A problem with numerical integration difficulties for a complex model

Dear all Sorry to bother you. I have encountered a problem with a complex model, involve a full TMDD PK model lined to a complicated multi-compartment PD model. I was only doing a simulation based on a published paper so I would prefer not to alter or simplify the model. The model kept having numerical difficulties no matter how I modify the TOL value (I have changed it from 0 to 6). And I am using ADVAN 8. Does someone have any idea what else I should try to do to resolve it? Here is the error message. The nonmem code and data are quite long and I could send you the code/data as files if requested. Many many thanks in advance for your kind help. NUMERICAL DIFFICULTIES WITH INTEGRATION ROUTINE. NO. OF REQUIRED SIGNIFICANT DIGITS IN SOLUTION VECTOR TO DIFFERENTIAL EQUATIONS, 6, MAY BE TOO LARGE. MESSAGE ISSUED FROM SIMULATION STEP Best Thank you very much and best regards! Penny (Peijuan) Zhu, Ph.D. PD Bio-Pharma CDMA Sandoz 1N025, 100 College Road West Princeton, NJ 08540