAP done on every iteration: $EST METHOD=IMP MAPITER=0 EONLY=1 NITER=20 Robert J. Bauer, Ph.D. Vice President, Pharmacometrics R&D ICON Early Phase Office: (215) 616-6428 Mobile: (925) 286-0769 robert.ba...@iconplc.com<mailto:robert.ba...@iconplc.com> www.iconplc.com<http://www.iconplc.com> From: owner-nmus...@globomaxnm.com [mailto:owner-nmus...@globomaxnm.com] On Behalf Of Panetta, Carl Sent: Tuesday, November 24, 2015 9:35 AM To: nmusers@globomaxnm.com Subject: [NMusers] IMP method not stationary I am having some issues with the IMP method using EONLY=1 option to generate an estimate of the objective function. Specifically I am first running the SAEM method and the model appears to be converging well (i.e. SAEMOBJ is stable). But when I then try to get the estimate of the objective function using the IMP method the OBJ value is not stable and actually is steadily increasing. (See the NONMEM output below.) The data and model for this problem are a 3 compartment linear PK model with zero-order absorption (using ADVAN7) where each compartment represents either the parent drug or one of the two measured metabolites. Overall the fits look good and the parameter estimates are reasonable. Note that if I only run the model with the parent drug and a one compartment model with zero-order absorption everything works as expected, i.e. the OBJ for the IMP step is very stable. Are there setting for the IMP step that I should be modifying to help stabilize the objective function with the more complex model (i.e. drug + metabolite) vs the more basic model (parent drug alone)? I appreciate any suggestions. Thanks, J. Carl Panetta, Ph.D. Department of Pharmaceutical Sciences St. Jude Children's Research Hospital 262 Danny Thomas Place Memphis, TN 38105 Office: (901) 595-3172 Mobile: (901) 921-3740 Fax: (901) 595-3125 carl.pane...@stjude.org<mailto:carl.pane...@stjude.org> NONMEM Command: $EST PRINT=200 INTERACTION NOABORT METH=SAEM NBURN=600 NITER=800 MAPITER=0 Output: Stochastic/Burn-in Mode iteration -600 SAEMOBJ= 9495.99674546385 iteration -400 SAEMOBJ= 8603.58235406272 iteration -200 SAEMOBJ= 8723.87279412471 Reduced Stochastic/Accumulation Mode iteration 0 SAEMOBJ= 8736.22287161761 iteration 200 SAEMOBJ= 8483.86390119489 iteration 400 SAEMOBJ= 8461.33184842421 iteration 600 SAEMOBJ= 8458.72312502707 iteration 800 SAEMOBJ= 8457.40631588857 NONMEM Command: $EST PRINT=1 INTERACTION NOABORT METH=IMP EONLY=1 ISAMPLE=3000 NITER=15 MAPITER=0 Output: iteration 0 OBJ= 11357.6200237143 eff.= 825098. Smpl.= 3000. Fit.= 0.99912 iteration 1 OBJ= 11480.4689169933 eff.= ******** Smpl.= 3000. Fit.= 0.99692 iteration 2 OBJ= 11794.3704982717 eff.= ******** Smpl.= 3000. Fit.= 0.99469 iteration 3 OBJ= 11877.2905908383 eff.= ******** Smpl.= 3000. Fit.= 0.99666 iteration 4 OBJ= 12350.7139467883 eff.= ******** Smpl.= 3000. Fit.= 0.99319 iteration 5 OBJ= 12822.3794461581 eff.= ******** Smpl.= 3000. Fit.= 0.98859 iteration 6 OBJ= 13338.5294969671 eff.= ******** Smpl.= 3000. Fit.= 0.98440 iteration 7 OBJ= 13800.6919759203 eff.= ******** Smpl.= 3000. Fit.= 0.98330 iteration 8 OBJ= 14072.5744654244 eff.= ******** Smpl.= 3000. Fit.= 0.98545 iteration 9 OBJ= 14703.6086363413 eff.= ******** Smpl.= 3000. Fit.= 0.98586 iteration 10 OBJ= 15703.8492953385 eff.= ******** Smpl.= 3000. Fit.= 0.97584 iteration 11 OBJ= 16114.3684511057 eff.= ******** Smpl.= 3000. Fit.= 0.96980 iteration 12 OBJ= 15968.9435824919 eff.= ******** Smpl.= 3000. Fit.= 0.98161 iteration 13 OBJ= 16309.4158350109 eff.= ******** Smpl.= 3000. Fit.= 0.96581 iteration 14 OBJ= 16001.2089520460 eff.= ******** Smpl.= 3000. Fit.= 0.97431 iteration 15 OBJ= 16920.1964345088 eff.= ******** Smpl.= 3000. Fit.= 0.95322 <br /><br /> ICON plc made the following annotations. ------------------------------------------------------------------------------ This e-mail transmission may contain confidential or legally privileged information that is intended only for the individual or entity named in the e-mail address. If you are not the intended recipient, you are hereby notified that any disclosure, copying, distribution, or reliance upon the contents of this e-mail is strictly prohibited. If you have received this e-mail transmission in error, please reply to the sender, so that ICON plc can arrange for proper delivery, and then please delete the message. Thank You, ICON plc South County Business Park Leopardstown Dublin 18 Ireland Registered number: 145835
