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