Re: target-mediate model: numerical difficulties

Dear Pavel, two initial thoughts: 1) Maybe run a sensitivity analysis in simulation mode and assess if you really need to describe the exact time course of the fast process. If not, then one option might be to fix one of the non-influential parameters. 2) Try to find the steady-state solution for the fast process and plug it in either directly as equation into the differential equation block. NONMEM has also special steady-state routines (see SS6 SS9 and ADVAN9 in the NONMEM help) which may be of help for you. Below are two specific and two more general references which seem very relevant. All the best Juergen ----------------------------------------------- Jurgen Bulitta, PhD Infectious Disease - Pharmacometrics University at Buffalo, NY, USA Phone: +1 716 645 2855 ext. 281 Fax: +1 716 645 3693 Email: [EMAIL PROTECTED] ----------------------------------------------- References: Mager DE, Krzyzanski W. Quasi-equilibrium pharmacokinetic model for drugs exhibiting target-mediated drug disposition. Pharm Res. 2005 Oct;22(10):1589-96. Epub 2005 Sep 22. Abraham AK, Krzyzanski W, Mager DE. Partial derivative-based sensitivity analysis of models describing target-mediated drug disposition. AAPS J. 2007 Jun 8;9(2):E181-9. I am sure, you have those two: Mager DE, Jusko WJ. General pharmacokinetic model for drugs exhibiting target-mediated drug disposition. J Pharmacokinet Pharmacodyn. 2001 Dec;28(6):507-32. Mager DE. Target-mediated drug disposition and dynamics. Biochem Pharmacol. 2006 Jun 28;72(1):1-10. Epub 2006 Feb 15. Review -----Ursprüngliche Nachricht----- Von: <[EMAIL PROTECTED]> Gesendet: 19.09.08 21:40:46 An: [email protected] Betreff: [NMusers] target-mediate model: numerical difficulties Hello NONMEM users, I am working on some target-mediated models. It is necessary to use ADVAN8 because differential equations describe very fast and very slow processes. The models run if I use option SLOW. If I do not use SLOW, different models for different drugs fail. The message is 0PROGRAM TERMINATED BY OBJ ERROR IN NCONTR WITH INDIVIDUAL 4 ID=XXXXXXXX NUMERICAL HESSIAN OF OBJ. FUNC. FOR COMPUTING CONDITIONAL ESTIMATE IS NON POSITIVE DEFINITE MESSAGE ISSUED FROM ESTIMATION STEP AT 0TH ITERATION, UPON EVALUATION OF GRADIENT WITH RESPECT TO OMEGA 0TRY SUBSTANTIALLY INCREASING "INITIAL ESTIMATE OF SIGMA" OR DECREASING "INITIAL ESTIMATE OF OMEGA" I tried to increase sigma, decrease omega, change the initial estimates, use different data and models. Nothing works. Is there a way around it? Option SLOW makes everything too slow. Thanks! Pavel