NONMEM error

Colleagues I have encountered a problem during NONMEM execution. Most subjects are dosed daily but a small number of subjects have large intervals (> 30 days) between successive doses. For subjects dosed daily, concentrations 24 hours after a dose are BQL and there is no evidence of accumulation. For the problem subjects, NONMEM either: 1. aborts (despite a NOABORT option) with an error message at the first dose after the lengthy gap 2. or sends the following error message: 0PRED EXIT CODE = 1 0INDIVIDUAL NO. 103 ID= 3.11040000000000E+04 (WITHIN-INDIVIDUAL) DATA REC NO. 56 THETA= 1.66E+02 1.15E-01 2.95E+01 1.81E+01 4.33E+01 3.01E+02 8.26E+00 0.00E+00 1.00E+00 0.00E+00 0.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 1.00E+00 OCCURS DURING SEARCH FOR ETA AT INITIAL VALUE, ETA=0 NUMERICAL DIFFICULTIES WITH INTEGRATION ROUTINE. MAXIMUM NO. OF EVALUATIONS OF DIFFERENTIAL EQUATIONS, 1000000, EXCEEDED. The error occurs with METHOD=1 but NOT with METHOD=0. For one subject in whom doses were administered on Days 1, 30, and 60 (followed by daily dosing), I deleted the first two dosing records and the error no longer occurs with METHOD=1. I speculate that the error might relate to the predicted concentration becoming Infinitesimally small after a lengthy interval between doses, However, I have no idea if this is the explanation. And I am reluctant to change the dataset so I seek other solutions. Any ideas as to an explanation or a work-around? Dennis Dennis Fisher MD P < (The "P Less Than" Company) Phone / Fax: 1-866-PLessThan (1-866-753-7784) www.PLessThan.com